Preclinical evaluation of FasT CAR-T cellsFasT CAR-T (F-CAR-T) proliferation in vitro

To characterize the in vitro proliferative capacity of F-CAR-T cells, F-CAR-T and C-CAR-T cells were manufactured in parallel (Supplementary Methods, and Fig. S1) using T-cells from 6 B-ALL patients. To investigate the ex vivo proliferation of F-CAR-T, frozen CD19 F-CAR-T and C-CAR-T cells from each patient were thawed and stimulated with irradiated CD19-expressing K562 cells. The number of CD19-targeting CAR-T cells was then determined during the course of cell expansion in vitro. As shown in Fig. 1A, upon CD19 antigen stimulation, F-CAR-T proliferation was much more robust compared to C-CAR-T proliferation. On day 17 post co-culture, F-CAR-T expanded 1205.61226.3 fold (MeanSD), while C-CAR-T expanded only 116.437.2 fold (MeanSD), (p=0.001). To characterize the mechanism underlying the superior proliferative ability of F-CAR-T, we purified CD19+ CAR-T cells from both F-CAR-T and C-CAR-T. The expression of genes involved in cell proliferation, cell cycle, and apoptosis was analyzed using Nanostring (detailed gene sets are in Table S2). Gene expression profiles showed higher F-CAR-T expression scores for genes associated with cell cycle regulation (F-CAR-T vs. C-CAR-T, p<0.01) and lower expression scores for apoptosis-related genes (F-CAR-T vs. C-CAR-T, p<0.05) in F-CAR-T cells (Fig. S2A).

A Ex vivo cell proliferation of F-CAR-T and C-CAR-T derived from B-ALL patients (n=6) (***P=0.001, F-CAR-T vs. C-CAR-T, d17, unpaired student two-tailed t-test). B Tscm, Tcm, and Tem were characterized by surface staining of CD45RO and CD62L and analyzed with flow cytometry (***P<0.001 comparing F-CAR-T and C-CAR-T). C T-cell exhaustion was characterized by PD-1, LAG3, and TIM-3 staining; Statistical analyses of the percentage of PD1+ LAG3+ Tim3+ (***P<0.001, comparing F-CAR-T and C-CAR-T), unpaired student two-tailed t-test). D RTCA assay was used to examine the specific killing of HeLa-CD19 cells. Growth of target HeLa-CD19 or HeLa cells were monitored dynamically. E CD19+ target Nalm6-Luc cells or F Raji-Luc cells were co-cultured with either F-CAR-T or C-CAR-T for 6h. Target cell killing efficacy was calculated by luciferase activity. NS, P>0.05 F-CAR-T vs. C-CAR-T (unpaired student t-test, two-tailed). F-CAR-T FasT CAR-T, C-CAR-T conventional CAR-T, Tcm (CD45RO+CD62L+) T central memory cells, Tem (CD45RO+CD62L) T effector memory cells, Tscm (CD45ROCD62L+) T stem cell memory, PD1 programmed cell death protein 1, TIM-3 T cell immunoglobulin and mucin domain containing-3, LAG3 lymphocyte-activation gene 3, RTCA real-time cell analyzer, E:T effector cells: target cells, NT normal T-cell.

Phenotypes of unstimulated F-CAR-T from three healthy donors were analyzed by flow cytometry. The CD45ROCD62L+ population was 45.7%2.2% which was comparable to the un-transduced T-cells (data not shown). Upon stimulation with CD19+ tumor cells for 9 days, C-CAR-T central memory cells (Tcm, CD45RO+CD62L+ and effector memory cells (Tem, CD45RO+CD62L) were 56.62%11.97% and 40.48%9.70%, respectively, among the C-CAR-T cells (Fig. 1B and Figs. S2B and S2). In contrast, Tcm cells (87.92%4.36%) was predominant in F-CAR-T, with only a small fraction of Tem (7.84%3.79%). In addition, F-CAR-T cells demonstrated more abundant T stem cell memory (Tscm) (3.841.22% vs 2.342.48%, p<0.05) than C-CAR-T cells. We also examined the exhaustion status of the stimulated CAR-T cells. A higher percentage of PD-1+LAG3+Tim3+T-cells were detected in the C-CAR-T (11.19%2.54%) compared to F-CAR-T (3.59%2.51%, p<0.001) (Fig. 1C). Together these data indicated that the F-CAR-T exhibited a younger phenotype and was less exhausted compared to C-CAR-T.

We used a real-time cell analyzer (RTCA) assay to measure the cytotoxicity of F-CAR-T and C-CAR-T against CD19+ cells in vitro. F-CAR-T and C-CAR-T killing of Hela-CD19 target cells were comparable using this assay (Fig. 1D). Similar levels of IFN- and IL-2 production were also observed (Fig. S2D). In a luciferase-based cytotoxicity assay, CD19+ B leukemia cell lines, Raji and Nalm6, were both effectively killed to similar or better levels at different E:T ratios (Fig. 1E, F).

To compare the in vivo cytotoxicity of F-CAR-T and C-CAR-T, severe immunodeficient NOG mice were engrafted with Raji-luciferase cells. One week after the tumor grafts were established, F-CAR-T and C-CAR-T were intravenously injected at various doses. The engrafted tumors progressed aggressively in control groups with either vehicle alone or control T-cells (Fig. 2A). In contrast, F-CAR-T or C-CAR-T treatment greatly suppressed tumor growth in a dose-dependent manner (Fig. 2A). In the high dose group (2106/mice), both F-CAR-T and C-CAR-T eliminated the tumor rapidly. However, in the low dose group (5105/mice), F-CAR-T showed more effective tumor-killing compared to C-CAR-T. On day 20, mice in the low dose F-CAR-T group became tumor-free, while C-CAR-T treated mice exhibited tumor relapse (Fig. 2A). We examined the CAR-T cell expansion in vivo after infusion. As shown in Fig. 2B, both F-CAR-T and C-CAR-T began to expand in the peripheral blood 7 days after infusion. C-CAR-T cell numbers reached their peak on day 14 and receded on day 21. In contrast, the F-CAR-T cell number peaked on day 21 and declined to a baseline level on day 28. F-CAR-T not only persisted longer but also underwent 26 folds greater expansion than C-CAR-T (Fig. 2B).

A Raji-Luc cell engraftment NOG mice were given high dose (2106/mice, n=3) and low dose (5105/mice, n=3) F-CAR-T/C-CAR-T along with control groups. Tumor growth was monitored with IVIS scan once every 3 days; B CAR-T expansion in peripheral blood of mice was analyzed by flow cytometry (n=6). ***P<0.001 for F-CAR-T HD vs. C-CAR-T HD; F-CAR-T LD vs. C-CAR-T LD; F-CAR-T HD vs. F-CAR-T LD; C-CAR-T HD vs. C-CAR-T LD (two-way ANOVA statistical analysis); C Schematic of the Nalm6 (1106) xenograft model, CAR-T (2106) infused 1 day after cyclophosphamide (20mg/kg) treatment. Bone marrow infiltration of F-CAR-T was analyzed 10 days after CAR-T infusion (n=3); D CD45+CD2 F-CAR-T vs. C-CAR-T in peripheral blood of mice were analyzed by flow cytometry; *P<0.05 (unpaired student two-tailed t-test). IVIS in vivo imaging system, PB peripheral blood, i.v. intravenous, HD high dose, LD low dose, Cy cyclophosphamide; *p<0.05; #: number.

We examined the BM infiltration of F-CAR-T cells after infusion into Nalm6-bearing mice (Fig. 2C). A larger population of CAR-T cells was observed 10 days after infusion in BM in F-CAR-T infused group than that in the C-CAR-T group (p<0.05) (Fig. 2D), suggesting F-CAR-T cells possessed a better BM homing capability than C-CAR-T.

The chemokine receptor CXCR4 is known to be critical for BM homing of T-cells [25, 26]. Indeed, a higher percentage of CXCR4+ T cells were detected in F-CAR-T than in the C-CAR-T. Interestingly, this phenotype was more pronounced for CD4+ T cells than CD8+ T cells (Fig. S3A). In a two-chamber system, more F-CAR-T cells could be detected in the lower chamber than their C-CAR-T counterparts (Fig. S3B).

Between Jan. 2019 and Oct. 2019, 25 pediatric and adult patients with CD19+R/R B-ALL were enrolled onto our phase 1 trial, including two patients who had relapsed following a prior allo-HSCT. Patient characteristics are detailed in Table 1. The median age of patients was 20 (range: 344) years old. Twenty patients were >14 years old, and five were 14 years old. The median percentage of pre-treatment BM blasts was 9.05% (range: 0.1982.9%). As our pre-clinical studies demonstrated that F-CAR-T cells had a superior expansion capability as compared to C-CAR-T, we infused a relatively low doses of F-CAR-T cells, ranging from 104105 cells/kg: 3.0104 cells/kg (n=2), 6.5 (5.867.43)104 cells/kg (n=9), 1.01 (1.01.16)105 cells/kg (n=12), 1.52(1.471.56)105 cells/kg (n=2), (Fig. S4). The median time from apheresis to the infusion of CD19+F-CAR-T cells was 14 days (range: 1220). Although the manufacturing time of F-CAR-T was next day, the quality control time and detailed final product releases including sterility testing require a minimum of 710 days to complete. In addition, transportation of cell products requires approximately two days. Of the 25 patients who received CD19 F-CAR-T infusion, 22 (88%) received bridging chemotherapy between apheresis and lymphodepleting chemotherapy to control rapid disease progression (Table S3).

F-CAR-T cells were manufactured successfully for all patients. The mean transduction efficiency of F-CAR-T was 35.4% (range: 13.170.3%) (Fig. S5A). Both CD4+/CAR+ (mean, 49.6%; range: 13.673.2%) and CD8+/CAR+ (mean, 41.5%; range: 20.677.7%) subsets were present in the CD3+CAR+ T cell subsets of all products. The mean proportion of Tscm, Tem, and Tcm cells in the CD3+CAR+ T cell subsets of all products was 23.3% (range: 3.5545.3%), 33.2% (range: 17.267.9%), and 36.1% (range: 20.758.1%), respectively (Fig. S5B). F-CAR-T products exerted significant IFN- release and cytotoxic effects against the CD19+ cell line HELA-CD19 (Fig. S5, C, D).

All 25 infused patients experienced adverse events (AEs) of any grade, with 25 (100%) experiencing grade 3 or higher adverse events. No grade 5 events related to F-CAR-T treatment were observed (Table 2).

CRS occurred in 24 (96%) patients with 18 (72%) grade 12 CRS,6 (24%) of grade 3, and no grade 4 or higher CRS (Fig. S6). In the >14 years old group, 16/20 (80%) patients developed mild CRS, and only 2/20 (10%) developed grade 3 CRS. For 14 years old patients, 2/5 (40%) had mild CRS, yet 3/5 (60%) experienced grade 3 CRS (Table S4). ICANS was observed in 7 (28%) patients, with 2 (8%) grade 3 ICANS occurring in patients >14 years old and 5 (20%) grade 4 ICANS all occurring in patients 14 years old. No grade 5 ICANS was developed (Fig. S7 and Table S4). The most frequent presentation of CRS was fever, particularly a high fever of >39C. The first onset of CRS symptoms occurred between day 3 and 8 post-CAR-T infusion with a median onset at day 4 (range: 110 days). The most common symptoms of ICANS were seizure (5/7) and depressed consciousness (5/7). The median time to ICANS onset from CAR-T cell infusion was 7 days (range: 58), and the median time to resolution was 2 days (Fig. S7). All CRS and ICANS events were managed including early intervention when fever of 39C persisted for 24h. Sixteen (64%) patients received tocilizumab with a median total dose of 160mg (range: 160320mg). Twenty-one (84%) patients received corticosteroids including dexamethasone (median total dose, 43mg; range: 4127mg) and or methylprednisolone (median total dose, 190mg; range: 401070mg). The vast majority of these patients discontinued corticosteroids within 2 weeks. The change in IL-6, IFN-, IL-10, and GM-CSF levels after infusion are selectively shown in Fig. S8. The peak levels of these four cytokines were observed between day 710. Among all 21 cytokines examined, only post-infusion IL-6 levels were associated with moderate to severe CRS and/or ICANS (Figs. S9 and S10).

Superior in vivo proliferation and persistence of F-CAR-T compared to C-CAR-T cells were observed regardless of dose levels. The median peak level was reached on day 10 (range: 714 days) with 1.9105 transgene copies/g of genomic DNA (range: 0.225.2105 transgene copies/g of genomic DNA) by qPCR and 83 F-CAR-T cells per l blood (range: 42102 F-CAR-T cells per l blood) by FCM (Fig. 3A, B). No significant differences were observed among the different dose groups in the mean F-CAR-T copies peak (Fig. 3C). Importantly, there was no significant difference in the mean F-CAR-T copies peak between patients who received corticosteroids compared to those who did not (Fig. 3D).

A F-CAR-T cells in peripheral blood by qPCR. Purple, dose level 1; black, dose level 2; blue, dose level 3; red, dose level 4; B F-CAR-T cells in peripheral blood by flow cytometry. Purple, dose level 1; black, dose level 2; blue, dose level 3; red, dose level 4; C Comparison of the mean peak copy number of F-CAR-T cells in peripheral blood at each dose level. Statistical significance was determined by the MannWhitney test. D Comparison of the mean peak copy number of F-CAR-T cells in peripheral blood with or without steroids. Statistical significance was determined by the MannWhitney test.

Fourteen days after F-CAR-T cell infusion, all patients achieved morphologic CR including 2/25 with CR and 23/25 CR with incomplete hematologic recovery (CRi), which further improved to 11/25 CR and 14/25 CRi 28 days post F-CAR-T (Table 1 and Fig. 4). More importantly, 23/25 (92%) had the minimal residual disease (MRD)-negative remission on day 14 and day 28 after F-CAR-T treatment. Patients achieving remission through CAR-T were given the option to proceed to allo-HSCT. With a median time of 54 days (range: 4581 days) post F-CAR-T infusion, 20 of 23 patients with MRD-negative status decided to pursue consolidative allo-HSCT including one patient who received a 2nd transplant. As of 18 October 2021, with a median follow-up duration of 693 days (range: 84973 days) among the 20 patients who had received allo-HSCT, one patient relapsed on day 172 and died 3 months after relapse, and four patients died from transplant-related mortality (TRM) including infection (n=3) and chronic GVHD (n=1) on day 84, day 215, day 220, and day 312, respectively. The other 15 patients remained in MRD-negative CR with a median remission duration of 734 days (range: 208973) except for one who became MRD-positive on day 294 with CD19+ disease. Among the other three patients (F05, F06, F16), one remained in MRD-negative CR on day 304, one remained in MRD-negative CR until day 303, received allo-HSCT but died from an infection on day 505, and one was lost to follow-up after day 114. Two patients who had MRD-positive CR after infusion withdrew from the study on day 42 and day 44, respectively, to seek other studies.

Clinical outcomes and consolidative allo-HSCT for the 25 patients who were treated with F-CAR-T therapy are shown. On day 28, 23/25 patients achieved MRD-negative CR/CRi. With a median time of 54 days (range: 4581) post F-CAR-T infusion, 20 of 23 patients with MRD-negative status received consolidative allo-HSCT. Among the 20 patients, 1 patient (F23) relapsed on day 172 and died 3 months after relapse. Four patients (F04, F09, F11, F12) died from transplant-related mortality (TRM) including infection (n=3) and chronic GVHD (n=1) on day 84, day 215, day 220, and day 312, respectively. The remaining 15 patients were in MRD-negative CR except for one (F18) who became MRD-positive on day 294. Among the other 3 patients (F05, F06, F16), 1 remained MRD-negative CR on day 304, 1 remained in MRD-negative CR until day 303, received allo-HSCT, and subsequently died from an infection on day 505. One patient was lost to follow-up after day 114. MRD minimal residual disease, CR complete remission, Allo-HSCT allogeneic hematopoietic stem cell transplantation.

F-CAR-T/T ratio in cerebrospinal fluid (CSF) was evaluated by FCM in 13/25 patients with available samples (Table S5). Between days 10 and 32, 9 patients were found to have considerable F-CAR-T penetration in their CSF, ranging from 40.65 to 79.2%, including 4 who developed severe ICANS. Among the other 4 patients, F-CAR-T cell abundance in the CSF ranged from 1.29% to 3.57%, and none experienced severe ICANS. Patients with higher levels of CAR-T in PB on day 10 consistently had higher levels of CAR-T in CSF with the exception of patient F15. Notably, CAR-T cells were still detectable in the CSF on day 101 with a 2.36% CAR-T/T ratio in patient F06, who also had undetectable circulating CAR-T cells at the same time.

In addition, concentrations of seven cytokines (IL-1b, IL-6, IL-10, IFN-, TNF-, MCP-1, and GM-CSF) in CSF samples from the above 10 of 13 patients were measured. Specifically, IL-1b was not detected in any of the 10 patients, and only one patient had detectable GM-CSF. For the other five cytokines, patients with severe ICANS had higher IL-6 levels in contrast to patients without severe ICANS, and the difference between the median level of IL-6 among these two groups of patients was statistically significant (Fig. S11). We did not observe significant differences among the other 4 cytokines between the two groups of patients. No clear relation between the CSF cytokine levels and the F-CAR-T/T % was observed.

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Next-day manufacture of a novel anti-CD19 CAR-T therapy for B-cell acute lymphoblastic leukemia: first-in-human clinical study | Blood Cancer Journal...

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REDWOOD CITY, Calif., June 07, 2022 (GLOBE NEWSWIRE) -- Jasper Therapeutics, Inc. ( JSPR), a biotechnology company focused on enabling cures with stem cell therapies, today announced that the Company is participating in the William Blair 42nd Annual Growth Stock Conference, to be held in Chicago from June 6-9, 2022.

Ronald Martell, Jaspers Chief Executive Officer, is scheduled to present on Thursday, June 9th at 8:00AM CT, with a breakout session to follow at 8:40AM CT. A live webcast of the presentation will be available at https://wsw.com/webcast/blair66/jasp/1933236 and at the Companys Investor Events webpage.

About Jasper TherapeuticsJasper Therapeutics, Inc. is a biotechnology company focused on the development of novel curative therapies based on the biology of the hematopoietic stem cell. The company is advancing two potentially groundbreaking programs. JSP191, an anti-CD117 monoclonal antibody, is in clinical development as a conditioning agent that clears hematopoietic stem cells from bone marrow in patients undergoing hematopoietic cell transplantation. It is designed to enable safer and more effective, and potentially curative, allogeneic hematopoietic cell transplants and gene therapies. A clinical study of JSP191 as a novel, disease-modifying, therapeutic for patients with lower risk MDS is also planned to begin in 2022. In parallel, Jasper Therapeutics, Inc. is advancing its preclinical mRNA hematopoietic stem cell grafts platform, which is designed to overcome key limitations of allogeneic and autologous gene-edited stem cell grafts. Both innovative programs have the potential to transform the field and expand hematopoietic stem cell therapy cures to a greater number of patients with life-threatening cancers, genetic diseases and autoimmune diseases than is possible today. For more information, please visit us at jaspertherapeutics.com.

Forward-Looking StatementsCertain statements included in this press release that are not historical facts are forward-looking statements for purposes of the safe harbor provisions under the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements are sometimes accompanied by words such as believe, may, will, estimate, continue, anticipate, intend, expect, should, would, plan, predict, potential, seem, seek, future, outlook and similar expressions that predict or indicate future events or trends or that are not statements of historical matters. These forward-looking statements include, but are not limited to, statements regarding the potential of the Companys JSP191 and mRNA engineered stem cell graft programs. These statements are based on various assumptions, whether or not identified in this press release, and on the current expectations of Jasper and are not predictions of actual performance. These forward-looking statements are provided for illustrative purposes only and are not intended to serve as, and must not be relied on by an investor as, a guarantee, an assurance, a prediction or a definitive statement of fact or probability. Actual events and circumstances are difficult or impossible to predict and will differ from assumptions. Many actual events and circumstances are beyond the control of Jasper. These forward-looking statements are subject to a number of risks and uncertainties, including general economic, political and business conditions; the risk that the potential product candidates that Jasper develops may not progress through clinical development or receive required regulatory approvals within expected timelines or at all; risks relating to uncertainty regarding the regulatory pathway for Jaspers product candidates; the risk that prior study results may not be replicated; the risk that clinical trials may not confirm any safety, potency or other product characteristics described or assumed in this press release; the risk that Jasper will be unable to successfully market or gain market acceptance of its product candidates; the risk that Jaspers product candidates may not be beneficial to patients or successfully commercialized; patients willingness to try new therapies and the willingness of physicians to prescribe these therapies; the effects of competition on Jaspers business; the risk that third parties on which Jasper depends for laboratory, clinical development, manufacturing and other critical services will fail to perform satisfactorily; the risk that Jaspers business, operations, clinical development plans and timelines, and supply chain could be adversely affected by the effects of health epidemics, including the ongoing COVID-19 pandemic; the risk that Jasper will be unable to obtain and maintain sufficient intellectual property protection for its investigational products or will infringe the intellectual property protection of others; and other risks and uncertainties indicated from time to time in Jaspers filings with the SEC. If any of these risks materialize or Jaspers assumptions prove incorrect, actual results could differ materially from the results implied by these forward-looking statements. While Jasper may elect to update these forward-looking statements at some point in the future, Jasper specifically disclaims any obligation to do so. These forward-looking statements should not be relied upon as representing Jaspers assessments of any date subsequent to the date of this press release. Accordingly, undue reliance should not be placed upon the forward-looking statements.

Contacts:

John Mullaly (investors)LifeSci Advisors617-429-3548[emailprotected]

Jeet Mahal (investors)Jasper Therapeutics650-549-1403[emailprotected]

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Jasper Therapeutics to Participate in the William Blair 42nd Annual Growth Stock Conference - GuruFocus.com

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The very thought of getting someone elses poop transfused in your body may make you cringe but stool transplant has not only helped patients with gastrointestinal tract issues, it has also saved those who have had bone marrow transplants.

At Deenanath Mangeshkar Hospitals Centre of Excellence in Infectious Diseases and Department of Haematology, Pune, seven of the 11 patients of bone marrow transplants developed Clostridium difficile infection. They were treated with faecal microbial transplant (FMT), also referred to as stool transplant, over the past year.

Research worldwide has shown that a faecal transplant can restore healthy bacteria in the lower intestine which can help control Clostridium difficile or C. diff. According to the Johns Hopkins University School of Medicine, FMT can be more effective than antibiotics for keeping C. diff in check in some cases.

Since C. diff infection can recur and cause colitis (inflammation in the colon), FMT restores good and healthy bacteria, said Dr Parikshit Prayag, infectious disease consultant and in-charge of the Centre of Excellence in Infectious Diseases at Deenanath Mangeshkar hospital.

Dr Sameer Melinkeri, head of the department of haemotology at the hospital, said C. diff infection-related diarrhoea can occur in a normal setting in which antibiotics can be used for treatment. However, antibiotic treatment for recurrent infections can involve one or more courses of medication and their effectiveness comes down with each subsequent bout. FMT can arrest such infections post bone marrow transplant as it can be life-threatening, he added.

FMT is also done for certain disease conditions like Graft vs host disease (GvHD). Most people who undergo a bone marrow transplant suffer from blood cancer. Graft vs host disease can occur at any time after an allogeneic transplant where the donated bone marrow or peripheral stem cells can attack the recipients body. It can develop in the GI tract, skin or liver, Dr Prayag said.

Latest research published in the Journal of International Medical Research and others has shown how FMT is a promising treatment for patients with steroid-resistant GvHD. We have seen clinically relevant results in six of our patients, Dr Prayag said.

So, who can be donors? They are selected based on certain parameters. They should not be immune-compromised or have taken antibiotics over the past six months, says Dr Sampada Patwardhan, head of the department of microbiology at the hospital. Donor screening has to be done carefully. We need to rule out infections, she said.

Procedures on the transplant delivery methods may vary like colonoscopy and use of nasojejunal tube. The recovery may take a week or more and in most cases there are at least two weekly installations of the stool (in liquid form).

Very few centres conduct FMT and among them, the centre at Deenanath Hospital actively treats cases involving bone marrow transplants. At a recent virtual meeting of the International Society of Blood Transfusion, Dr Prayag made a strong case for encouraging stool transplants. The condition of C. diff is also underdiagnosed in the country as there isnt adequate infrastructure to correctly detect the problem, he pointed out.

In fact, FMT is being touted as a treatment option for many gut health issues. In an opinion article published on June 30 in the journal Trends in Molecular Medicine, a team from Harvard Medical School and Brigham and Womens Hospital (BWH) proposes that individuals bank samples of their own gut microbiota when they are young and healthy for potential use later in life in an autologous FMT.

A report in Science Daily quotes corresponding author Yang-Yu Liu, an associate professor of medicine at Harvard and an associate scientist in the Channing Division of Network Medicine at BWH, as saying, The idea of rewilding the human microbiome has taken off in recent years and has been hotly debated from medical, ethical and evolutionary perspectives. It is still unknown if people in industrialized societies can gain some health benefit by restoring their microbiome to an ancestral state. In this paper, we proposed a way to rejuvenate the human gut microbiome.

The report also listed OpenBiome, a non-profit stool bank based in Somerville, Massachusetts, as the first stool bank to offer an option for individuals to bank their own stool for future treatment of C. diff infection. Yang and his colleagues are now looking at if this treatment can be used for other diseases.

Conceptually, the idea of stool banking for autologous FMT is similar to when parents bank their babys cord blood for possible future use. However, there is greater potential for stool banking, and we anticipate that the chance of using stool samples is much higher than for cord blood. But there are many practical issues to implementing this idea, Yang is quoted as saying, hinting at optimal storage and cryopreservation issues.

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Cutting Edge: Poop therapy can save your gut, and your life - The Indian Express

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Ulcerative colitis, or UC, is a form of inflammatory bowel disease characterized by chronic and relapsing large intestine inflammation. Genetics account for only a minority of UC cases; hence, to develop treatments, researchers need to understand better the environmental contributions to this condition.

Gut microbes are in perpetual contact with the gastrointestinal tract, so they comprise important but poorly defined environmental variables contributing to UC development. Many studies have reported changes in gut microbiome composition in patients with UC compared to healthy individuals. While that suggests a potential role for gut microbes in UC pathogenesis, researchers have yet to pinpoint the causative microbes and associated bacterial proteins.

Dennis Wolans lab at Scripps Research is interested in identifying small-molecule activators and inhibiting bacterial enzymes involved in proliferation of human disease. Wolan said he was curious about what bacterial enzymes of the microbiome contribute to UC development.

Many publications have focused on the role of the microbiome in both health and disease states, he said. Most of these were focused on the taxonomical and phylogenic differences in the microbiome. But what about the associated bacterial proteins? What proteins are these gut bacteria making in disease conditions, and how are these interacting with the human body?

One protein of interest was serine proteases, a type of proteolytic enzyme that cleaves peptides at the serine amino acid. Researchers long have recognized that they coordinate many physiological processes and play key roles in regulating the inflammatory response. Previous studies have suggested increased proteolytic activity in microbial samples harvested from people with inflammatory disorders such as UC and Crohns disease.

Peter ThuyBuon, a graduate student and later a postdoc in the Wolan lab, led a project to study differential protein expression in healthy and UC fecal samples. He and the team described the project in a recent paper in the journal Molecular & Cellular Proteomics. In addition to standard mass spectrometry, ThuyBuon used a small molecular approach called affinity-based proteomic profiling to target and enrich for different types of proteases in the fecal samples.

We showed that there were 176 discrete host and microbial protein groups differentially enriched between healthy and UC patients, Wolan said. Furthermore, further enrichment of these proteins showed significantly higher levels of serine proteases in UC patients.

This finding has inspired exciting future research questions. For example, are elevated serine proteases the driver of UC or merely the effect of UC disease progression?

There is a lot of exciting work to be done using these findings, Wolan said. Future molecular studies should focus on how serine proteases might be contributing to UC and whether their levels can be manipulated to modify disease progression.

Functional proteomics has shown the potential role of serine proteases in UC. Future steps will include drug discovery and design of small-molecule regulators of bacterial enzymes.

Wolan said, Ultimately, the moderation of microbiome distribution in UC via external small-molecule intervention can serve as a foundation for UC prevention and treatment.

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Proteases implicated in ulcerative colitis - ASBMB Today

Bone Marrow Stem Cells Comments Off on Proteases implicated in ulcerative colitis – ASBMB Today | July 8th, 2022

Chemotherapy has transformed cancer care, but its benefits come with side effects. Chemo brain is the name some people give to the brain fog and fuzziness that can result from these lifesaving treatments.

Chemotherapy works by destroying fast-reproducing cancer cells. But it can kill other healthy cells along the way, including certain brain cells. The destruction of brain cells can impact your emotional state and ability to think, leading to memory and concentration problems, among other concerns.

This article will explore what types of cognitive and emotional changes you might expect from chemotherapy, what factors increase your risk for these symptoms, and what you can do to treat them.

Various emotional and cognitive symptoms can occur during chemotherapy, and they should be categorized separately. Even though they both apply to your brain and can be considered mental side effects, emotion and cognition are different.

Cognition refers broadly to the intellectual processes of absorbing, analyzing, and using information. Emotions are our feelings and responses to experiences, environments, and relationships. For example, trouble focusing is a cognitive side effect, whereas irritability is an emotional one.

Lets go over some of the most common chemotherapy side effects in both categories.

Cognitive changes are usually the most noticeable impacting daily functioning, work or school performance, and personal relationships.

Confusion or delirium is the most common of these symptoms, affecting roughly 57 to 85 percent of people undergoing chemotherapy, compared to 15 to 30 percent of people hospitalized for other medical reasons.

Cognitive changes can look different depending on the individual but commonly include:

In addition to chemo, other factors can contribute to emotional stress as part of a cancer diagnosis. The emotional impacts of chemo can look like shifts in mood, depression or anxiety. Personality changes are common, too.

These can be linked to chemotherapy treatments, the disease process, and coping with a cancer diagnosis.

Learn more about the emotional impacts of a cancer diagnosis and cancer treatment.

There are several reasons why chemotherapy can impact your mental and emotional health.

One reason is that chemo medications cross the blood-brain barrier, causing inflammation. Brain shrinkage, or a loss of neurons, has been observed as a result of both cancer and chemotherapy.

Cognitive changes can also be heightened by complications of cancer treatment or other medical conditions. Chronic pain and lack of sleep or appetite from chemotherapy treatments can have profound negative life impacts.

This can affect your energy and strength levels, making it hard to focus or regulate your emotions.

Cancers spread to the brain can also directly affect cognitive and emotional functioning. This can be separate from, or in addition to, chemo.

While chemotherapy aims to slow or stop the spread of cancer, increased changes in mental status and cognition can also be signs of metastasis, or that the cancer is spreading.

Your doctor may also want to rule out intolerances or reactions to your chemotherapy treatment.

Treating cancer requires an individualized and multidisciplinary approach. Often, a rehabilitation plan is involved in helping you cope with or heal from the effects of chemotherapy and other intensive treatments, including any surgeries.

Your doctor may want to adjust your chemotherapy regimen depending on your side effects.

Cognitive rehabilitation is sometimes included in a chemotherapy plan and offers activities or exercises to help keep your mind sharp and focused during treatment.

The American Cancer Society suggests that exercise and meditation can go a long way in reducing the mental toll of chemotherapy and other cancer treatments.

Also, talk therapy, including cognitive behavioral therapy (CBT), may help you process the complex emotions arising from a cancer diagnosis and treatment.

Talk therapies can help you develop coping techniques that may help you manage fatigue, confusion, and any depression or anxiety you are experiencing due to chemotherapy.

There are particular cancer and chemotherapy medications that can increase the chances of confusion, delirium, and other cognitive changes in some people. Your doctor should review any risks of a potential treatment option with you when designing your chemo regimen.

Consider coming to your appointment prepared with questions about what risk of physical and mental impacts chemo may cause. Ensure your doctor knows all medications you are currently taking to avoid adverse reactions.

If you choose to move forward with treatment, your doctor may be able to help you find ways to preserve your thinking abilities should chemo affect them, or at the very least learn to cope with the changes.

There are certain risk factors that may increase your chance of experiencing mental side effects during chemotherapy.

Besides taking specific medications or having brain cancer, this can include having:

Chemotherapy can effectively manage cancer and bring about remission. But the medications for chemotherapy are strong and highly toxic to other cells and systems in your body. This treatment can cause unpleasant physical, mental, and emotional symptoms.

The physical effects of chemotherapy like nausea and hair loss are well-known, but substantial mental and cognitive changes can also happen with this therapy. Chemo brain refers to the fatigue, confusion, and overall brain fog some people experience.

Talk with your doctor about the specific risks versus benefits for your type of cancer, stage, and prescribed chemotherapy regimen. Your medical team should be able to help you with therapies and strategies that can help you cope with the emotional and cognitive toll of cancer and chemotherapy.

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Does Chemotherapy Have Cognitive and Emotional Side Effects? - Healthline

Skin Stem Cells Comments Off on Does Chemotherapy Have Cognitive and Emotional Side Effects? – Healthline | July 8th, 2022

Introduction

Stem cells are highly specialized cell types with an impressive ability to self-renew, able to transform into one or even more specific cell types that play a significant role in the regulation and tissue healing process.17 To self-renew, a stem divides into two identical daughter stem cells and a progenitor cell and the embryonic and adult cells contain stem cells.1,2,8

Curing patients with serious medical conditions has been the focus of all disciplines of medical research for many years. Stem cell treatment has evolved into a highly exciting and progressed field of scientific research. Major advances have recently been introduced in fundamental and translational stem-cell-based treatment studies. As stem cell research progressed, many therapeutic options were investigated. The development of therapeutic procedures has sparked a great deal of interest.1,9 Humanity has known for many years that it is possible to regenerate lost tissue. Recently, the regenerative medicine research has taken hold, defying the tremendous scientific advances in the molecular biology sciences only. Technological advances provide limitless opportunities for transformational and potentially restorative therapies for many of humanitys most illnesses. A variety of human organs have successfully yielded stem cells. Besides this, the cell therapy is rapidly bringing good advancements in the healthcare system, intending to restore and possibly replace injured tissue, as well as organs, and ultimately restore the functional capacity of the body.2,10,11

The stem cells can be obtained from various sources of Adult (Adult body tissues), Embryonic (Embryos), Mesenchyma (Connective tissue or stroma), and Induced pluripotent stem [ips] cells (Skin cells or tissue-specific cells).3,68,1215

Due to various stem cells cellular characteristics, the therapeutic clinical possibilities of stem-cell-based treatment are considered promising. These cells can regrow and restore various types of body tissues, for this reason, they are recognized as precursor cells to all kinds of cells.15 The following are the distinguishing features: 1. Self-renewal- Divide without distinction to generate an infinite supply, 2. Multi-potency- One mature cell may distinguish more than one, 3. Pluripotency- Create all sorts of cells except for embryonic membrane cells, 4. Toti- potency- Produce various sorts of cells, including embryonic stem cells.1,2,6,7,16

Stem cells are essential human cells that really can self-renew and make a distinction into particular mature cell types.3,6 The different types of stem cells are embryonic, induced pluripotent, and adult kind of cell types. They all share the important feature of self-renewal, and the ability to discern themselves. It should be mentioned that, the stem cells are not homogeneous, but instead appear in a progressive order. Totipotent stem cells are the most basic and immature stem cells. The above cells can form a complete embryo and also extra-embryonic tissue. This one-of-a-kind efficiency is only present for a short period, starting with ovum development and completing whenever the embryo achieves the 4 to 8 cell phases. Having followed that, cells that divide until they approach the blastocyst, about which point they end up losing their totipotency and acquire a pluripotent character trait, at which cells can only distinguish through each embryonic germ stack. After a few divisions, the pluripotency character trait starts to fade and the distinguishing ability has become more lineage constrained, where its cells are becoming multipotent, indicating they could only transform into the cells connected to a cell or tissue of origin.10 Many researchers believe that adult stem cells should be used in stem cell therapies.6,17

The stem cells can be transformed into a wide range of specialized functional cell types.3,18 In response to injury or maturation, those same stem cells can propagate in massive quantities.19 Adult, embryonic, and induced pluripotent stem cells are examples of stem cell-based therapies.14,15,1921 The stem cells, due to their capability to distinguish the specific cell types requisite for a diseased tissue regeneration, can provide an effective solution, while tissue and organ transplantation are considered necessary.10 The sophistication of stem cell-based treatment interventions, on the other hand, probably leads researchers to seek stable, credible, and readily available stem cell sources capable of converting into numerous lineages. As an outcome, it is critical to exercise caution when selecting the type of stem cells to be used in therapeutic trials.12,14,22

Only with the explosive growth of basic stem cell research in recent years, the comparatively recent study sector of Translational Research had also grown exponentially, starting to build on major research knowledge and insight to advance new therapies. Once the necessary regulatory clearances have been obtained, the clinical translation process can start. Translational research is important because it acts as a filtration system, ensuring that only safe and effective therapeutic approaches start making it to the clinic.23 Recent research illustrating, the successful application of stem cell transplantation to patient populations suggests that, such restorative approaches have been used to address a wide variety of complicated ailments of future concerns.19,24

Currently, clinical trials are available for a variety of stem cell-based treatments based on adult stem cells. To date, the WHO International Clinical Experiments Registration process has recorded more than 3000 experiments involved based on adult stem cells. Furthermore, preliminary trials involving novel and intriguing pluripotent stem cell therapies have been registered. These studies findings will assist the ability to comprehend and the timeframes required to obtain effective treatments and it will contribute to a better knowledge of the different disorders or abnormalities.10

The role of stem cells in modern medicine is vital, both for their widespread application in basic research and for the opportunities they provide for developing new therapeutic strategies in clinical practice.6,16 In recent times, the number of studies involving stem cells has expanded tremendously. Globally, thousands of studies claiming to use stem cells in experimental therapies have now been in the investigation field. This may give the impression that such treatments have already been shown to be extremely effective in the context of healthcare. Despite some promising results, the vast majority of stem cell-based therapeutic applications are still in the experimental stage itself.6,25

The stem cells are a valuable resource for understanding organogenesis as well as the bodys continual regenerative capacity. These cells have brought up enormous anticipations among doctors, investigators, patients, and the public at large because of their ability to distinguish into a variety of cell types.25 These cells are necessary for living beings for a variety of reasons and can play a distinguishable role. Several stem cells can play all cell types roles, and when stimulated effectively, they can also repair damaged tissue. This capability has the potential to save lives as well as treat human injuries and tissue destruction. Moreover, different kinds of stem cells could be used for several purposes, including tissue formation, cell deficiency therapeutic interventions, and stem cell donation or retrieval.3,6,26

New research demonstrating that the successful application of stem cell treatments to patients has expressed hope that such regenerative strategies might very well one day is being used to address a wide variety of problematic ailments. Furthermore, clinical trials incorporating stem cell-based therapeutics have advanced at an alarming rate in recent years. Some of these studies had a significant impact on a wide range of medical conditions.10 As a regenerative medicine strategy, cell-based treatment is widely regarded as the most fascinating field of study in advanced science and medicine. Such technological innovation paves the way for an infinite number of transformational and potentially curable solutions to some of humanitys most pressing survival issues. Moreover, it is gradually becoming the next major concern in medical services.11

Modern data, which shows that the successful stem cell transplantation in beneficiaries has raised hopes on the certain rejuvenating approaches, will one day be used to treat many different types of challenging chronic conditions.24 Preliminary data from highly innovative investigations have documented that the prospective advancement of stem cells provides a wide range of life-threatening ailments that have so far eluded current medical therapy.2,10,11 Furthermore, clinical trials involving stem cell-based therapies have advanced at an unprecedented rate. Many of these studies had a significant impact on various disorders.19 Despite the increasing significance of articles concerning viable stem cell-based treatments, the vast majority of clinical experiments have still yet to receive full authorization for stem cell treatments confirmation.11,12,27

Even though the first case of AIDS were noted nearly 27 years ago, and the etiologic agent was noticed 25 years ago, still for the effective control of the AIDS pandemic continues to remain elusive.28 The HIV epidemic started in 1981 when a new virus syndrome defined by a weakened immune system was revealed in human populations across the globe. AIDS showed up to have a substantial reduction in CD4+ cell counts and also elevated B-cell multiplication.15,2831

The agent that causes AIDS, later named HIV, is a retroviral disease with a genomic structural system made up of 2 identical single-stranded RNA particles.3234 According to the Centres for Disease Control and Prevention, with over 1.1 million Americans are presently infected with the virus.31 Compromised immune processes in HIV and AIDS, as well as partial immune restoration, barriers are confirmed for HIV disease eradication. Innovative developmental strategies are essential to maximizing virus protection and enabling the host immune response to eliminate the virus.35

The progression of HIV infection in humans is divided into the following stages of acute infection, chronic infection, and AIDS.15,36 During the acute infection phase, the circulation has a high viral replication, is extremely infectious, that may or may not demonstrate flu-like clinical signs. In the chronic stage, the viral load is lesser than in the acute stage, and individuals are still infectious but may be symptomless. The patient has come to the end stage of AIDS whenever the CD4+ cell count begins to fall below 200 cells/mm or even when opportunistic infections are advanced.15,36

There are currently two types of HIV isolated HIV-1 and HIV-2.15,37,38 However, HIV-1 is the most common cause of AIDS throughout the world, while HIV-2 is only found in a few areas of an African country. Although both virions can cause AIDS, HIV-2 infection is much more likely to occur in central nervous system disorder.15 Besides this, HIV-2 seems to be less infectious than HIV-1, and HIV-2 infection induces AIDS to develop more slowly. Even though both HIV-1 and HIV-2 have a comparable genetic structure comprised of group-specific antigen, polymerase, and envelope genes, their genome organizational structures are differed.15,3739

HIV infiltrates immune cell types, CD4+ T cell types, and monocytes, resulting in a drop in T-cell counts below a critical level and the failure of cell-mediated immune function.15,40 The glycoprotein (gp120) observed in the virion envelope comes into contact with the CD4 particle with high affinity, allowing HIV to infect T cells. By interacting with their co-receptors, CXCR4 and CCR5, the virus infiltrates T cells and monocytes. The retrovirus uses reverse transcriptase to convert its RNA into DNA after attaching it to and entering the host cell. These newly replicated DNA copies then exit the host cell and infect other cells.15,40,41

HIV-1 is a retrovirus and belongs to a subset of retroviruses known as lentiviruses.38,42 Infection is the most common global health concern around the world.15 It has destroyed the millions of peoples health and continues to wreak havoc on the individual health of millions more. The pandemic of HIV-1 is the most devastating plague in the history of humans, as well as a significant challenge in the areas of medicine, public health, and biological science of research activities.34,43 Antiretroviral therapy is the only treatment that is commonly used. This is not a curative treatment; it must be used for the rest of ones life.15 Although antiretroviral therapy has reduced significantly HIV intensity and transmission, the virus has not been eradicated, and its continued presence can lead to additional health issues.44

Infection with the human immunodeficiency virus necessitates entry into target cells, such as through adhesion of the viral envelope to CD4 receptor sites.43 Cellular antiviral responses fail to eliminate the virus, resulting in a gradual depletion of CD4+ T cells and, finally, a severely compromised immune functioning system. Unfortunately, there is no cure for the virus that destroys immunity.4447 In advanced HIV infection, memory T-cell depletion primarily affects cellular and adaptive immune responses, with a minor impact on innate immune responses.48 Globally, 37.7 million people were living with HIV in 2020, and with 1.5 million individuals are infected with the virus.49 The advancement of stem cell therapy and the conduct of implemented clinical trials have revealed that stem cell treatment has high hopes for a range of medical conditions and implementations.15

Stem cell treatment has shown impressive outcomes in HIV management and has the potential to have significant implications for HIV treatment and prevention in the future. In HIV patients, stem cell therapy helps to suppress the viral load even while enabling antiretroviral regimens to be tapered. Interestingly, this practice led to a significant improvement in procedure outcomes soon after starting antiretroviral treatment.15 Stem cell transplantation can alleviate a wide variety of diseases that are currently incurable. They could also be used to create a novel anti-infection therapy strategic plan and to enhance the treatment of immunologic conditions such as HIV infection. HIV wreaks havoc on immune system cells.30,50

The virus infects and replicates within T-helper cells (T-cells), which are white immune system cells. T-cells are also referred to as CD4 cells. HIV weakens a persons immune system over time by pulverizing more CD4 cells and multiplying itself. More pertinently, if the individual has been unable to obtain anti-retroviral medicine, he will progressively fail to control the infectious disease and illnesses.3,15,42

Despite 36 years of scientific research, investigators are still trying to cure human HIV and its potential problem, AIDS.3,5153 HIV continues to face unconquerable dangers to human survival. This virus has developed the potential to avoid anti-retroviral therapy and tends to result in victim death.52 Investigators are still looking for effective and all-encompassing treatment for HIV and its complexity, AIDS.54 This massive amount of data revealed potential AIDS treatment targets.55 Thousands of research projects have yielded a great deal of information on the elusive AIDS life cycle to date.5456 These massive amounts of data supplied possible targets for AIDS treatment.33,55,56 In HIV-infected patients, using stem cell therapy can augment the process of keeping the viral load stagnant by permitting antiretroviral regimens to be tapered.15

Overall, stem cell-based strategies for HIV and AIDS treatment have recently emerged and have become a key area of research. Ideally, effective stem cell-based therapeutic approaches might have several benefits.30 Clinical studies encompassing stem cell therapy have shown substantial therapeutic effects in the treatment of various autoimmune, degenerative, and genetic problems.15,25 Substantial progress has been developed in the treatment of HIV infection using stem cell-based techniques.30

Successfully treated, clinical studies have shown that total tissue recovery is feasible.15,57 In the early 1980s, the first stem cell transplants were accomplished on HIV-positive patients who were unsure of their viral disease. Following the above preliminary aspects, many HIV-positive patients with concurrent malignant tumours or other hematologic disorders underwent allogeneic stem cell transplantation around the world.42 After ART became a common treatment option for patients,58,59 the procedures prognosis improved dramatically. In addition, a retrospective study of 111 HIV+ transplant patients demonstrated a mildly lower overall survivorship performance in comparison to an HIV-uninfected comparison group.60

Earlier, the primary problem for people living with HIV and AIDS was immunodeficiency caused by a loss of productive T-cells. Some clinicians intended to replenish lost lymphocytes through adoptive cell transplants in the initial days before efficacious antiretroviral therapy options were available. Immunologically, it is relatively simple in an isogeneic condition, as illustrated on HIV-positive individuals with just a correlating identical twin who received T-lymphocytes and stem cell transfusions to rebuild the weak immune status of the patient.60 Cell therapy transfusion may be used to remove resting virion genomes from CD4+ immune cells and macrophages mostly through genome-editing or cytotoxic anti-viral cells.15,60 Cell technology and stem cell biological reprogramming developments have made a significant contribution to novel strategies that may give confidence to HIV healing process.3 However, human embryonic stem cells can be distinguished into significant HIV target cells, according to several research findings.30,61,62

Initially, stem cell transplantation was believed to influence the clinical significance of HIV infection, but viral regulation was not accomplished in the discipline. Moreover, improvements in stem cell transplants utilizing synthetic or natural resistant cell resources, in combination with novel genetic manipulative tactics or the advancement of cytotoxic anti-HIV effector cells, have significantly accelerated this sector of HIV cell management.60 Multiple techniques are being introduced to overcome HIV, either through protecting cells from infectious disease or by continuing to increase immune responses to the viral infection.30 The various methods are as follows: Bone marrow stem cells Therapies, Autologous stem cell transplantations, Hematopoietic stem cell transplantation, Genetical modifications of Hematopoietic stem cells (HSCT), HSCT and HAART therapeutic approach, Human umbilical cord mesenchymal stem cell transplantation, Mesenchymal stem/stromal cells (MSCs) applications, CCR5 Delta32/Delta32 Stem-Cell Transplantation, CRISPR and stem cell applications, Induced Pluripotent Stem Cells applications.

According to the findings, circulating replicative HIV remains the most significant threat to effective AIDS therapy. As a result, a method for conferring resistance to circulating HIV particles is required. The effective viral burden in the human body would be significantly reduced if it were possible to defeat reproducing HIV particles.43,44 For the treatment of AIDS, a restorative approach that relies on bone marrow stem cells has been suggested.52 The proposed treatment method captures and eventually destroys circulating HIVs using receptor-integrated red blood cells. Red blood cell membranes can be equipped with the CD4 receptor and the C-C chemokine receptor type 5 and C-X-C chemokine receptor type 4 co-receptors, which will selectively bind circulating HIV particles.15,30,32,33,43,44,46,6365

The term autologous pertains to blood-forming stem cells obtained from the patient for use as a source of fresh blood cells followed by high-dose chemotherapeutic agents.66 Lymphoma is still the biggest cause of mortality in HIV patients. Autologous stem cell recovery or transplantation with high-dose treatments has long been supported as a treatment for certain types of cancer in HIV-negative patients, including leukaemia and lymphoma. Individuals over the age of 65, as well as those with health problems such as HIV, were excluded from initial transfusion experiments. Moreover, the treatment regimen mortality of transplantation has also been reduced significantly due to its use of peripheral blood stem cells rather than bone marrow and the use of newer marginal conditioning therapeutic strategies. HIV-infected clients may be able to utilize enough stem cells for an autologous transplant advancement in HIV management. High-dose Autologous stem cell transplant (ASCT) treatments are better than conventional treatment in people with relapsed non-Hodgkin lymphoma, according to randomized trial evidence. Similarly, studies on HIV-negative people with Hodgkin Lymphoma have shown that ASCT would provide patients with repetitive illness with long-term progression-free survival.66,67 Even so, the clinical trial on Allogeneic Hematopoietic Cell Transplant for HIV Patients with Hematologic Malignancies report was explained as, the cell-associated HIV DNA and inducible infectious virus were not detectable in the blood of patients who attained complete chimerism.68

The study on long-term multilineage engraftment of autologous genome-edited hematopoietic stem cells in nonhuman primates report findings was Genome editing in hematopoietic stem and progenitor cells (HSPCs) is a potential innovative approach for the treatment of numerous human disorders. This report shows that genome-edited HSPCs engraft and contribute to multilineage repopulation following autologous transplantation in a clinically relevant large animal model, which is an important step toward developing stem cell-based genome-editing therapeutics for HIV and possibly other illnesses.69

Research on comprehensive virologic and immune interpretation in an HIV-infected participant again just after allogeneic transfusion and analytical interruption of antiretroviral treatment findings are the instance of HIV-1 cure having followed allogeneic stem cell transplantation (allo-SCT), resulting allo-SCTs in HIV-1 positive participants have failed to cure the disease. It describes adjustments in the HIV reservoir in a single chronically HIV-infected client who had undergone allo-SCT for acute lymphoblastic leukaemia treatment and was obtaining suppressive antiretroviral treatment.

To estimate the size of the HIV-1 reservoir and describe viral phylogenetic and phenotypic modifications in immune cells, the investigators just used leukapheresis to obtain peripheral blood mononuclear cells (PBMCs) from a 55-year-old man with chronic HIV infection prior and after allo-SCT. Once HIV-1 was found to be unrecognizable by numerous tests, including the PCR measurement techniques both of overall and fully integrated HIV-1 DNA, recompilation virus precise measurement by significant cell input quantifiable viral outgrowth assay, and in situ hybridization of intestine tissue, the client accepted to an analytic treatment interruption (ATI) with recurrent clinical observing on day 784 post-transplantation. He continued to remain aviremic off ART until ATI day 288, once a reduced virus rebound of 60 HIV-1 copies/mL resulted, which expanded to 1640 HIV-1 copies/mL five days later, urging ART reinitiation. Rebounding serum HIV-1 action sequences were phylogenetically distinguishable from pro-viral HIV-1 DNA discovered in circulating PBMCs before transplantation. It was indicated that allo-SCT tends to result in significant reductions in the magnitude of the HIV-1 reservoir and a >9-month ART-free cessation from HIV-1 multiplication.34

The Impact of HIV Infection on Transplant Outcomes after Autologous Peripheral Blood Stem Cell Transplantation: A Retrospective Study of Japanese Registry Data reported as ASCT is a successful treatment option for HIV-positive patients with non-Hodgkin lymphoma and multiple myeloma (MM). HIV infection was associated with an increased risk of overall mortality and relapse after ASCT for NHL in a study population.70

The procedure of delivering hematopoietic stem cells mostly through intravenous infusion to restore normal haematopoiesis or treat cancer is known as hematopoietic stem cell transplantation.71 There has recently been a rise in the desire to develop strategies for treating HIV/AIDS diseases employing human hematopoietic stem cells,30 along with this Hutter and Zaia were evaluated the background of Haematopoietic stem cell transplantation (HSCT) in HIV-infected individuals.42

Attempts to use HSCT as a technique for immunologic restoration in AIDS patients or as a therapeutic intervention for malignant tumours were initially insufficient. Regretfully, in the absence of sufficient ART, HSCT seemed to have no impact on the evolution of HIV infection, and the majority of the patients ended up dead of rapidly deteriorating immunosuppression or reoccurring lymphoma or leukaemia. A specific instance report described how an un-associated, matched donor supplied allogeneic HSCT to a patient with refractory lymphoma. The virus was unrecognizable by isolating or PCR of peripheral blood mononuclear cells commencing on day 32 after transplantation. Although HIV-1 was unrecognizable by cultural environment or PCR of several tissues examined at mortem, the patient died of recurring lymphoma on day 47. Another client who obtained both allogeneic HSCT and zidovudine had similar results, with HIV-1 becoming unnoticeable in the blood by PCR analysis. In some other particular instances, a 25-year-old woman with AIDS who obtained an allogeneic HSCT from a corresponding, unfamiliar donor after controlling with busulfan and cyclophosphamide and ART with zidovudine and IFN-2 regimen continued to live for 10 months before falling victim to adult respiratory distress. However, PCR testing of autopsy tissues revealed that they were HIV-1 negative.72

Recent research discovered significant progress towards the clinical application of stem cell-based HIV therapeutic interventions, principally illustrating the opportunity to effectively undertake a large-scale phase two HSC-based gene therapy experiment. In this investigation, the research team used autologous adult HSCs that had been transduced to a retroviral vector that usually contains a tat-vpr-specific anti-HIV ribozyme to develop cells that were less vulnerable to productive infection,73 whereas vector-containing cells have been discovered for extended periods (more than 100 weeks in most people) and CD4+ T cell gets counted were significantly high within anti-HIV ribozyme treating people group compared with the placebo group, the impacts on viral loads were minimal. The studys success, even so, is based on the realization that a stem cell-based strategy like this is being used as a more conventional and efficacious therapeutic approach.30 Some other latest clinical studies used a multi-pronged RNA-based strategic plan which included a CCR5-targeted ribozyme, an shRNA targeting tat/rev transcripts, and a TAR segment decoy.74

These crucial research findings are explained on lentiviral-based gene therapy vectors that can genetically manipulate both dividing and non-dividing HSCs and are less likely to cause cellular changes than murine retro-viral-based vectors. Long-term engraftment and multipotential haematopoiesis have been demonstrated in vector-containing and expressing cells, according to the researchers. Whereas the antiviral effectiveness was not reviewed, the results demonstrate the strategys protection, which helps to expand well for the possibility of a lentiviral-based approach in the upcoming years.30

A further approach, with a different emphasis, has been started up in the hopes of trying to direct immune function to target specific HIV to overcome barriers to attempting to clear the virus from the patient's body. These strategies use gene treatment innovations on peripheral blood cells to biologically modify cells so that they assert a receptor or chimeric particle that enables them to especially target a specific viral antigen,75 deception of HIV-infected peoples peripheral blood T cells raises issues to be addressed, such as the effects of ongoing HIV infection and ex vivo modification on the capabilities and lifetime of peripheral blood cells. Further to that, the above genetically manipulated cells would demonstrate their endogenous T cell receptors, and the representation of the newly introduced receptor could outcome in cross-receptor pairing, resulting in self-reactive T cells. Most of these deficiencies could be countered by enabling specific developmental strategies to take place that can start generating huge numbers of HIV-specific cells in a renewable, consistent way that can restore defective natural immune activity against HIV.30

One strategy being recognized is the application of B cells obtained from HSCs to demonstrate anti-HIV neutralizing specific antibodies. While animal studies have shown that neutralizing antibodies could protect against infection, and extensively neutralizing antibodies have been noticed in some HIV-infected persons, safety from a single engineered antibody might be exceptional.76,77 Realizing antibody binding and virus neutralization may assist in the development of chimeric receptors or single-chain therapeutic antibodies with recognition domains for other techniques that identify cellular immunity against HIV-infected cells.78,79 Thereby, genetically modifying HSCs to generate B cells that produce neutralizing anti-HIV specific antibodies, or engineering HSCs to enable multipotential haematopoiesis of cells that express a chimeric cellular receptor usually contains an antibody recognition domain, indicate one arm of an HSC-based engineered immunity process.30

A further technique of using HSCs that were genetically altered with molecularly cloned T-cell receptors or chimeric molecules particular to HIV to yield antigen-specific T cells. The basic difference in this strategy is that the cells produced from HSCs after standard advancement in the bone marrow and thymus are made subject to normal central tolerance modalities and are antigen-specific naive cells, and therefore do not have the ex-vivo manipulation and impaired functioning or exhaustion problems that other external cell modification methods would have. In this context, the latest actual evidence research using a molecularly cloned T cell receptor particular to an HIV-1 Gag epitope in the aspect of HLA-A*0201 revealed that HSC altered in this ability can progress into fully functioning, mature HIV specialized CD8+ T cells in human thymic tissue that conveys the acceptable constrained HLA-A*0201 particles.80 This explores the possibility of genetically engineering HSCs with a molecularly cloned receptor and signifies a step toward a better understanding and application of initiated T cell responses, which would probably result in the eradication of HIV infection from the body, similar to the natural immune function of other virus infections and pathogenic organisms.30

In an allogeneic transplantation, donor stem cells replace the patients cells.66 Allogeneic hematopoietic stem cell transplantation (HSCT) has appeared as one of the most potent treatment possibilities for many people who suffer from hemopoietic system carcinomas and non-malignant ailments.81 Both HIV-cured people have received HSCT utilizing CCR5 132 donor cells.82,83 This implies that HIV eradication necessitates a decrease in the viral reservoir through the myeloablative procedures,8486 Having followed that, immune rebuilding with HIV-resistant cells was carried out to prevent re-infection.45 The possibility of adoptive transfer of ex vivo-grown, virus-specific T-cells to prevent and control infectious diseases (eg, Cytomegalovirus and EBV) in immunocompromised patients helps to make adoptive T-cell treatment a feasible strategy to inhibit HIV rebound having followed HSCT.81,87,88

The Engineered Zinc Finger Protein Targeting 2LTR Inhibits HIV Integration in Hematopoietic Stem and Progenitor Cell-Derived Macrophages: In Vitro Study, the researchers investigated the efficacy and safety of 2LTRZFP in human CD34+ HSPCs. Researchers used a lentiviral vector to transduce 2LTRZFP with the mCherry tag (2LTRZFPmCherry) into human CD34+ HSPCs. The study findings suggest that the anti-HIV-1 integrase scaffold is an enticing antiviral molecule that could be utilised in human CD34+ HSPC-based gene therapy for AIDS patients.89

The fundamental element of HIV management is stem cell genetic modification, which involves genetically enhanced patient-derived stem cells to overcome HIV infection. In this sector, numerous experimental studies, in vitro as well as in vivo examinations, and positive outcomes for AIDS patients have been conducted.65,74 Genetic engineering for HIV-infected individuals can provide a once-only intervention that minimizes viral load, restores the immune system, and minimizes the accumulated toxicities concerned with highly active antiretroviral therapy (HAART).73 HSCs can be genetically altered, permitting for the addition of exogenous components to the progeny that protects them from direct infectious disease and/or enables them to target a specific antigen. Besides that, HSC-based strategies can enhance multilineage hemopoietic advancement by re-establishing several arms of the immune function. Eventually, as HSCs can be produced autologously, immunologic tolerance is typically high, enabling effective engraftment and subsequent distinction into the fully functioning mature hematopoietic cells.30

The utilization of human HSCs to rebuild the immune function in HIV disease is one application that tries to preserve newly formed cells from HIV infection, while another attempts to develop immune cells that attack HIV infected cells. While each initiative has many different aspects at the moment, they represent huge attention to HIV/AIDS therapies that, most likely when integrated with the other therapeutic approaches, would result in the body trying to overcome the obstacles needed for the virus to be effectively cleaned up.30

While HSC transplantation technique and processes are not accurately novel, as they are commonly and effectively used to address a wide variety of haematological diseases and malignant neoplasms,90 trying to combine them with a gene therapeutic strategy represents a unique and possibly potent therapeutic approach for HIV and AIDS-related ailments. As the results of HIV-infected patients who obtained autologous HSCT continued to improve, there was growing interest in genetically altered stem cells that were tolerant to HIV disease. Multiple logistical challenges have impeded the advancement of genetically modified hematopoietic stem cells as a conceivable therapeutic option for HIV/AIDS.72,73

UCLAs Eli and Edythe Broad Center for Restorative Medicine and Stem Cell Studies is one bit closer to constructing an instrument to arm the bodys immune system to attack and defeat HIV. Dr. Kitchen et al are the first ones to disclose the use of a chimeric antigen receptor (CAR), a genetically manipulated molecule, in blood-forming stem cells. In the experiment, the research team introduced a CAR gene into blood-forming stem cells, which were then moved into HIV-infected mice that had been genetically programmed. The scientists found that CAR-carrying blood stem cells efficiently transformed into fully functioning T cells that have the ability to kill HIV-infected cells in mice. The outcome was an 80-to-95 percentage reduction in HIV levels, suggesting that stem-cell-based genetic engineering with a CAR might be a viable and effective approach for treating HIV infection among humans. The CAR initiative, according to Dr. Kitchen, is much more able to adapt and ultimately more efficient, which can conceivably be used by others. If any further experiment showcases keep promising, the scientists expect that a practice based on their strategy will be accessible for clinical development within the next 510 years.91

HSCT and HAART therapeutic approaches in treating HIV/AIDS as the emergence of highly active antiretroviral therapy (HAART) in the 1990s improved survival rates of HIV infection, leading to a major dramatic drop in the occurrence of AIDS and AIDS-related mortalities. As an outcome, there is much less involvement with using HSCT as a therapy for HIV infection.28,33,43,67,86

A randomized clinical trial of human umbilical cord mesenchymal stem cell transplant among HIV/AIDS immunological non responders investigation, the researchers examined the clinical efficacy of transfusion of human umbilical cord mesenchymal stem cells (hUC-MSC) for immunological non-responder clients with long-term HIV disease who have an unmet medical need in the aspect of effective antiretroviral therapy. From May 2013 to March 2016, 72 HIV-infected participants were admitted in this stage of the randomized, double-blind, multi-center, placebo-controlled dose-determination investigation. They were either given a high dose of hUC-MSC of 1.5106/kg body weight as well as small doses of hUC-MSC of 0.5106/kg body weight, or a placebo application. During the 96-week follow-up experiment, interventional and immunological character traits were analysed. They found that hUC-MSC therapy was both safe and efficacious among humans. There was a significant rise in CD4+ T counts after 48 weeks of treatment in both the high-dose (P 0.001) and low-dose (P 0.001) groups, but no changes in the comparison group.92

One interesting invention made by a team of UC Davis investigators is the recognition of a particular form of stem cell that can minimize the quantity of the virus that tends to cause AIDS, thus dramatically increasing the bodys antiviral immune activity. Mesenchymal stem/stromal cells (MSCs) furnish an incredible opportunity for a creative and innovative, multi-pronged HIV cure strategic plan by augmenting prevailing HIV potential treatments. Even while no antivirals have been used, MSCs have been able to increase the hosts antiviral responses. MSC therapeutic approaches require specialized delivery systems and good cell quality regulation. The studys findings lay the proper scientific foundation for future research into MSC in the ongoing treatment of HIV and other contagious diseases in the clinical organization.35

Infection with HIV-1 necessitates the existence of both specific receptors and a chemokine receptor, particularly chemokine receptor 5 (CCR5).46 Resistance to HIV-1 infection is attained by homozygozygozity for a 32-bp removal in the CCR5 allele.93 In this investigation, stem cells were transplanted in a patient with severe myeloid leukaemia and HIV-1 infection from a donor who was homozygous to Chemokine receptor 5 delta 32. The client seemed to have no viral relapses after 20 months of transplantation and attempting to stop antiretroviral medicine. This finding highlights the essential role that CCR5 tries to play in HIV-1 infection maintenance.86

In comparison, additional HIV-1-infected people who have received allogeneic stem cell transplants with cells from CCR5 truly wild donors did not have long-term relapses from HIV-1 rebound, with 2 of these patients trying to report viral reoccurrence 12 as well as 32 weeks after analytic treatment interruption, respectively. Among these 2 patients, allogeneic stem cell transplantation probably reduced but did not eliminate latently HIV-infected cells, enabling persistent viral reservoirs to activate viral rebound. This viewpoint may not rule out the potential that allogeneic hematopoietic stem cell transplantation might result in a much more comprehensive or near-complete elimination of viral reservoirs, enabling long-term drug-free relapse of HIV-1 infection in some contexts.84 As just one report demonstrated a decade earlier, a curative treatment for HIV-1 remained elusive. The Berlin Patient has undergone 2 allogeneic hematopoietic stem cell transplantations to cure his acute myeloid leukaemia utilizing a potential donor with a homozygous genetic mutation in HIV coreceptor CCR5 (CCR532/32).15,34,46,64,65,72,82,84,86,9496 Other similar studies with CCR5 receptor targets are as follows: Automated production of CCR5-negative CD4+-T cells in a GMP compatible, clinical scale for treatment of HIV-positive patients,97 Mechanistic Models Predict Efficacy of CCR5-Deficient Stem Cell Transplants in HIV Patient Populations,98 Conditional suicidal gene with CCR5 knockout.99

Clustered regularly interspaced short palindromic repeats CRISPR/Cas9 is a promising gene editing approach that can edit genes for gain-of-function or loss-of-function mutations in order to address genetic abnormalities. Despite the fact that other gene editing techniques exist, CRISPR/Cas9 is the most reliable and efficient proven method for gene rectification.100103

Genome engineering employing CRISPR/Cas has proven to be a strong method for quickly and accurately changing specific genomic sequences. The rise of innovative haematopoiesis research tools to examine the complexity of hematopoietic stem cell (HSC) biology has been fuelled by considerable advancements in CRISPR technology over the last five years. High-throughput CRISPR screenings using many new flavours of Cas and sequential and/or functional outcomes, in specific, have become more effective and practical.104,105

The power of the CRISPR/Cas system is that it can specifically and efficiently target sequences in the genome with just a single synthetic guide RNA (sgRNA) and a single protein. Cas9 is directed to the specific DNA sequence by the sgRNA, which causes double stranded breaks and activates the cells DNA repair processes. Non-homologous end joining can cause insertiondeletion (indel) substitutions at the target location, whereas homology-directed repair can use a template DNA to insert new genetic material.104,106

The possibility for CRISPR/Cas9 to be used in the hematopoietic system was emphasised as pretty shortly after it was initiated as a new genome editing method.106,107 The efficiency with which CRISPR-mediated alteration can be used to evaluate hematopoietic stem/progenitor and mature cell function via transplantation. As a result, hematopoietic research has significantly advanced with the implementation of these technologies. Whilst single-gene CRISPR/Cas9 programming is a significant tool for testing gene function in primary hematopoietic cells, high-throughput screenings potentially offer CRISPR/Cas9 an even greater advantage in hematopoietic research.104

While understanding human haematological disorders requires the ability to mimic diseases, the ultimate goal is to transfer this innovation into therapies. Despite significant advancements in CRISPR technology, there are still barriers to overcome before CRISPR/Cas9 can be used effectively and safely in humans. CRISPR has also been used to target CCR5 in CD34+ HSPCs in an effort to make immune cells resistant to HIV infection, as CCR5 is an important coreceptor for HIV infection.104

CRISPR is a modern genome editing technique that could be used to treat immunological illnesses including HIV. The utilization of CRISPR in stem cells for HIV-related investigation, on the other end, was ineffective, and much of the experiment was done in vivo. The new research idea is about increasing CRISPR-editing efficiencies in stem cell transplantation for HIV treatment, as well as its future perspective. The possible genes that enhance HIV resistance and stem cell engraftment should be explored more in the future studies. To strengthen HIV therapy or resistance, double knockout and knock-in approaches must be used to build a positive engraftment. In the future, CRISPR/SaCas9 and Ribonucleoprotein (RNP) administration should be explored in the further investigations.108 As well as some different title studies were explained the effectiveness of the CRISPR gene editing technology on the management of HIV/AIDS including: CRISPR view of hematopoietic stem cells: Moving innovative bioengineering into the clinic,104 CRISPR-Edited Stem Cells in a Patient with HIV and Acute Lymphocytic Leukaemia,109 Sequential LASER ART and CRISPR Treatments Eliminate HIV-1 in a Subset of Infected Humanized Mice,110 Extinction of all infectious HIV in cell culture by the CRISPR-Cas12a system with only a single crRNA,111 HIV-specific humoral immune responses by CRISPR/Cas9-edited B cells,112 CRISPR-Cas9 Mediated Exonic Disruption for HIV-1 Elimination,113 RNA-directed gene editing specifically eradicates latent and prevents new HIV-1 infection,114 CRISPR/Cas9 Ablation of Integrated HIV-1 Accumulates Pro viral DNA Circles with Reformed Long Terminal Repeats,115 CRISPR-Cas9-mediated gene disruption of HIV-1 co-receptors confers broad resistance to infection in human T cells and humanized mice,116 Inhibition of HIV-1 infection of primary CD4+ T-cells by gene editing of CCR5 using adenovirus-delivered CRISPR/Cas9,117 Transient CRISPR-Cas Treatment Can Prevent Reactivation of HIV-1 Replication in a Latently Infected T-Cell Line,118 CCR5 Gene Disruption via Lentiviral Vectors Expressing Cas9 and Single Guided RNA Renders Cells Resistant to HIV-1 Infection,119 CRISPR/Cas9-Mediated CCR5 Ablation in Human Hematopoietic Stem/Progenitor Cells Confers HIV-1 Resistance In Vivo.109

Induced pluripotent stem cells (iPSCs) have significantly advanced the field of regenerative medicine by allowing the generation of patient-specific pluripotent stem cells from adult individuals. The progress of iPSCs for HIV treatment has the potential to generate a continuous supply of therapeutic cells for transplantation into HIV-infected patients. The title of the study is reported on Generation of HIV-1 Resistant and Functional Macrophages from Hematopoietic Stem Cellderived Induced Pluripotent Stem Cells. In this investigation, researchers used human hematopoietic stem cells (HSCs) to produce anti-HIV gene expressing iPSCs for HIV gene therapy. HSCs were dedifferentiated into constantly growing iPSC lines using 4 reprogramming factors and a combination anti-HIV lentiviral vector comprising a CCR5 shRNA and a human/rhesus chimeric TRIM5 gene. After directing the anti-HIV iPSCs toward the hematopoietic lineage, a large number of colony-forming CD133+ HSCs were acquired. These cells were distinguished further into functional end-stage macrophages with a normal phenotypic profile. Upon viral challenge, the anti-HIV iPSC-derived macrophages displayed good protection against HIV-1 infection. Researchers have clearly shown how iPSCs can establish into HIV-1 resistant immune cells and explain their prospective use in HIV gene and cellular therapies.120

Some other similar titles of the studies reported on the effectiveness of IPSCs on HIV/AIDS managements are as follows: Generation of HIV-Resistant Macrophages from IPSCs by Using Transcriptional Gene Silencing and Promoter-Targeted RNA,121 Generation of HIV-1-infected patients gene-edited induced pluripotent stem cells using feeder-free culture conditions,122 A High-Throughput Method as a Diagnostic Tool for HIV Detection in Patient-Specific Induced Pluripotent Stem Cells Generated by Different Reprogramming Methods,123 Genetically edited CD34+ cells derived from human iPS cells in vivo but not in vitro engraft and differentiate into HIV-resistant cells,124 Engineered induced-pluripotent stem cell-derived monocyte extracellular vesicles alter inflammation in HIV humanized mice,125 Sustainable Antiviral Efficacy of Rejuvenated HIV-Specific Cytotoxic T Lymphocytes Generated from Induced Pluripotent Stem Cells.126

Recently, one HIV patient appeared to be virus-free after having undergone a stem-cell transfusion in which their WBCs were changed with HIV-resistant variations.84 Timothy Ray Brown also noted as the Berlin patient, who is still virus-free, was the first individual to undertake stem-cell transplantation a decade earlier. The most recent patient, like Brown, had a type of leukaemia that was vulnerable to chemo treatments. They required a bone marrow transplantation, which involved removing their blood cells and replacing them with stem cells from a donor cell.5,31,34,41,127130 Rather than simply choosing a suitable donor, Ravindra Gupta et al chose one who already had 2 copies of a mutant within the CCR5 gene,128,131 which provides resistance to HIV infection.3

Additionally, this gene encodes for a specific receptor of white blood cells that are assisted in the bodys immunological responses. The transplant, according to Guptas team, completely replaced the clients White cells with HIV-resistant forms.41,83 Cells in the patients blood disrupted expressing the CCR5 receptor, making it unfeasible for the clients form of HIV to infect the above cells again. The scientists determined that the virus had been cleared from the patients blood after the transplantation. Besides that, after 16 months, the client has withdrawn antiretroviral treatment. The infection was not detected in the most recent follow-up, which occurred 18 months after the treatment was discontinued. Adam, also known as the London patient, was the second person to be cured of HIV as a result of a stem cell transfusion. This discovery is an important step forward in HIV research because it may aid in the detection of potential future therapeutic interventions. It must be noted, but even so, that this is not an extensively used HIV treatment. For HIV-infected patients, antiretroviral drugs have been the foremost therapeutic option.3,31,41,94,129,130 It also encourages many investigators and clinicians to look at the use of stem cells in the treatment of a wide range of serious medical conditions. The reprogramming abilities of stem cells, as well as their accessibility, have created a window of opportunity in medical research. The clinical utility of stem cells is forecast to expand rapidly in the coming years.

On Feb 15, 2022, scientific researchers confirmed that a woman had become the 3rd person in history to be successfully treated for HIV, the virus that causes AIDS, after just receiving a stem-cell transfusion that has used cells from cord blood. Within those transplant recipients, adult hematopoietic stem cells have been used; these are stem cells that eventually develop into all blood cell types, which include white blood cells, these are a vital component of the immune framework. Even so, the woman who had fairly recently been completely cured of HIV infection had a more unique experience than that of the 2 men who were actually cured before her.132

The clients physician, Dr. JingMei Hsu of Weill Cornell Medicine in New York, informed them that, she had been discharged from the hospital just 17 days after her procedure was performed, even with no indications of graft vs host ailment. The woman was HIV-positive but also had acute myeloid leukaemia, a blood cancer of the bone marrow that affects blood-forming cells. She had likely received cord blood as a successful treatment for both her cancer and HIV once her doctors decided on a potential donor well with HIV-blocking gene mutation. Cord blood comprises a high accumulation of hematopoietic stem cells; the blood is obtained during a childs birth and donated by the parents.132

The patients donor was partly nearly matched, and she received stem cells from a close family member to enhance her immune function after the transfusion. The procedure was performed on the woman in August of 2017. She chose to discontinue taking antiretroviral drugs, the standardized HIV intervention, 37 months upon her transfusion. After more than 14 months, there is no evidence of the viral infection or antibodies against it in her blood. Umbilical cord blood, in reality, is much more commonly accessible and simpler to try to match to beneficiaries than bone marrow. Perhaps, some research suggests that the method could be more available to HIV patients than bone marrow transplantation. Nearly 38 million people worldwide are infected with HIV. The potential for using partly matched umbilical cord blood transplantation increases the chances of choosing appropriate suitable donors for these clients considerably.132

It is really exciting to see the earlier terminally ill diseases of being effectively treated. In recent times, there has been a surge of focus on stem cell research.3 Stem cell therapy advancements in inpatient care are receiving a growing amount of attention.20 HIV/AIDS has been and remains a significant health concern around the world. Effective control of the HIV pandemic will necessitate a thorough understanding of the viruss transmission.32

Despite concerns about full compliance and adverse reactions, HAART has demonstrated to be able to succeed and is a sign specifically targeted form of treatment against HIV advancement. As illustrated by the first case of HIV infection relapse attained by bone marrow transplant, anti-HIV HPSC-based stem cell treatment and genotype technology have established a possible future upcoming technique to try to combat HIV/AIDS.

Investigators have conducted experiments with engineering distinct anti-HIV genetic traits trying to target different phases of HIV infection utilizing advanced scientific modalities. In numerous in vivo and in vitro animal studies, HSPCs and successive mature cells were secured from HIV infection by trying to target genetic factors in the infection. Anti-HIV gene engineering of HSPCs is safe and efficacious.15

The number of stem-cell-based research trials has risen in recent years. Thousands of studies claiming to use stem cells in experimental therapies have been registered worldwide. Despite some promising results, the majority of clinical stem cell technologies are still in their early life. These achievements have drawn attention to the possibility of the potential and advancement of various promising stem cell treatments currently in development.11

HIV remains a major danger to humanity. This virus has developed the ability to evade antiretroviral medication, resulting in the death of individuals. Scientists are constantly looking for a treatment for HIV/AIDS that is both effective and efficient.52 The 1st treatments in HIV+ clients were conducted in the early 1980s, even though they were cognizant of their viral disease. Following these early cases, allogeneic SCT was used to treat HIV+ patients with associated cancer or other haematological disorders all over the world. Stem cell transplantation developments have also stimulated the improvement of innovative HIV therapeutic approaches, especially for large goals like eradication and relapse.60

Numerous stem cell therapy progressions have been recognized with autologous and allogeneic hematopoietic stem cell transplantation, as well as umbilical cord blood mesenchymal stem cell transplant in AIDS immunologic non-responders. Whereas this sector continues to advance and distinguishing directives for these cells become much more effective, totipotent stem cells such as hESC and the recently reported induced pluripotent stem cells (iPSC) could be very useful for genetic engineering methods to counter hematopoietic abnormalities such as HIV disease.133135

Immunocompromised people are at a higher risk of catching life-threatening diseases. The perseverance of latently infected cells, which is formed by viral genome inclusion into host cell chromosomes, is a significant challenge in HIV-1 elimination. Stem cell therapy is producing impressive patient outcomes, illustrating not only the broad relevance of these strategies but also the huge potential of cell and gene treatment using adult stem cells and somatic derivative products of pluripotent stem cells (PSCs).

Stem cells have enormous regeneration capacity, and a plethora of interesting therapeutic uses are on the frontier. This is a highly interdisciplinary scientific field. Evolutionary biologists, biological technicians, mechanical engineers, and others that have evolved novel concepts and decided to bring them to medical applications are required to make important contributions. Further to that, recent advancements in several different research areas may contribute to stem cell application forms that are novel. Several hurdles must be conquered, however, in the advancement of stem cells. On the other hand, this discipline appears to be a promising and rapidly expanding research area.

Stem cell-based approaches to HIV treatment resemble an innovative approach to trying to rebuild the ravaged bodys immune system with the utmost goal of eliminating the virus from the body. We will probably see effective experiments from the next new generation of stem cell-based strategies shortly, which will start serving as a base for the further development and use of these techniques in a range of treatment application areas for other chronic diseases.

My immense pleasure was mentioned to family members and friends, who supported and encouraged me in every activity.

There was no funding for this work.

The authors declare that they have no conflicts of interest in relation to this work.

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Originally posted here:
PROMISING STEM CELL THERAPY IN THE MANAGEMENT OF HIV & AIDS | BTT - Dove Medical Press

IPS Cell Therapy Comments Off on PROMISING STEM CELL THERAPY IN THE MANAGEMENT OF HIV & AIDS | BTT – Dove Medical Press | July 8th, 2022

Stem Cells. Author manuscript; available in PMC 2020 Jul 1.

Published in final edited form as:

PMCID: PMC6658105

NIHMSID: NIHMS1024291

1NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland

1NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland

1NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland

2Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA

3Cellular Imaging Section and Vascular Biology Program, Institute for Cell Engineering, Johns Hopkins University, Baltimore, MD, USA

1NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland

2Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA

3Cellular Imaging Section and Vascular Biology Program, Institute for Cell Engineering, Johns Hopkins University, Baltimore, MD, USA

Author contributions:

Barbara Lukomska: Conception and design, financial support, collection and/or assembly of data, final approval of manuscript

Miroslaw Janowski: Conception and design, financial support, collection and/or assembly of data, manuscript writing, final approval of manuscript

It was shown as long as half a century ago that bone marrow is a source of not only hematopoietic stem cells, but also stem cells of mesenchymal tissues. Then the term of mesenchymal stem cells (MSCs) has been coined in early 1990s and over a decade later the criteria for defining MSCs have been released by International Society for Cellular Therapy. The easy derivation from a variety of fetal and adult tissues and not demanding cell culture conditions made MSCs an attractive research object. It was followed by the avalanche of reports from preclinical studies on potentially therapeutic properties of MSCs such as immunomodulation, trophic support and capability for a spontaneous differentiation into connective tissue cells, and differentiation into majority of cell types upon specific inductive conditions. While ontogenesis, niche and heterogeneity of MSCs are still under investigation, there is a rapid boost of attempts in clinical applications of MSCs, especially for a flood of civilization-driven conditions in so quickly aging societies in not only developed countries, but also very populous developing world. The fields of regenerative medicine and oncology are particularly extensively addressed by MSC applications, in part due to paucity of traditional therapeutic options for these highly demanding and costly conditions. There are currently almost 1000 clinical trials from entire world registered at clinicaltrials.gov and it seems that we are starting to witness the snowball effect with MSCs becoming a powerful global industry, however spectacular effects of MSCs in clinic still need to be shown.

Keywords: Mesenchymal stem cells, clinical, differentiation, immunomodulation, paracrine activity, history

Friedenstein was one of the pioneers of the theory that bone marrow is a reservoir of stem cells of mesenchymal tissues in adult organisms. It was based on his observation at the turn of the 1960s and 1970s., that ectopic transplantation of bone marrow into the kidney capsule, results not only the proliferation of bone marrow cells, but also the formation of bone [1] (). This indicated the existence in the bone marrow of a second, in addition to hematopoietic cells, stem cell population giving rise to bone precursors. Due to the ability of these cells to create osteoblasts, Friedenstein gave them the name of osteogenic stem cells. Friedenstein was also the first to isolate from bone marrow adherent fibroblast-like cells with the ability to grow rapidly in vitro in the form of clonogenic colonies (CFU-F; colony forming unit-fibroblast). These cells derived from CFU-F colonies were characterized by the ability to differentiate in vitro not only to osteocytes, but also to chondrocytes and adipocytes. After transplantation of CFU-F colonies into the recipient, they were capable of co-formation of the bone marrow micro-environment [2,3]. The term mesenchymal stem cells has been proposed by Caplan in 1991 because of their ability to differentiate into more than one type of cells that form connective tissue in many organs [4]. This name has become very popular and is currently the most commonly used, even though it raised doubts about the degree of their stemness [5]. Today, there are many substitutes in the literature for the abbreviation of MSCs, including Multipotent Stromal Cells, Marrow Stromal Cells, Mesodermal Stem Cells, Mesenchymal Stromal Cells and many more. In its latest work, Caplan recommends renaming these cells to Medicinal Signaling Cells due to the emphasis on the mechanism of their therapeutic effects after transplantation, which is believed to be based mainly on the secretion of factors facilitating regenerative processes [6].

The roots of research on bone marrow-derived stem cells of connective tissue, which has been then named: mesenchymal stem cells

Due to the growing controversy regarding the nomenclature, the degree of stemness and the characteristics of the cells discovered by Friedenstein, the International Society for Cellular Therapy (ISCT) in 2006 published its position specifying the criteria defining the population of MSCs, which was accepted by the global scientific community. These guidelines recommend the use of the name multipotent mesenchymal stromal cells, however, the name mesenchymal stem cells still remains the most-used. The condition for the identification of MSCs is the growth of cells in vitro as a population adhering to the substrate, as well as in the case of cells of human origin, a phenotype characterized by the presence of CD73, CD90, CD105 surface antigens and the lack of expression of proteins such as: CD45, CD34, CD14, CD11b, CD79a or CD19 or class II histocompatibility complex antigens (HLA II, human leukocyte antigens class II). Moreover, these cells must have the ability to differentiate towards osteoblasts, adipocytes and chondroblasts [7,8]. In addition to the markers mentioned in the ISCT guidelines, the following antigens turned out to be useful in isolating the human MSCs from the bone marrow: STRO-1 (antigen of the bone marrow stromal-1 antigen, cell surface antigen expressed by stromal elements in human bone marrow-1), VCAM / CD106 (vascular cell adhesion molecule 1) and MCAM / CD146 (melanoma cell adhesion molecule), which characterizes cells growing in vitro in a adherent form, with a high degree of clonogenicity and multidirectional differentiation ability [911].

The common mesenchymal core in both versions of MSC abbreviation comes from the term mesenchyme, which is synonymous with mesenchymal tissue or embryonic connective tissue. It is used to refer to a group of cells present only in the developing embryo derived mainly from the third germ layer - mesoderm. During the development these cells migrate and diffuse throughout the body of the embryo. They give rise to cells that build connective tissue in adult organisms, such as bones, cartilage, tendons, ligaments, muscles and bone marrow. The view about the differentiation of MSCs during embryonic development from mesenchymal cells is widely spread [4]. This is due, inter alia, to the observed convergence in the expression of markers such as: vimentin, laminin 1, fibronectin and osteopontin, which are typical for mesoderm cells during embryonic development, as well as characteristic for in vitro adherent bone marrow stroma cells [12]. However, the true origin of MSCs is unknown. In the literature, we can find also reports indicating that they are ontogenetically associated with a group of cells derived from ectoderm, which originate from Sox1 + cells (SRY - sex determining region Y) that appear during the development of embryonic neuroectoderm and neural crest. These cells inhabit newborn bone marrow and meet the criteria corresponding to their designation as MSCs. However, with the development of animals, the population of these cells disappears and is replaced by cells with a different, unidentified origin [13]. It has also been shown that in the bone marrow of the developing mouse embryo, at least two MSCs populations with distinct expression of the nestin protein and the intensity of cell divisions can be distinguished. The former one originates from mesoderm that does not express nestin, and is characterized by intense proliferation and is involved in the process of creating the embryo skeleton. The latter one is derived from the cells of the neural crest, which expresses nestin and is non-dividing and remains passive during bone formation while in the adult organism contributes to a niche of hematopoietic cells [14]. It seems, therefore, that the ontogenesis of MSCs is associated with cells belonging to different germ layers and their original source determines the role and functions that they play in the adult body.

In 1978, the concept of a niche was defined as a place in the body that is settled by stem cells and whose environment allows them to be maintained in an undifferentiated state [15]. MSCs were first obtained from the bone marrow stroma where they constitute an element of stromal cells, participating in the production of signals modulating the maturation of hematopoietic cells. However, the precise location of the niche for MSCs has not been known so far. In the context of research results indicating that MSCs can be isolated from many mesoderm-derived tissues during embryonic development, a common element was sought for all sources from which MSCs can be isolated and a theory was proposed about the existence of their niche within the blood vessels that are present in all structures from which these cells were isolated.

Crisan and colleagues have shown that cells inhabiting the perivascular space of blood vessels, isolated from human tissues such as skeletal muscle, pancreas, adipose tissue and placenta, with the phenotype CD146 +, NG2 + (neuroglycan-2), PDGF-R + (-type platelet-derived growth factor receptor), ALP + expressing endothelial, hematopoietic and muscle cell markers described as pericytes were precursors for cells that after in vitro expansion meet the criteria for determining them as MSCs [16]. Analogously to the described by Friedenstein MSCs, CD146 + cells colonizing the perivascular space of sinusoidal sinus vessels, are responsible for the production of signals allowing the reconstruction of the bone marrow microenvironment after transplantation to heterotopic location [11]. Whats more, tracing the fate of pericytes in the process of rebuilding a damaged tooth in rodents has shown that they are transforming into odontoblasts, which arise from MSCs found in the pulp. However, the same studies showed that in the process of reconstruction of incisors in mice, a different population of odontoblasts, which is not formed from pericytes, but from MSCs of different origin migrating to the area of damage, prevailed quantitatively [17]. The second cell population associated with blood vessels, proposed as a counterpart of MSCs in the body is advent building cells with the CD34+ CD31- CD146- phenotype, which after isolation and in vitro culture meet the criteria defining the population as MSCs. However, these cells also have the ability to differentiate into pericytes [18,19]. Although pericytes and MSCs have a very similar gene expression profile as well as an analogical capacity for differentiation, it has been shown that the functionality of these cells varies. In vitro studies of endothelial cell interactions in co-culture with MSCs or pericytes have shown that only pericytes are able to form highly branched, dense, cylindrical structures with large diameter, typical for well-organized blood vessels, while isolated from the bone marrow MSCs do not have such abilities. Currently, it is believed that there is a link between pericytes and MSCs, but their mutual relations are not well defined. There are speculations that MSCs are an intermediate form of pericytes or their subpopulation, but there is still no conclusive evidence confirming this hypothesis [20,21].

While the cells fulfilling criteria for MSCs can be harvested from various tissues at all developmental stages (fetal, young, adult and aged) using their plastic adherence property, there are profound differences between obtained MSC populations [22,23]. Bone marrow was historically the first source from which MSCs were obtained, however, over time, there have been reports of the possibility of isolation from other sources of cells with similar properties. Mesenchymal cells are obtained from both tissues and secretions of the adult body, such as adipose tissue, peripheral blood, dental pulp, yellow ligament, menstrual blood, endometrium, milk from mothers, as well as fetal tissues: amniotic fluid, membranes, chorionic villi, placenta, umbilical cord, Wharton jelly, and umbilical cord blood [2437]. MSCs of fetal origin as compared to cells isolated from tissues of adult organisms are characterized by a faster rate of proliferation as well as a greater number of in vitro passages until senescence [38]. However, MSCs derived from bone marrow and adipose tissue are able to create a larger number of CFU-F colonies, which indirectly indicates a higher degree of their stemness. The comparison of gene expression typical for pluripotent cells shows that only in cells isolated from the bone marrow we can observe the expression of the SOX2 gene, the activation of which is associated with the self-renewal process of stem cells as well as with neurogenesis during embryonic development [39]. Discrepancies in the ability of MSCs obtained from various sources to differentiate have also been described. The lack of differentiation of MSCs derived from umbilical cord blood towards adipocytes as well as the greater tendency of MSCs from bone marrow and adipose tissue to differentiate towards osteoblasts were observed [39,40].

In addition to the diverseness observed between MSCs from different sources, there are also differences associated with obtaining them from individual donors. Among the cells isolated from the bone marrow from donors of different ages and sexes, up to 12-fold differences in the rate of their proliferation and osteogenesis were found, combined with a 40-fold difference in the level of bone remodeling marker activity - ALP (alkaline phosphatase). At the same time, no correlations were found resulting from differences in the sex or age of donors [41]. However, the results of studies by other authors indicate that the properties of MSCs isolated from the bone marrow are strongly associated with the age of the donor. Cells collected from older donors are characterized by an increased percentage of apoptotic cells and slower rate of proliferation, which is associated with an increased population doubling time. There is also a weakened ability of MSCs from older donors to differentiate towards osteoblasts [42]. Heo in his work shows the different ability of MSCs to osteogenesis combining it with different levels of DLX5 gene expression (transcription factor with the homeodomain 5 motif) in individual donors, however independent of the type of tissue from which the cells were isolated [39].

The next stage in which we can observe diversity among the MSCs population is in vitro culture. The morphology of cultured cells that originate from the same isolation allows for differentiation into three sub-populations. There are observed spindle-shaped proliferating cells resembling fibroblasts (type I); large, flat cells with a clearly marked cytoskeleton structure, containing a number of granules (type II) and small, round cells with high self-renewal capacity [43,44]. The original hypothesis assumed that all cells that make up the MSCs population are multipotent, and each colony of CFU is capable of differentiating into adipocytes, chondrocytes and osteoblasts, as confirmed by appropriate studies [45]. However, in the literature we can find reports that cell lines derived from a common colony of CFU-F differ in their properties, characterized by uni-, di- or multipotence [46]. Some of the authors showed the division of clonogenic MSCs colonies into as much as eight groups distinct in their potential for differentiation. At the same time, it is suggested that there is a hierarchy within which cells subordinate to each other are increasingly directed towards osteo- chondro- or adipocytes and gradually lose their multipotential properties to di- and unipotential ones. This transformation may also be associated with a decrease in the rate of cell proliferation and the level of CD146 protein expression (CD; cluster of differentiation) - proposed as a marker of multipotency [47].

One of the main advantages of MSCs are their immunomodulatory properties. MSCs grown in vitro have the ability to interact and regulate the function of the majority of effector cells involved in the processes of primary and acquired immune response () [48]. They exert their immunomodulatory effects by inhibiting the complement-mediated effects of peripheral blood mononuclear cell proliferation [49,50], blocking apoptosis of native and activated neutrophils, as well as reducing the number of neutrophils binding to vascular endothelial cells, limiting the mobilization of these cells to the area of damage [51,52]. In addition, cytokines synthesized by activated MSCs stimulate neutrophil chemotaxis and secretion of pro-inflammatory chemokines involved in recruitment and stimulation of phagocytic macrophage properties [53]. Moreover MSCs limit mast cell degranulation, secretion of pro-inflammatory cytokines by these cells as well as their migration towards the chemotactic factors [54]. Native MSCs have the ability to block the proliferation of de novo-induced NK cells, but they are only able to partially inhibit the proliferation of already activated cells [55]. They also contribute to the reduction of cytotoxic activity of NK cells [56]. Moreover MSCs can block the differentiation of CD34 + cells isolated from the bone marrow or blood monocytes into mature dendritic cells both by direct contact as well as by secreted paracrine factors [57,58]. They inhibit the transformation of immature dendritic cells into mature forms and limit the mobilization of dendritic cells to the tissues [59]. Under their influence, M1 (pro-inflammatory) macrophages are transformed into M2 type cells with an anti-inflammatory phenotype, and the IL-10 (IL, interleukin) secreted by them inhibits T-cell proliferation [60,61]. In vitro studies have demonstrated a direct immunomodulatory effect of MSCs on lymphocytes. During the co-culture of MSCs with lymphocytes, suppression of activated CD4 + and CD8 + T cells and B lymphocytes was observed [62]. In addition, MSCs reduce the level of pro-inflammatory cytokines synthesized by T-lymphocytes, such as TNF- (tumor necrosis factor ) and IFN- (interferon ) [63], and increase synthesis of anti-inflammatory cytokines, e.g. IL-4. In the presence of MSCs, the inhibition of the differentiation of naive CD4 + T lymphocytes to Th17 + lymphocytes (Th; T helper cells) was observed, while the percentage of T cells differentiating towards CD4 + CD25 + regulatory T cells was found to increase [64,65]. Glennie et al. described this condition as anergy of activated T cells in the presence of MSCs [62]. MSCs also have the ability to limit the synthesis of immunoglobulins like IgM, IgG and IgA (Ig; immunoglobulin) classes secreted by activated B cells, thereby blocking the differentiation of these cells to plasma cells. They also reduce the expression of chemokines and their receptors on the surface of B lymphocytes, which probably have a negative effect on their ability to migrate [66].

The schematic representation of immunomodulatory capabilities of MSCs

Mesenchymal stem cells secrete a wide range of paracrine factors, collectively referred to as the secretome, which support regenerative processes in damaged tissues. They comprise the components of the extracellular matrix, proteins involved in the adhesion process, enzymes as well as their activators and inhibitors, growth factors and binding proteins, cytokines and chemokines, and probably many more [67]. These factors can have distinct impact on the processes they regulate (). MSCs secrete factors promoting angiogenesis, such as: vascular endothelial growth factor (VEGF) but they may also inhibit this process, through expression of monokine induced by interferon and tissue inhibitors of metalloproteinases 1 and 2 [68,69]. An important role is also played by chemokines secreted by MSCs in the process of blocking or stimulating cell chemotaxis, such as: CCL5 (RANTES, regulated by activation, expression and secretion by normal T lymphocytes), CXCL12 (SDF-1, stromal cell-derived factor 1) or CCL8 (MCP-2; monocyte chemoattractant protein 2). An essential group of factors from the point of view of regeneration processes are growth factors with an anti-apoptotic effect, including: HGF (hepatocyte growth factor), IGF-1 (insulin-like growth factor 1), VEGF, CINC-3 (cytokine induced by a chemoattractant for neutrophil chemoattractant), TIMP-1 (tissue inhibitor of metalloproteinases 1), TIMP-2 (tissue inhibitor of metalloproteinases 2), osteopontin, growth hormone, FGF-BP (bFGF binding protein), and BDNF (brain-derived growth factor; -derived neurotrophic factor) and stimulating proliferation as: TGF- (transforming growth factor ), HGF, EGF (epidermal growth factor), NGF (nerve growth factor; nerve growth factor), bFGF (basic fibroblast growth factor), IGFBP-1, IGFBP-2 (IGFBP; insulin-like growth factor 1 binding protein, IGF-Protein-1 protein) and M-CSF (stimulant factor t molar macrophage colony; macrophage colony-stimulating factor) [68,70,71]. Growth factors secreted by MSCs have also ability to reduce fibrosis of tissues during regeneration. These include KGF (keratinocyte growth factor), HGF, VEGF, and Ang-1 (angiopoietin-1), SDF1, IGF-1, EGF, HGF, NGF, TGF- [71,72]. There are reports about the antibacterial properties and interaction of the MSC secretome with cancer cells. Data on the impact of MSCs on neoplasia are not conclusive, however, it is assumed that both the tumor type and the origin of MSCs are of great importance for the final effect [73]. It was shown that factors enclosed within the MSCs secretome are able to reduce the proliferation, viability and migration of certain types of cancer cells (such as non-small-cell lung carcinoma) [74]. Others have shown that factors released by MSCs may increase motility, invasiveness and the ability to form metastases (including, for example, breast cancer cells) [75]. In response to bacteria, levels of cytokines such as IL- 6, IL-8, CCL5, PGE2, TNF-, IL-1, IL-10, VEGF and SDF-1 secreted by MSCs are subject to change [76]. MSCs contain also substances with antibacterial, anti-parasitic and antiviral activity [77].

The mechanisms mediating MSC-dependent trophic support

Another broad and dynamically developing field in recent years which is related to paracrine MSCs activity is their ability to secrete extracellular vesicles (EVs), which include exosomes, microvesicles and apoptotic bodies. Their composition largely coincides with the components contained in the cells from which they originate. Physiologically they play an important role in the regulation of biological functions, homeostasis and the immune response of the body. It is also postulated that the biological activity of microvesicles is comparable to that of MSCs [78]. Experiments conducted using supernatant derived from in vitro culture of MSCs showed that the factors contained in their secretome are responsible for a large part of the effects exerted by MSCs during the regeneration of the damaged area including the protection of other cells against apoptosis, induction of their proliferation, prevention of excessive fibrosis of tissues, stimulation of the angiogenesis process and immunomodulatory effects, as well as the induction of endogenous stem cells differentiation [65,68,69,7982].

As mentioned above, the ability to differentiate into three types of cells such as: osteocytes, chondrocytes and adipocytes is one of the criterion for MSCs [8]. This phenomenon can be traced in vitro by placing MSCs in a medium containing specific supplements, for the adipogenesis process they are mainly dexamethasone, indomethacin, insulin and isobutylmethylxanthin [83], for chondrogenesis cell culture in DMEM medium (Dulbecco / Vogt Modified Eagles Minimal Essential Medium) supplemented with insulin, transferrin, selenium, linoleic acid, selenium acid, pyruvate, ascorbic phosphate, dexamethasone and TGF- III [84], which may additionally be aided by the addition of IGF-1 and BMP-2 (BMP; bone morphogenetic proteins) [85]. In turn the osteogenesis is induced by the presence of ascorbic acid, -glycerophosphate and dexamethasone [86]. Differentiation of MSCs in the appropriate cell type is assessed by identifying the production of respectively: fat droplets (adipogenesis), proteoglycans and type II collagen synthesis (chondrogenesis) or mineralization of calcium deposits and the increase of alkaline phosphatase expression (osteogenesis). However, many literature reports indicate that by the treatment with appropriate factors MSCs might be also a source of other cell types. Caplan and Dennis in their work from 2006 present a process that they call mesengenesis, in which MSCs give also rise to myoblasts, bone marrow stromal cells, fibroblasts, cells co-creating connective tissue of the body as well as ligaments and tendons [87]. Addition of 5-azacytidine to MSCs allows to obtain muscle cells, including cardiomyocytes and myoblasts having the ability to create multinucleated miotubes and expressing markers such as: -myosin heavy chain, -actin cardiac form and desmin [88]. In addition, in vitro studies have made it possible to obtain from MSCs at least two types of cells derived from the endoderm through their transdifferentiation into hepatocytes and -cells of pancreatic islets. The liver cells are obtained from MSCs in two stages by culturing them in modified Dulbeccos medium supplemented with EGF, bFGF and nicotinamide, and in the next stage with the addition of oncostatin M, dexamethasone, insulin, transferrin and selenium. The resulting cells show the presence of markers typical for hepatocytes such as albumin, -fetoprotein and hepatocyte nuclear factor 4 (HNF-4) [89]. By the treatment with a mixture of growth factors secreted by regenerating cells of the pancreas as well as by the use of acitin A, sodium butyrate, taurine and nicotinamide the pancreatic islets of -cells capable of producing insulin were obtained from MSCs [90,91]. It has also been shown that stimulation with appropriate factors may result in the differentiation of MSCs into cells derived ontogenetically from ectoderm, such as neurons. The use of BME stimulation in vitro (-mercaptoethanol) followed by NGF leads to the differentiation of MSCs into cholinergic nerve cells expressing their typical proteins such as NF-68 neurofilaments (68 kDa Neurofilament protein with 68 kDa molecular mass), NF-200 (neurofilament protein with a molecular weight 200kDa, 200kDa neurofilament protein), NF-160 (neurofilament protein molecular weight 160kDa, 160kDa neurofilament protein), choline acetyltransferase and synapsin I [92]. Other factors mentioned as compounds inducing the transformation of MSCs into nerve cells are insulin, retinoic acid, bFGF, EGF, valproic acid, BME and hydrocortisol [93]. In addition, GNDF (glial cell-derived neurotrophic factor), BDNF (brain-derived neurotrophic factor), retinoic acid, 5-azacytidine, isobutylmethylxanthine and indomethacin stimulate the transformation of MSCs into mature neurons that express markers of nervous systems cells such as: nestin, -III tubulin, microtubule associated protein - MAP2 (microtubule associated protein 2) and neuron-specific enolase (ENO2; enolase 2) [94]. These studies show that under strictly controlled conditions prevailing during in vitro culture, in the presence of chemicals and growth factors, MSCs are able to turn into cells derived from all three embryonic germ layers ().

The differentiation potential of MSCs

It has been more than half a century since the curiosity has been revealed that not only hematopoietic cells, but also those capable of forming connective tissue reside in the bone marrow. Subsequent studies have begun to reveal the increasingly fascinating properties of these cells, which go far beyond forming connective tissue. This, combined with their easy derivation from various tissues, made them an attractive research object. Immunomodulatory properties, aiding repair of various tissues as well as differentiation potential to practically any types of cells stunned a whole host of scientists and established MSCs as a driving force of regenerative medicine and began also to play an increasingly important role in oncology [95]. We are currently observing a flood of clinical trials with the use of MSCs, and their number doubles every few years and currently reaches almost 1000 registered items on the clinicaltrials.gov website.

MSCs compose a negligible fraction of cells derived from in vivo tissues and there is no effective method to capture them directly. Therefore, MSCs need to be subjected to the process of in vitro expansion, which in clinical context is called biomanufacturing and biobanking and both terms are frequently used interchangeably to describe the process from procurement of cell source to deliver cells to the patients bed. The processing of MSCs must be performed according to current Good Manufacturing Practice (cGMP) as any other therapeutic agent and is subjected to extensive regulatory effort. Food and Drug Administration (FDA) is the main authority responsible for acceptance of medical products including those containing living cells such as MSCs in the USA. FDA has issued a perspective on MSC-based product characterization [96] and up-dated it in FDA Grand Round delivered by Steven Bauer, PhD, Chief of Cell and Tissue Therapies Branch at FDA on March 08, 2018. Both sources are an excellent overview of regulatory challenges related to the biobanking of MSCs. In general, any new product must obtain investigational new drug status (INDs) to be used in clinical trial before filing application for marketing, and there were 66 INDs submitted to FDA between 2006 and 2012. Based on that FDA engaged into regulatory research project called MSC consortium to characterize MSC based-products with an output of 16 research papers. The main organ responsible for the regulation of medical market in all Member States is European Medicines Agency (EMA) consisting of seven smaller committees. The MSCs-containing products should be classified as Advanced Therapy Medical Product (ATMP) and in detail considered as Somatic Cell Therapy Medicinal Product (CTMP) [97]. Its release on medical market has to be first accredited by Committee for Advanced Therapies (CAT) which creates the general opinion and evaluates the quality, safety and efficiency of the product. After CAT assessment the final acceptance should be then approved by Committee for the Medicinal Products for Human Use (CHMP). This type of legalization is called Centralized Marketing Authorization and it allows to use ATMP products in all European Union countries. Currently, there is a variety of protocols used for biomanufacturing and biobanking of MSCs, and once the successful stories become strong, the landscape of MSC production will probably solidify with predicted reduction of MSC production approaches due to economic and regulatory pressures.

Summing up, it seems that the MSCs are becoming a powerful global industry, ready to respond to the unmet needs of modern medicine struggling with the proper care and quality of life of rapidly aging societies, which is already affecting not only developed countries, but also very populous developing countries. In conclusion, we are beginning to observe the effect of the snowball in which ever new discoveries related to MSC are increasingly stimulating clinical applications of the MSC, which is beginning to contribute to the transformation of medical care.

Significance Statement

The research on bone marrow-derived stem cells of connective tissue is evolving and continuously expanding with a recent boost of interest in clinical applications reflected by an avalanche of nearly 1000 registered clinical trials. While, the current name: mesenchymal stem cells (MSCs) have been coined as late as early 90-ies, it is important to commemorate of the fiftieth anniversary of research on them and provide a big picture from roots of first paper in 1968, through identification of their various potential therapeutic activities such as immunomodulation, trophic support and capability for differentiation and taking role in cell replacement strategies.

This work was funded by NCR&D grant EXPLORE ME within the STRATEGMED I program and by NIH R01 NS091100-01A1.

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Mesenchymal stem cells: from roots to boost - PMC

Cardiac Stem Cells Comments Off on Mesenchymal stem cells: from roots to boost – PMC | July 8th, 2022

Lab-grown human heart cells provide a powerful tool to understand and potentially treat heart disease. However, the methods to produce human heart cells from pluripotent stem cells are not optimal. Fortunately, a new study out of the University of WisconsinMadison Stem Cell & Regenerative Medicine Center is providing key insight that will aid researchers in growing cardiac cells from stem cells.

The research, published recently in eLife, investigates the role of extracellular matrix (ECM) proteins in the generation of heart cells derived from human pluripotent stem cells (hPSCs). The ECM fills the space between cells, providing structural support and regulating formation of tissues and organs. With a better understanding of ECM and its impact on heart development, researchers will be able to more effectively develop heart muscle cells, called cardiomyocytes, that could be useful for cardiac repair, regeneration and cell therapy.

How the ECM impacts the generation of hPSC-cardiomyocytes has been largely overlooked, says Jianhua Zhang, a senior scientist at the Stem Cell and Regenerative Medicine Center. The better we understand how the soluble factors as well as the ECM proteins work in the cell culture and differentiation, the closer we get to our goals.

Researchers like Zhang have been looking to improve the differentiation of hPSCs into cardiomyocytes, or the ability to take hPSCs, which can self-renew indefinitely in culture while maintaining the ability to become almost any cell type in the human body and turn them into heart muscle cells. To investigate the role of the ECM in promoting this cardiac differentiation of hPSCs, Zhang tested a variety of proteins to see how they impacted stem cell growth and differentiation specifically, ECM proteins including laminin-111, laminin-521, fibronectin and collagen.

Our study showed ECM proteins play significant roles in the hPSC adhesion, growth, and cardiac differentiation. And fibronectin plays an essential role and is indispensable in hPSC cardiac differentiation, says Zhang. By understanding the roles of ECM, this study will help to develop more robust methods and protocols for generation of hPSC-CMs. Furthermore, this study not only helps in the field for cardiac differentiation, but also other lineage differentiation as well.

While the new study provides important insight into heart cell development, it is built upon a 2012 study Zhang led which looked at the most efficient way to develop cardiac differentiation of stem cells.

This study is actually a follow-up paper to the Matrix Sandwich Method that we developed for efficient cardiac differentiation of hPSCs, Zhang says. In order to culture the stem cells, we needed to have an ECM layer on the bottom of the plate. Otherwise, the stem cells would not attach to the plate. We would then add another layer of ECM on top of the growing stem cells, and we found that this helped promote the most effective differentiation.

While it was clear that this layering, or sandwich, method more efficiently and reproducibly differentiated hPSC-cardiomyocytes, researchers did not fully understand why. The new study explains why the ECM layers are crucial and identifies fibronectin as a key ECM protein in the development of hPSC-cardiomyocytes.

The most exciting part of this study is now I understand why the Matrix Sandwich Method worked. We were able to identify the fibronectin and its integrin receptors as well as the downstream signaling pathways in this study, Zhang explains. With a better understanding of ECMs roles in stem cell growth and cardiac differentiation, we now hope to investigate the roles of fibronectin and other ECM proteins in promoting the hPSC-cardiomyocytes transplantation for cell therapy.

The next step could help researchers realize the full potential of using hPSC-cardiomyocytes for disease modeling, drug screening, cardiac regeneration and cell therapy. This is very meaningful to Zhang, who began working in cardiovascular research more than 16 years ago.

I became interested in stem cell and heart research when I began working with the stem cells and saw them turning into heart cells beating in a cell culture dish under a microscope, Zhang says. It was amazing. Ive become more and more dedicated to this research, and I can really see the potential of using the stem cell technologies to cure disease and improve our health.

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New study allows researchers to more efficiently form human heart cells from stem cells - University of Wisconsin-Madison

Cardiac Stem Cells Comments Off on New study allows researchers to more efficiently form human heart cells from stem cells – University of Wisconsin-Madison | July 8th, 2022

He called his wife Ann once in the driver's seat to continue the conversation they'd been having over breakfast.

As he made his way towards Mosman in the usual Sydney traffic, a beat-up Toyota Corona was in the queue directly behind him.

At the intersection of Bardwell Rd and Military Rd, the Corona deliberately swerved into Dr Chang's car and so the two cars pulled over on the side of the road.

It was 8am when Phillip Lim and Chiew Seng Liew - the occupants of the Corona - pulled a pistol on Chang.

They wanted money. Lim planned to extort $3 million from a wealthy Asian businessman living in Australia, so he could set up a gambling den or massage parlour. They'd picked Dr Chang after seeing an article about him in a magazine.

Dr Chang pulled out his wallet immediately, but there were numerous witnesses watching on in horror.

Mosman Collectivequotes Chang as yelling out to someone, "call the police, theyve got guns."

He was shot twice - once in the head, once in the stomach. He died at the scene.

Liew was sentenced to a maximum of 26 years in prison for firing the two shots that killed Dr Chang. After 21 years, he was released and deported back to his home country of Malaysia in 2012.

As The Sydney Morning Heraldreported, it was a decision that "devastated" Dr Chang's family.

"I made a mistake," Liew told the Sevennetwork upon his release. "I did the wrong thing and made the family suffer ... You know I want to apologise for the family."

His co-accused Lim was granted parole after serving his minimum 18-year sentence, which expired in 2009.

Hailed as a "medical genius," Dr Chang was celebrated and admired around the world.

While he personallysaved hundreds of lives, he always had his eye on millions - which could be achieved through medical research.

After his death, the Victor Chang Foundation created by Dr Chang in 1984 with the aim of sharing expertise between Australia and Asia through training in the fields of cardiothoracic surgery, heart and lung transplantation and cardiology, continued on with his work.

But his dream was carried forward even further,with the establishment of The Victor Chang Cardiac Research Institute in 1994. It was opened by Princess Dianawho told those gathered, "Dr Chang was no ordinary cardiac surgeon. He was a visionary."

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Dr Victor Chang saved hundreds of lives. 31 years ago today, he was murdered. - Mamamia

Cardiac Stem Cells Comments Off on Dr Victor Chang saved hundreds of lives. 31 years ago today, he was murdered. – Mamamia | July 8th, 2022

Get PDF Sample on this Market @ https://www.databridgemarketresearch.com/request-a-sample/?dbmr=global-exosome-therapeutic-market&Raj

The global exosome therapeutics market competitive landscape provides details by a competitor. Details included are company overview, company financials, revenue generated, market potential, investment in research and development, new market initiatives, production sites and facilities, company strengths and weaknesses, product launch, product trials pipelines, product approvals, patents, product width, and breadth, application dominance, technology lifeline curve. The above data points provided are only related to the companys focus related to the exosome therapeutics market.

For instance,

Collaboration, joint ventures, and other strategies by the market player are enhancing the company market in the global exosome therapeutics market, which also provides the benefit for an organization to improve their offering for treatment products.

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Some of the major companies influencing this market include:

Some of the major companies providing the global exosome therapeutics market are Stem Cells Group, Exosome Sciences, AEGLE Therapeutics, Capricor Therapeutics, Avalon Globocare Corp, CODIAK, Kimera Labs, Stem Cell Medicine Ltd, Exopharm, Jazz Pharmaceuticals, Inc., evox THERAPEUTICS, ReNeuron Group plc, and EV Therapeutics, among others.

Market Segmentation:-

The global exosome therapeutics market is segmented on the basis of type, source, therapy, transporting capacity, application, route of administration, and end user. The growth among segments helps you analyze niche pockets of growth and strategies to approach the market and determine your core application areas and the difference in your target markets.

The global exosome therapeutics market is categorized into seven notable segments which are based on type, source, therapy, transporting capacity, application, route of administration, and end user.

Regions Covered in Artificial Intelligence in Genomics 2022 Global Market Report:

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Exosome Therapeutics Market Research Report Size, Share, New Trends and Opportunity, Competitive Analysis and Future Forecast Designer Women -...

Cardiac Stem Cells Comments Off on Exosome Therapeutics Market Research Report Size, Share, New Trends and Opportunity, Competitive Analysis and Future Forecast Designer Women -… | July 8th, 2022

Wilmington, Delaware, United States, Transparency Market Research Inc.: Cell line development is an important technology in life sciences. Stable cell lines are used for various applications including monoclonal antibody and recombinant protein productions, gene functional studies, and drug screening

Read Report Overview - https://www.transparencymarketresearch.com/cell-line-development-market.html

Manual screening method is a traditional method used for cell line development. This method is tend to be disadvantageous as it is labor-intensive and time-consuming. Automation in tools used for cell line development is likely to replace manual methods of cell line development.

Cell line development and culturing is being rapidly adopted in areas of biological drug developments for various chronic diseases, regenerative medicines such as stem cells & cell-based therapies, recombinant protein, and other cellular entities for pharmaceuticals, diagnostics, and various other industries.

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Key Drivers and Opportunities of Global Cell Line Development Market

Rise in focus on research & development, owing to increase in prevalence of cancer and other chronic diseases is anticipated to drive the market. Several institutes, such as Cancer Research Institute, National Cancer Institute, Advanced Centre for Treatment, Research and Education in Cancer (Cancer Research Centre [ICRC]), and NCI Community Oncology Research Program (NCORP), are engaged in research & development for cancer diagnosis and treatment. Hence, the initiative of government and non-government organizations is likely boost the growth of the market.

Mammalian cell lines are widely used as production tools for various biologic drugs. Technological advancement in cell line development in mammalian cell culturing is likely to fuel the growth of the market. For instance, according to an article published in Pharmaceuticals (Basel), the U.S. Food and Drug Administered approved 15 novel recombinant protein therapeutics from 2005 to 2011 on an average.

Advances in bioinformatics and recombinant technologies have led to development of new cell lines for synthesis or production of essential peptides, enzymes, saccharides, and other molecules which are being used in pharmaceuticals and various other industries.

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North America to Capture Major Share of Global Cell Line Development Market

North America is expected to account for major share of the global cell line development market due to well-established health care infrastructure and rise in government initiatives. Furthermore, adoption of innovative technologies is likely to augment the market in the region.

The cell line development market in Asia Pacific is expected to grow at a rapid pace during the forecast period, owing to increasing risk of communicable diseases, cancer, and chronic & rare diseases and surge in geriatric population. For instance, according to an article published in BioMed Central Ltd, in 2018, 2.9 million cancer deaths occurred and 4.3 million new cancer cases were recorded in China.

Key Players Operating in Global Cell Line Development Market

The global cell line development market is highly concentrated due to the presence of key players. A large number of manufacturers hold major share in their respective regions. Key players engaged in adopting new strategies are likely to drive the global cell line development market. Key players are developing new, cost-effective biologic products. This is anticipated to augment the market.

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Major players operating in the global cell line development market are:

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Cell Line Development Market: Increase in Prevalence of Cancer and Other Chronic Diseases to Drive the Market - BioSpace

Cardiac Stem Cells Comments Off on Cell Line Development Market: Increase in Prevalence of Cancer and Other Chronic Diseases to Drive the Market – BioSpace | July 8th, 2022

Homology Medicines, Inc.

AAVHSC16 Biodistribution Properties in Preclinical Models Demonstrated Potential for Systemic Delivery of Genetic Medicines to Brain, Heart and Muscle

BEDFORD, Mass., July 05, 2022 (GLOBE NEWSWIRE) -- Homology Medicines, Inc. (Nasdaq: FIXX), a genetic medicines company, announced today the peer-reviewed publication of data showing that AAVHSC16, one of the capsids in its family of 15 naturally occurring AAVHSCs, demonstrated low levels of tropism to the liver while maintaining robust distribution to the central nervous system (CNS) and peripheral organs following a single I.V. administration in preclinical models. The Company believes that its unique properties, with high levels of tropism to the brain, heart and muscle, and no elevations in liver enzymes, could make AAVHSC16 an attractive capsid for new disease indications with Homologys genetic medicines platform.

Our ongoing efforts to fully characterize our family of 15 naturally occurring AAVHSCs as it relates to biodistribution, tissue tropism and the role different features of the capsids play, continues to reveal their unique profiles that allow us to best select capsids for different diseases, said Albert Seymour, Ph.D., President and Chief Scientific Officer of Homology Medicines. In the case of AAVHSC16 with its ability to reach key tissues without targeting the liver in preclinical models, we can potentially expand into additional disease areas where we want to deliver to the CNS, cardiac tissue, or muscle while avoiding exposure in the liver. By continuing to publish our discoveries about the unique structure and function of our AAVHSCs, we believe we can contribute to the fields greater understanding and development of AAV-based therapies that will ultimately benefit more patients.

Homologys AAVHSC capsids differ from each other by one to four amino acids, resulting in differences in biodistribution and transduction efficiencies. As described in the manuscript, AAVHSC16 has two unique amino acids, 501I and 706C, in addition to 505R that is shared across six AAVHSC serotypes. A series of experiments demonstrated that these amino acids contribute to AAVHSC16s unique properties, which include significantly reduced liver tropism compared to other AAVs, no liver enzyme elevations, and high tissue tropism to the CNS and other peripheral organs. Specifically, these data demonstrated:

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Naturally Occurring Variations in AAVHSC16 Alter Cellular Binding Affinity In Vitro

AAVHSC16 does not share the galactose (a type of glycan) binding feature of other AAVHSCs and Clade F AAVs in vitro. AAVHSC16 did not show improved binding or a difference in number of vector genomes (vgs) or eGFP expression in cells with terminally exposed galactose, while other AAVHSCs tested did.

The combination of the unique naturally occurring amino acids at positions 501I and 505R in AAVHSC16 were shown to contribute to reduced galactose-binding.

AAVHSC16 Has Significantly Reduced Liver Transduction in In Vivo and In Vitro Models, with High Tropism to other Tissues Following a Single I.V. Administration

In murine models, a single I.V. administration of AAVHSC16 showed significantly lower levels of liver tropism compared to AAVHSC15 and AAV9. The liver was the only organ with significant differences as AAVHSC16 demonstrated high levels of tropism to all other organs evaluated, including the brain, heart and muscle; these levels were comparable to those observed with AAVHSC15 and AAV9.

Further, in non-human primates (NHPs), a single I.V. administration of AAVHSC16 resulted in substantially lower liver expression than AAVHSC15, while maintaining high and equivalent levels of transduction in the brain, heart and muscle.

In vitro data also showed that AAVHSC16 led to lower expression in primary human liver cells compared to other tested wild type AAVHSCs and AAV9, and it revealed that AAVHSC16s 706 residue was the main contributor to this outcome.

AAVHSC16 Did Not Lead to Elevations in Liver Function Tests

In NHPs, a single I.V. administration of AAVHSC16 at 7E+13 and 1E+14 vg/kg doses did not result in elevated ALT (alanine transaminase) or AST (aspartate transferase) levels at any timepoint post-dose compared to baseline levels or vehicle-treated controls.

Comparing AAVHSC16 liver transduction and ALT and AST levels to AAV9 and other AAVHSCs further suggested that the lack of ALT and AST elevations with AAVHSC16 is associated with its lower liver tropism.

The publication, Natural Variations in AAVHSC16 Significantly Reduce Liver Tropism and Maintain Broad Distribution to Periphery and CNS, was peer-reviewed and published in the journal Molecular Therapy - Methods & Clinical Development. For more information, please click here or http://www.homologymedicines.com/publications.

About Homology Medicines, Inc.Homology Medicines, Inc. is a clinical-stage genetic medicines company dedicated to transforming the lives of patients suffering from rare diseases by addressing the underlying cause of the disease. The Companys clinical programs include HMI-102, an investigational gene therapy for adults with phenylketonuria (PKU); HMI-103, a gene editing candidate for PKU; and HMI-203, an investigational gene therapy for Hunter syndrome. Additional programs focus on metachromatic leukodystrophy (MLD), paroxysmal nocturnal hemoglobinuria (PNH) and other diseases. Homologys proprietary platform is designed to utilize its family of 15 human hematopoietic stem cell-derived adeno-associated virus (AAVHSCs) vectors to precisely and efficiently deliver genetic medicines in vivo through a gene therapy or nuclease-free gene editing modality, as well as to deliver one-time gene therapy to produce antibodies throughout the body through the GTx-mAb platform. Homology has a management team with a successful track record of discovering, developing and commercializing therapeutics with a focus on rare diseases. Homology believes its initial clinical data and compelling preclinical data, scientific and product development expertise and broad intellectual property position the Company as a leader in genetic medicines. For more information, visit http://www.homologymedicines.com.

Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements, including, without limitation, statements regarding the potential to expand the application of AAVHSC16 to other disease areas; our expectations surrounding the potential, safety, and efficacy of our product candidates; the potential of our gene therapy and gene editing platforms; and our position as a leader in the development of genetic medicines. These statements are neither promises nor guarantees, but involve known and unknown risks, uncertainties and other important factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements, including, but not limited to, the following: the impact of the COVID-19 pandemic on our business and operations, including our preclinical studies and clinical trials, and on general economic conditions; we have and expect to continue to incur significant losses; our need for additional funding, which may not be available; failure to identify additional product candidates and develop or commercialize marketable products; the early stage of our development efforts; potential unforeseen events during clinical trials could cause delays or other adverse consequences; risks relating to the regulatory approval process; interim, topline and preliminary data may change as more patient data become available, and are subject to audit and verification procedures that could result in material changes in the final data; our product candidates may cause serious adverse side effects; inability to maintain our collaborations, or the failure of these collaborations; our reliance on third parties, including for the manufacture of materials for our research programs, preclinical and clinical studies; failure to obtain U.S. or international marketing approval; ongoing regulatory obligations; effects of significant competition; unfavorable pricing regulations, third-party reimbursement practices or healthcare reform initiatives; product liability lawsuits; securities class action litigation; failure to attract, retain and motivate qualified personnel; the possibility of system failures or security breaches; risks relating to intellectual property; risks associated with international operations, such as political and economic instability, including in light of the conflict between Russia and Ukraine; and significant costs incurred as a result of operating as a public company. These and other important factors discussed under the caption Risk Factors in our Quarterly Report on Form 10-Q for the quarter ended March 31, 2022, and our other filings with the Securities and Exchange Commission (SEC) could cause actual results to differ materially from those indicated by the forward-looking statements made in this press release. Any such forward-looking statements represent managements estimates as of the date of this press release. While we may elect to update such forward-looking statements at some point in the future, we disclaim any obligation to do so, even if subsequent events cause our views to change.

Company Contacts:Theresa McNeelyChief Communications Officer and Patient Advocatetmcneely@homologymedicines.com781-301-7277

Media Contact:Cara Mayfield Vice President, Patient Advocacy and Corporate Communications cmayfield@homologymedicines.com 781-691-3510

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Homology Medicines Announces Peer-Reviewed Publication on Novel Discovery of AAVHSC with Robust Distribution to the Central Nervous System and...

Cardiac Stem Cells Comments Off on Homology Medicines Announces Peer-Reviewed Publication on Novel Discovery of AAVHSC with Robust Distribution to the Central Nervous System and… | July 8th, 2022

Clusters of the earliest hematopoietic cells being born in the walls of the umbilical artery of a mouse embryo. The cells colored in red represent embryonic multipotent progenitor cells (eMPPs). Credit: Sachin H. Patel/Boston Childrens Hospital

Barcoding studies discovered two independent sources for blood cells in mice. If confirmed in humans, our understanding of blood cancers, bone marrow transplants, and the aging immune system will change.

The origins of our blood may not be quite what we thought. Using cellular barcoding in mice, groundbreaking research finds that blood cells originate not from one type of mother cell, but two, with potential implications for blood cancers, bone marrow transplant, and immunology. Fernando Camargo, PhD, of the Stem Cell Program at Boston Childrens Hospital led the study, published in the journal Nature on June 15, 2022.

Historically, people have believed that most of our blood comes from a very small number of cells that eventually become blood stem cells, also known as hematopoietic stem cells, says Camargo, who is also a member of the Harvard Stem Cell Institute and a professor at Harvard University. We were surprised to find another group of progenitor cells that do not come from stem cells. They make most of the blood in fetal life until young adulthood, and then gradually start decreasing.

The researchers are now following up to see if the findings also apply to humans. If so, these cells, known as embryonic multipotent progenitor cells (eMPPs), could potentially inform new treatments for boosting aging peoples immune systems. They could also shed new light on blood cancers, especially those in children, and help make bone marrow transplants more effective.

Camargos team applied a barcoding technique they developed several years ago. Using either an enzyme known as transposase or CRISPR gene editing, they inserted unique genetic sequences into embryonic mouse cells in such a way that all the cells descended from them also carried those sequences. This enabled the team to track the emergence of all the different types of blood cells and where they came from, all the way to adulthood.

Previously, people didnt have these tools, says Camargo. Also, the idea that stem cells give rise to all the blood cells was so embedded in the field that no one attempted to question it. By tracking what happened in mice over time, we were able to see new biology.

Through barcoding, the researchers found that eMPPs, as compared with blood stem cells, are a more abundant source of most lymphoid cells important to the immune responses, such as B cells and T cells. Camargo believes the decrease in eMPPs that they observed with age may explain why peoples immunity weakens as they get older.

Were now trying to understand why these cells peter out in middle age, which could potentially allow us to manipulate them with the goal of rejuvenating the immune system, says Camargo.

In theory, there could be two approaches: extending the life of eMPP cells, perhaps through growth factors or immune signaling molecules, or treating blood stem cells with gene therapy or other approaches to make them more like eMPPs.

Camargo is also excited about the potential implications for better understanding and treating blood cancers. For example, myeloid leukemias, striking mostly older people, affect myeloid blood cells such as granulocytes and monocytes. Camargo thinks these leukemias may originate from blood stem cells, and that leukemias in children, which are mostly lymphoid leukemias, may originate from eMPPs.

We are following up to try to understand the consequences of mutations that lead to leukemia by looking at their effects in both blood stem cells and eMPPs in mice, he says. We want to see if the leukemias that arise from these different cells of origin are different lymphoid-like or myeloid-like.

Finally, the recognition that there are two types of mother cells in the blood could revolutionize bone marrow transplant.

When we tried to do bone marrow transplants in mice, we found that the eMPPs didnt engraft well; they only lasted a few weeks, says Camargo. If we could add a few genes to get eMPPs to engraft long term, they could potentially be a better source for a bone marrow transplant. They are more common in younger marrow donors than blood stem cells, and they are primed to produce lymphoid cells, which could lead to better reconstitution of the immune system and fewer infection complications after the graft.

Reference: Lifelong multilineage contribution by embryonic-born blood progenitors by Sachin H. Patel, Constantina Christodoulou, Caleb Weinreb, Qi Yu, Edroaldo Lummertz da Rocha, Brian J. Pepe-Mooney, Sarah Bowling, Li Li, Fernando G. Osorio, George Q. Daley and Fernando D. Camargo, 15 June 2022, Nature.DOI: 10.1038/s41586-022-04804-z

Sachin H. Patel, MD, PhD, of the Stem Cell Program (now at University of California San Francisco) and Constantina Christodoulou, PhD (now at Bristol Myers Squibb) were co-first authors on the paper. The study was funded by the National Institutes of Health (HL128850-01A1, P01HL13147), the Evans MDS Foundation, the Alex Lemonade Foundation, the Leukemia and Lymphoma Society, and the Howard Hughes Medical Institute. The authors declare no competing interests.

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The Origins of Our Blood May Not Be What We Thought - SciTechDaily

Bone Marrow Stem Cells Comments Off on The Origins of Our Blood May Not Be What We Thought – SciTechDaily | June 30th, 2022

Srinagar, June 29: In a recent case, doctors at HCMCT Manipal Hospitals, Dwarka successfully treated a 9-year-old patient from Iraq who was suffering from a rare disease called Diamond Blackfan anemia presenting as aplastic anaemia.

She presented with low hemoglobin, low platelets, and low TLC. The team led by Dr. Divya Bansal successfully performed a bone marrow transplant where the donor was the patients 3-year-old sister.

Diamond-Blackfan anemia (DBA) is a rare blood disorder that occurs when the bone marrow fails to make red blood cells, which are essential for carrying oxygen from the lungs to all the other parts of the body. In this case, the patient had a extremely rare presentation of Diamond Blackfan anemia, where her bone marrow was suppressed and she had low hemoglobin, platelets, and TLC.

This was a challenging case as she was platelet transfusion refractory; no matter how many platelets she was given, her platelet count did not rise, and she was bleeding profusely from the nose and mouth, which was life threatening. Transplant in this condition was particularly challenging, as conditioning therapy, which is given before donor stem cell infusion, further depletes the platelets.

Speaking about this case, Dr. Divya Bansal, Consultant of Clinical Hematology and Bone Marrow Transplant, HCMCT Manipal Hospital, Dwarka said, "This was a different case, the little girl was brought to us with a history of weakness and bleeding from the nose and mouth. We evaluated her further and found that she had congenital bone marrow failure syndrome, diamond blackfan anemia. There was a high PNH clone (paroxysmal nocturnal hemoglobinuria), which is another uncommon condition in the general population and even more so in children. She had a congenital cause as well as an acquired cause for aplastic anemia. Luckily, one of her sisters, who was just 3 years old, turned out to be a 100% HLA match for a bone marrow transplant. However, the difference between donor weight and recipient weight was very wide. The recipient was around 40 kg, and the donor was around 12 kg. Generally, a 10% weight difference is accepted. The protocol is that when you have a major weight difference, then the stem cell collection is done in two settings. But due to the time factor, we had to do it in one sitting only."

The patient contracted a dreadful infection at an early stage of the transplant. However, with the assistance of experienced experts and cutting-edge technology at Manipal Hospitals, the patient was successfully treated, and she was engrafted on day 14 of the transplant, and the chimerism was performed on the 30th day. She is now 100 percent donor chimerism, which means that all the cells in her body are from the donor. This was a success story for us because it was a rare disease with exceedingly rare complications and presentation but was done successfully.

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9-year-old Iraqi girl diagnosed with rare blood disorder successfully treated at HCMCT Manipal Hospitals - Rising Kashmir

Bone Marrow Stem Cells Comments Off on 9-year-old Iraqi girl diagnosed with rare blood disorder successfully treated at HCMCT Manipal Hospitals – Rising Kashmir | June 30th, 2022

Stem Cell Therapy Market Is Expected To Reach USD455.61 Billion By 2027 At A CAGR Of 16 percent.

Maximize Market Research has published a report on theStem Cell Therapy Marketthat provides a detailed analysis for the forecast period of 2022 to 2027.

Stem Cell Therapy Market Scope:

The report provides comprehensive market insights for industry stakeholders, including an explanation of complicated market data in simple language, the industrys history and present situation, as well as expected market size and trends. The research investigates all industry categories, with an emphasis on key companies such as market leaders, followers, and new entrants. The paper includes a full PESTLE analysis for each country. A thorough picture of the competitive landscape of major competitors in the Stem Cell Therapy market by goods and services, revenue, financial situation, portfolio, growth plans, and geographical presence makes the study an investors guide.

To Get A Copy Of The Sample of the Stem Cell Therapy Market, Click Here:https://www.maximizemarketresearch.com/request-sample/522

Stem Cell Therapy Market Overview:

Stem cells, which are the most important in the body, exist in both humans and animals. Stem cells, which may multiply and grow into almost any cell type in the body, are employed in surgery and medicine. There are two types of stem cells: adult stem cells and embryonic stem cells. Embryonic stem cells are stem cells derived from human embryos (ESCs). They are pluripotent, which means they can develop into practically any type of cell in the body. Regenerative medicine or cornerstone treatment are other terms for stem cell therapy. Regenerative medicines can restore cells and replace those that have been damaged or killed.

Mesenchymal stem cells may penetrate and integrate into different organs, heal cardiovascular, lung, and spinal cord injuries, and ameliorate the condition of autoimmune illnesses, liver disorders, and bone and cartilage diseases. Stem cells are an effective therapy option for infections induced by inflammation, immune system failure, or tissue degradation.

Stem Cell Therapy MarketDynamics:

The use of stem cells in regenerative medicine, notably in dermatology, is likely to drive significant growth in the global Stem Cell Therapy Market during the forecasted period. Additionally, increased oncology use, as a result of a large number of pipeline medications under development for the treatment of tumors or malignancies, would move the market ahead. The stem cell business is expected to flourish in the future as the number of regenerative medicine clinics increases. Moreover, the rising prevalence of chronic diseases has assisted the growth of the stem cell treatment sector.

Long work hours, a lack of physical activity, and unhealthy eating and drinking habits all lead to the development of chronic diseases and need stem cell therapy. Moreover, the growing death rate from chronic diseases throughout the world is expected to propel the worldwide Stem Cell Therapy Market ahead. Additionally, the growing popularity of personalized pharmaceuticals is driving the worldwide Stem Cell Therapy Market. Researchers have identified new procurement strategies that can be used to generate personalized pharmaceuticals.

Because stem cells are generated by killing human embryos, they raise several ethical concerns. Human embryos are recognized as potential life, and eliminating them, even if they can save a human life, is considered immoral. Concerns about using embryonic stem cells to develop stem cell therapies are restricting the global market growth.

To get more Report Details, Click here:https://www.maximizemarketresearch.com/market-report/stem-cell-therapy-market/522/

Stem Cell Therapy MarketRegional Insights:

The market for stem cell treatment was dominated by North America, Asia Pacific, and Europe. This geographical segments significant share of the stem cell therapy market can be attributed to increased public-private financing and research grants for producing safe and effective stem cell treatment products, as well as the growing number of clinical trials, as well as North Americas major share of the stem cell therapy market with increased sales of stem cell therapy.

Stem Cell Therapy MarketSegmentation:

By Treatment:

By Therapeutic Application:

By Cell Source:

By End users:

Stem Cell Therapy Market Key Competitors:

About Maximize Market Research:

Maximize Market Research is a multifaceted market research and consulting company with professionals from several industries. Some of the industries we cover include medical devices, pharmaceutical manufacturers, science and engineering, electronic components, industrial equipment, technology and communication, cars and automobiles, chemical products and substances, general merchandise, beverages, personal care, and automated systems. To mention a few, we provide market-verified industry estimations, technical trend analysis, crucial market research, strategic advice, competition analysis, production and demand analysis, and client impact studies.

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Stem Cell Therapy Market Is Expected To Reach USD 455.61 Billion By 2027 At A CAGR Of 16 percent By Forecast 2027 Says Maximize Market Research (MMR)...

Spinal Cord Stem Cells Comments Off on Stem Cell Therapy Market Is Expected To Reach USD 455.61 Billion By 2027 At A CAGR Of 16 percent By Forecast 2027 Says Maximize Market Research (MMR)… | June 30th, 2022

Salvatore Viscomi always wanted to be involved in a science fiction project and he found one.

Viscomi is the chief medical officer of GoodCell, a Massachusetts-based startup where people can bank their own white blood cells with a simple blood draw. Labs can then tweak those cells to become what are called induced pluripotent stem cells (iPSCs).

Already sounds like the premise of a novella, right? Well those iPSCs are where things get really fantastical: those cells can become any type of cell in the human body.

There lies in the therapy, Viscomi, who initially was involved in GoodCell as an investor and advisor before becoming CMO, tells Freethink.

Specific white blood cells can be turned into induced pluripotent stem cells (iPSCs) cells which can become any type of cell in the body.

The new stem cells could be made into pancreatic cells to treat diabetes, blood cells to replace those ravaged by leukemia, or neurons to treat brain disorders, according to UCLAs Broad Stem Cell Research Center.

While the white blood cells that can become iPSCs called peripheral blood mononuclear cells, or PBMCs can come from donors or the patients own bone marrow, both have drawbacks.

Donor cells, like any transplant, may require immunosuppression to prevent rejection, which can leave recipients vulnerable to infections. (A particularly acute issue now, with the invisible war with pathogens going hot all around us.)

And extracting cells from the bone marrow involves anesthesia and long needles nothing near as simple as a blood draw.

Now, we dont have to make that difficult decision, Viscomi says.

Finding your potential: Human iPSCs were first created in Japan in 2007. Kyoto University researcher Shinya Yamanaka received a Nobel Prize for his work with University of Cambridges John B. Gurdon, which discovered how to turn adult cells back into stem cells.

According to a recent article by Yamanaka, as of September 2020, clinical trials of iPSC therapies are currently in the works for Parkinsons, heart failure, spinal cord injury, macular degeneration a very common vision disorder in those over 50 and cancer immunotherapy, among sundry others.

There are, however, challenges to be overcome before iPSCs can find their way to patients.

As of September 2020, clinical trials of iPSC therapies are currently in the works for Parkinsons, heart failure, and spinal cord injury, among sundry others.

There is the potential that the stem cells will proliferate beyond what we want them to, leading to tumors. The body may reject even its own stem cells, with conflicting experiments in mice finding possible evidence of rejection, possibly due to abnormal expression of genes in the new cells.

Theres another challenge as well: the ability to crank out enough iPSCs needed for therapies to be practical.

Despite all of that, however, pluripotent stem cells like iPSCs provide unprecedented opportunities for cell therapies against intractable diseases and injuries, Yamanaka wrote.

Banking on yourself: Banking your cells ahead of time can help ensure the cells are as young and healthy as possible, as they do deteriorate with age, Viscomi says.

To bank your own cells, GoodCell requires a 40cc blood draw, the minimum amount required for producing enough iPSCs. Customers receive a draw kit from GoodCell, which they can take to a lab their current partner is Quest or have a phlebotomist do it at home.

That sample is sent to GoodCells laboratory, where the white blood cells that can become iPSCs are isolated, extracted, and slowly frozen (to avoid damaging them).

Theyre stored at really super cold temperatures, Viscomi says. Its a slow freezing process, really kind of a proprietary way of storing them in the best way we know today in terms of keeping them viable.

GoodCell stores the white blood cells for potential use in future stem cell therapies.

If members request it, the company can also run genetic tests for heritable conditions on the material in the sample, which they will test for actionable conditions only, Viscomi says. Tests for non-heritable genetic changes are currently being developed.

Were taking a really comprehensive look at personalized medicine, Viscomi says.

Because of the potentially sensitive nature of the samples, all uses of the patients data must be opted in to, Viscomi says, while the stem cells banks themselves are hardened, bunkers outfitted with cameras, backup power supplies, and designed to resist natural disasters. The privacy systems were tested across a two year beta period.

GoodCell officially began offering personal stem cell banking services on June 6.

Wed love to hear from you! If you have a comment about this article or if you have a tip for a future Freethink story, please email us at tips@freethink.com.

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This startup wants you to have a personal stem cell stash - Freethink

Spinal Cord Stem Cells Comments Off on This startup wants you to have a personal stem cell stash – Freethink | June 30th, 2022

The parents of a 12-year-old boy who's on life support are appealing the decision of the UK Royal Courts of Justice to remove his oxygen and other life-sustaining treatment. They're taking their case to a Court of Appeal hearing in London on Wednesday.

As CBN News reported earlier this month, Family Division of the High Court Judge Emma Arbuthnot ruled "on the balance of probabilities" Archie Battersbee had already died after doctors told the court "it was highly likely" he was "brain stem dead."

Archie's mother and father, Holly Dance and Paul Battersbee are trying to give their son every chance at life after he was found unconscious on April 7 with a cord around his neck. He reportedly had participated in what is believed to be an online blackout challenge, according to watchdog Christian Concern.

The boy has remained on life support at the Royal London Hospital and has not regained consciousness.

Judge Arbuthnot ordered, "Medical professionals at the Royal London Hospital (1) to cease to ventilate mechanically Archie Battersbee; (2) to extubate Archie Battersbee; (3) to cease the administration of medication to Archie Battersbee, and (4) not to attempt any cardio or pulmonary resuscitation on Archie Battersbee when cardiac output ceases or respiratory effort ceases."

"The steps I have set out above are lawful," the judge contended. But she also gave Archie's mother and father, Holly Dance and Paul Battersbee permission to appeal her ruling.

Arbuthnot said there was a "compelling reason" why appeal judges should consider the case, according to ITV News.

According to Christian Concern, this is believed to be the first time that someone in the UK has been declared 'likely' to be dead based on an MRI test.

At a High Court hearing about Archie's case on June 20, Christian Legal Centre attorney Edward Devereux QC argued that evidence should instead show 'beyond reasonable doubt', as in criminal proceedings, that Archie is dead, rather than using a balance of probabilities test.

Archie's parents have been fighting a legal battle to give their son more time and to allow him to have more medical tests to assess whether his condition improves before making the decision about withdrawing his life support.

In a statement, Archie's mother, Hollie, and sister-in-law, Ella Carter, asked: "If Archie can be pronounced dead via an MRI, which is outside the bounds of the law, then what's going to be next?"

They also thanked everyone for the support the family has received from around the world.

"Archie's words, if he was sitting next to me right now, would be 'it melts my heart' and I'll use those words now, because everyone's support does melt my heart. So, thank you and please continue to support us in this fight," the statement said.

Proof of Life?

Archie's parents say a video of him gripping his mother's fingers is proof that he's still alive and his brain is functioning.

But his doctors believe there's no hope for the boy to recover since they believe his brain stem is dead. Scans reportedly show blood is not flowing to the area, according to Sky News. The stem lies at the base of the brain above the spinal cord. It is responsible for regulating most of the body's automatic functions essential for life. Doctors previously said Archie's stem is 50% damaged and that 10% to 20% of the stem is in necrosis where cells have died and/or are decaying.

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Lawyers for the Barts Health NHS Trust said that doctors have repeatedly recreated the moment of the boy holding a clinician's hand, but the hospital workers said it was just "friction" not a grip, which the doctors say is consistent with muscle stiffness.

Eminent Pediatric Neurologist Testified About Cases of Persons Diagnosed as 'Brain Dead' Who Later Recovered

Dr. D. Alan Shewmon, M.D., professor emeritus of Neurology and Pediatrics at the University of California, gave expert testimony about numerous documented cases where persons diagnosed as 'brain dead' subsequently recovered.

When asked whether there was sufficient evidence for a reliable diagnosis of death in Archie's case, Shewmon replied, "Absolutely not."

An online petition to the hospital's chief executive officer has been created to ask that legal action be withdrawn in Archie's case. So far, more than 89,000 people have signed it.

A GoFundMe page has also been set up on the boy's behalf. So far, the account has raised 29,042 GBP (or approximately $35,479 in U.S. dollars).

Archie's mom told Christian Concern earlier this month that the judge's ruling that he's "likely" to be dead is not good enough.

"Basing this judgment on an MRI test and that he is 'likely' to be dead, is not good enough. This is believed to be the first time that someone has been declared 'likely' to be dead based on an MRI test," she explained.

"The medical expert opinion presented in Court was clear in that the whole concept of 'brain death' is now discredited, and in any event, Archie cannot be reliably diagnosed as brain-dead," Dance continued.

She reiterated that she does not believe her son has been given enough time to heal.

"I do not believe Archie has been given enough time. From the beginning, I have always thought 'why the rush?' His heart is still beating, he has gripped my hand, and as his mother, I know he is still in there," she noted.

"Until it's God's way, I won't accept he should go. I know of miracles when people have come back from being brain dead," Dance said.

Andrea Williams, chief executive of the Christian Legal Centre, said in a statement that Archie's case has raised "significant moral, legal and medical questions as to when a person is dead."

"Archie's parents believe that the time and manner of his death should be determined by God and claim a right to pray for a miracle until and unless that happens. That belief must be respected. The ideology of 'dignity in death', meaning a planned time of death as fixed and carried out by the doctors, should not be brutally imposed on families who do not believe in it," Williams said.

"We will continue to stand with the family as they appeal the ruling and continue to pray for a miracle," she concluded.

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Parents of 12-Year-Old Boy Praying for a Miracle, Appealing UK Judge's Decision to Remove Life Support - CBN.com

Spinal Cord Stem Cells Comments Off on Parents of 12-Year-Old Boy Praying for a Miracle, Appealing UK Judge’s Decision to Remove Life Support – CBN.com | June 30th, 2022

The end of Roe v. Wade will not only jeopardize access to abortion in many states, it could have wide-ranging and unpredictable consequences for medical care, including fertility treatment, contraception, and cancer care.

This post-Roe world will be, in many ways, a new era for medical care in the United States, one that could transform medical services for conditions that range far beyond pregnancy, either by making them illegal or by putting their legality in question.

The consequences are unpredictable. Michelle Banker, director of reproductive rights and health litigation at the National Womens Law Center, told me in an interview before Fridays decision that the effect on other types of health care will depend upon the answers to open and untested questions in US courts. Some of it will rest on how judges will interpret new state abortion bans. States could also be emboldened by the Supreme Courts ruling to pass new legislation that restricts other medical services.

History would suggest places that outlaw abortion tend to have less access to other reproductive care as well. In Ireland, which only recently legalized abortion, there is still less access to in vitro fertilization and certain contraceptives than in the rest of Europe, even after abortion became legal. In the US, a health system that is already fractured will become even more so, limiting access to medical care particularly for marginalized patients. Whether you can get certain health care services may be predicated on where you live (or whether you can afford to travel).

The breadth of the potential health care consequences is so broad, Banker said. The first place to start is this is going to result in the death of pregnant people.

The United States has the highest maternal mortality rates among wealthy nations; Black Americans have a significantly higher mortality rate than anywhere else in the developed world. The risk of death from carrying a pregnancy to term is much higher than the risk of death from undergoing an abortion. One estimate puts the number of forced birth in the first year after Roe is overturned at 75,000; the maternal mortality rate in the US is about 1 in 10,000.

The impact the end of Roe could have on pregnancy care could reach much further. As the Atlantics Sarah Zhang wrote, pregnant women undergo genetic and other tests throughout their pregnancy, meant to assess the health of the fetus and identify any anomalies that could be fatal or life-altering. In some cases, parents who learn about these anomalies choose abortion. But that may no longer be so simple if abortion is now outlawed or severely limited. Decisions about whether to get genetic testing and when could be affected.

By the same token, most abortion bans would carve out exceptions if the health of the mother were in jeopardy. But whether a complication represents a life-threatening risk to the mothers health is in part a judgment call on the part of her doctor and the possibility of legal consequences could make the cost of mistakes much higher.

At the very least, there may well be a chilling effect due to providers and patients uncertainty as to whether treatment could expose them to civil or criminal liability, Banker said.

Fetal personhood laws that convey constitutional protections to unborn fetuses would further limit a pregnant persons choices in medical care. Several states have attempted to pass such a law, but they have thus far been held up by the courts. This new post-Roe jurisprudence could embolden those states and others to put such measures into place. Law enforcement or private citizens, depending on the state law, could bring complaints. The recently signed Texas law, for example, deputizes private citizens by creating a financial incentive for them to take civil action against people who seek or provide abortions.

Or, in a less extreme example, what happens if a pregnant person is also receiving cancer treatment or taking mental health medication that could affect the health of their fetus? If they stop receiving that medical care, their health could be in danger. But if they continue to receive it, the fetus could be affected. What are they and their doctor supposed to do?

The laws that criminalize abortion are going to impact medical decision-making, and thats terrifying, Banker said.

Supporters of abortion rights fear that, unchained by the Supreme Court, states could push deeper and deeper into the lives of pregnant women and the decisions they make about how to conduct themselves.

People have been arrested for substance use during pregnancy, based on reasoning that they are harming the growth of the pregnancy. Tennessee passed the first law permitting the prosecution of pregnant women who use drugs. That alone is objectionable to people who oppose a criminalized approach to substance use. But they also worry that such laws are just the tip of the iceberg in a post-Roe reality. Could a pregnant woman be charged with a crime if she drinks a glass of wine? Or if she goes on a hiking trip that a complainant thinks would imperil the health of her fetus?

These questions will be answered by the specifics of state laws and the discretion of prosecutors in different places. But they are questions that were unfathomable just a few months ago.

How far down this path could states go? said Elizabeth Nash, who tracks state policy at the Guttmacher Institute, in an interview before Fridays Supreme Court ruling. That might sound a bit far-fetched to people but we have seen states take drastic actions in relation for some pregnant people.

Beyond medical care during pregnancy, the end of Roe could usher in a wave of new restrictions on access to contraception and fertility treatment.

The right to contraception is currently upheld by two previous Supreme Court decisions: Griswold v. Connecticut enshrined the right for married people and Eisenstadt v. Baird did the same for unmarried people.

But the current Court is clearly not bound by those precedents if they are willing to overturn Roe v. Wade. And some prominent Republicans, such as Sen. Marsha Blackburn (R-TN), have referred to those prior court decisions as constitutionally unsound in the days since the Alito draft leaked.

That puts case law in jeopardy because it relies on this idea that rights not specifically named in the Constitution are only entitled to special protection if they are deeply rooted in the nations traditions, Banker said.

Other experts I spoke to agreed. The stage is very much set for state legislators to ban contraception if they want to, Sean Tipton, who works on policy issues at the American Society for Reproductive Medicine, told me before the Supreme Court ruled.

Would state legislators want to ban condoms or even birth control pills? Maybe not. But new laws or even state abortion bans could target other kinds of birth control.

Many of these states want to define the beginning of life as early as possible in the biological process. Oklahoma, for one, passed a law that recognized an unborn childs life as beginning at fertilization. Other states describe the moment of conception. But, as Tipton pointed out, the early stages of pregnancy are, medically speaking, a process. There is not a single moment of conception.

But if states define life in such a way, then contraceptives that could prevent a fertilized egg from becoming implanted could be under threat.

IUDs and the morning-after pill would be threatened under such a legal regime. In the vast majority of cases, IUDs work by preventing fertilization: the sperm and the egg never meet in the first place. But they also might prevent implantation under certain circumstances. There is also some controversy about whether Plan B, the morning-after pill, prevents fertilization in the first place or whether it blocks the implantation of a fertilized egg. The latter could arguably be illegal in states that recognize life at fertilization. Lawmakers in Idaho, for example, announced hearings on whether to ban emergency contraceptives and possibly IUDs before the Supreme Court had even issued its final ruling.

Then there are fertility treatments particularly in vitro fertilization that depend on fostering a larger number of eggs but typically only use a small number of them. If an embryo is conferred the same rights as a toddler, are those procedures suddenly illegal?

As Tipton put it to me, what if a doctor puts 199 embryos in a freezer for IVF treatment, and 198 of them come out of the freezer okay? Does that mean a homicide has been committed? he said.

Experts imagine other possible restrictions on procedures like IVF, particularly in states that define life as beginning at conception or fertilization. That alone could put IVF in legal jeopardy. States could also institute new restrictions on those procedures, now that the right to privacy has been redefined. Maybe the number of embryos could be limited. Maybe state legislators restrict which people are allowed to avail themselves of those services to only straight married couples, for example.

And while there is a tension between ostensibly pro-life politicians restricting access to fertility care, there is an expectation that anti-abortion advocates would be willing to let these medical services be collateral damage in order to achieve the goal of outlawing abortion.

Most right-to-life proponents are not interested in doing anything to hurt fertility patients, Tipton said. But theyre very willing to throw those patients under the bus to end abortion.

The new jurisprudence could also affect access to health care that has nothing to do with pregnancy or reproduction, experts say.

Medical care for people undergoing a gender transition would be one possible casualty. The decision in particular puts gender-affirming care in its crosshairs, Banker said.

In the opinion, Alito cited a 1974 decision, Geduldig v. Aiello, that takes what Banker calls a very narrow and cramped view of what constitutes sex discrimination. For Alitos purposes, that narrow view of sex discrimination supports the argument that banning abortion would not constitute discrimination against pregnant people on the basis of sex.

But Banker says the same logic could be applied to gender-affirming health care such as surgery or hormonal treatments. If the Supreme Courts definition of sex discrimination is now much narrower than it used to be, then opponents of those services could argue that denying a person gender-affirming medical care is not actually discriminatory.

Those arguments are easily refuted under modern precedent, Banker told me. But the drafts language and citation to Geduldig raises concerns that we may see those arguments gain more traction.

Old battles over medical research or treatment could also resurface, Tipton said. Modern science has developed treatments for spinal cord injuries, myelofibrosis, and even certain cancers by relying on stem cells. More treatments are in clinical trials right now. But their prospects could be compromised if access to those materials is limited. Some stem cells are collected from adult body tissue, but others come from embryos.

Much of this will depend on how aggressive anti-abortion advocates decide to be, and on the success of abortion rights advocates in mounting a political and legal response to a ruling overturning Roe.

But it will undoubtedly be a new era for health care in the United States, with potentially devastating consequences for patients with a wide array of medical needs.

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The end of Roe v. Wade affects more than just abortion - Vox.com

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Global Surgical Mesh Market Is Estimated To Be Valued At US$ 1.29 Bn In 2022, And Is Forecast To Surpass US$ 2.2 Bn Valuation By The End Of 2032

Sales of surgical meshes are expected to account for more than 21 Mn units by 2032-end, owing to their increasing application in untapped markets, says a Fact.MR analyst.

Fact.MR A Market Research and Competitive Intelligence Provider: The global surgical mesh market is estimated to exceed a valuation of US$ 1.29 Bn in 2022, and expand at a significant CAGR of 5.5% by value over the assessment period (2022-2032).

The availability of surgical meshes in absorbable and non-absorbable forms has expanded their application for temporary as well as permanent reinforcement. In recent years, demand for surgical meshes has escalated in aiding breast reconstruction as they reduce the exposure risk of the implant. Increasing health literacy in North America and Europe will create ample opportunities for surgical mesh manufacturers over the coming years.

Sedentary lifestyle and increasing obesity among the population have resulted in several chronic health issues. The consequent weakening of the muscles extends space for organ prolapse and hernia. Putting these organs back in place by stitching the muscles together can result in muscle tearing and the recurrence of prolapse. However, reinforcing the weakened muscles with the help of a surgical mesh has shown to decrease recurrence and increase the longevity of the repair.

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Winning Strategy

To attract new customers, market players are focusing on portfolio enhancement. Robust investments in R&D are driving product innovation for key market players. Meshes inhibiting the growth of bacterial films and preventing tissue adhesions are luring new consumers. Collaboration of manufacturers with scientific personnel and operating surgeons have enabled bespoke designing of meshes to best fit patients needs.

Manufacturers are also aiming for portfolio expansion through acquisition and partnerships. Partnering with companies that offer a well-aligned portfolio has significantly increased consumer penetration for key manufacturers. However, augmenting relations with local players and operating surgeons will be a key determinant of the products commercial success.

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Scientific collaborations and robust R&D investments have also guided product innovation and became a common strategic approach adopted by leading surgical mesh manufacturing companies to upscale their market presence.

For instance:

Surgical Mesh Industry Research by Category

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Fact.MR, in its new offering, presents an unbiased analysis of the global surgical mesh market, presenting historical market data (2017-2021) and forecast statistics for the period of 2022-2032.

The study reveals essential insights on the basis of product type (synthetic, biosynthetic, biologic, hybrid/composite), nature of mesh (absorbable, non-absorbable, partially absorbable), surgical access (open surgery, laparoscopic surgery), use case (hernia repair, pelvic floor disorder treatment, breast reconstruction, others), and raw material (polypropylene, polyethylene terephthalate, expanded polytetrafluoroethylene, polyglycolic acid, decellularized dermis/ECM, others), across seven major regions (North America, Latin America, Europe, East Asia, South Asia & ASEAN, Oceania, MEA).

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With a repertoire of over thousand reports and 1 million-plus data points, the team has analysed the healthcare domain across 50+ countries for over a decade. The team provides unmatched end-to-end research and consulting services.

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Technical Advancements & Innovative Products Likely to Expand Application of Surgical Meshes in Untapped Domains, States Fact.MR - BioSpace

Cardiac Stem Cells Comments Off on Technical Advancements & Innovative Products Likely to Expand Application of Surgical Meshes in Untapped Domains, States Fact.MR – BioSpace | June 30th, 2022

A paper recently published in the journal Biomaterials reviewed the new advances in three-dimensional bioprinting (3DBP) for regenerative therapy in different organ systems.

Study:Advances in 3D bioprinting of tissues/organs for regenerative medicine and in-vitro models. Image Credit:luchschenF/Shutterstock.com

Organ/tissue shortage has emerged as a significant challenge in the medical field due to patient immune rejections and donor scarcity. Moreover, mimicking or predicting the human disease condition in the animal models is difficult during preclinical trials owing to the differences in the disease phenotype between animals and humans.

3DBP has gained significant attention as a highly-efficient multidisciplinary technology to fabricate 3D biological tissue with complex composition and architecture. This technology allows precise assembly and deposition of biomaterials with donor/patients cells, leading to the successful fabrication of organ/tissue-like structures, preclinical implants, and in vitro models.

In this study, researchers reviewed the 3DBP strategies currently used for regenerative therapy in eight organ systems, including urinary, respiratory, gastrointestinal, exocrine and endocrine, integumentary, skeletal, cardiovascular, and nervous systems. Researchers also focused on the application of 3DBP to fabricate in vitro models. The concept of in situ 3DBP was discussed.

In this extensively used low-cost bioprinting method, rotating screw gear or pressurized air is used without or with temperature to extrude a continuous stream of thermoplastic or semisolid material. Different materials can be printed at a high fabrication speed using this technology. However, low cell viability and the need for post-processing are the major drawbacks of extrusion bioprinting.

In this method, liquid drops are ejected on a substrate by acoustic or thermal forces. High fabrication speed, small droplet volume, and interconnected micro-porosity gradient in the fabricated 3D structures are the main advantages of this technique. However, limited printed materials and clogging are the biggest drawbacks of inkjet bioprinting.

A laser is used to induce the forward transfer of biomaterials on a solid surface in the laser-assisted bioprinting method. High cell viability and nozzle-free noncontact process are the biggest advantages of laser-assisted bioprinting, while metallic particle contamination and the time-consuming nature of the printing process are the major disadvantages.

Several studies were performed involving the development of neuronal tissues using the 3DBP method. The pressure extrusion/syringe extrusion (PE/SE) bioprinting technique was used for central nervous tissue (CNS) tissue replacement. The layered porous structure was fabricated using glial cells derived using human induced pluripotent stem cell (iPSC) and a novel bioink based on agarose, alginate, and carboxymethyl chitosan (CMC) formed synaptic networks and displayed a bicuculline-induced enhanced calcium response.

Similarly, stereolithography (SLA) was used to fabricate a 3D scaffold for CNS and the viability of the scaffold was evaluated for regenerative medicine application. Layered linear microchannels were printed using poly(ethylene glycol) diacrylate-gelatin methacrylate (PEGDA-GelMA) and rat E14 neural progenitor cells (NPCs). The 3D scaffold restored the synaptic contacts and significantly improved the functional outcomes. Cyclohexane was used to bond polystyrene fibers to matrix bundle terminals during crosslinking.

Multiphoton excited 3-dimensional printing (MPE-3DP) was employed for the regeneration of myocardial tissue. A layer-by-layer structure was fabricated using GelMA/ sodium 4-[2-(4-morpholino)benzoyl-2-dimethylamino]-butylbenzenesulfonate (MBS) and human hciPSC-derived cardiomyocytes (CMs), endothelial cells (ECs), and smooth muscle cells (SMCs). The crosslinking was performed by photoactivation. The structure promoted electromechanical coupling and improved cell proliferation, vascularity, and cardiac function.

Fused deposition modeling (FDM) and PE/SE bioprinting method were used for complex tissue and organ regeneration. A micro-fluid network heart shape structure was fabricated using polyvinyl alcohol (PVA), agarose, sodium alginate, and platelet-rich plasma and rat H9c2 cells and human umbilical vein endothelial cells (HUVECs). 2% calcium dichloride was used during the crosslinking mechanism. The fabricated structure possessed a valentine heart with hollow mechanical properties and a self-defined height.

SE printing was utilized to fabricate a capillary-like network using collagen type1/ xanthan gum and human fibroblasts and ECs for applications in blood vessels. The fabricated network possessed endothelial networks and sprouting between the fibroblast layers.

Bone, cartilage, and skeletal muscle tissue can be repaired and regenerated using the 3DBP technique. For instance, FDM printing was used to print multifunctional therapeutic scaffolds for the treatment of bone. Filopodial projections were fabricated using polylactic acid (PLA) platform loaded with hyaluronic acid (HA)/ iron oxide nanoparticles (IONS)/ minocycline and human MG-63 and human bone marrow stromal cells (hBMSCs), which improved the osteogenic stimulation of the IONS and HA.

PE/SE method was used to fabricate disks and cuboid-shaped scaffolds using - tricalcium phosphate (TCP) microgel and human fetal osteoblast (hFOB) and bone marrow-derived mesenchymal stem cell (BM-MSC) for bone repair, multicellular delivery, and disease model. The fabricated structures promoted osteogenesis.

PE/SE bioprinting was also utilized to fabricate complex porous layered cartilage-like structures using alginate/gelatin/HA, rat bone marrow mesenchymal stem cells (BMSCs), and cow cardiac progenitor cells (CPCs) for hyaline cartilage regeneration. The CPCs upregulated gene expression of proteoglycan 4 (PRG4), SRY-box transcription factor 9 (SOX9), and collagen II.

PE/SE printing was also used to fabricate multinucleated, highly-aligned myotube structures using polyurethane (PU), poly(-caprolactone) (PCL), and mouse C2C12 myoblasts and NIH/3T3 fibroblasts for in-situ expansion and differentiation of skeletal muscle tendon. The fabricated constructs demonstrated more than 80% cell viability with initial tissue differentiation and development.

SLA bioprinting technique was used to fabricate bi-layered epidermis-like structure using collagen type I, mouse NIH 3T3 fibroblast cells, and human keratinocyte cells for tissue model and engineering. The fabricated constructs effectively imitated the tissue functions.

Similarly, PE was employed to fabricate microporous structures using human amniotic mesenchymal stem cells (AFSCs) and heparin-HA-PEGDA for wound healing. The construct improved the wound closure and reepithelialization, increased extracellular matrix synthesis and vascularization, and prolonged the cell paracrine activity.

PE technique was utilized to prepare a multilayered cornea-like structure using human keratocytes and methacrylated collagen (ColMA)-alginate. The cell viability of the keratocytes decreased from 90% to 83% after printing.

PE/SE bioprinting was utilized to bioprint multilayered liver-like structures using GeIMA and human HepG2/C3A for liver tissue engineering. Similarly, hepatocytes were also bioprinted to fabricate multiple organ precursors with branching vasculature. A small intestine model with improved intestinal function and high cell proliferation was fabricated using caco-2 cell-loaded polyethylene vinyl acetate (PEVA) scaffold.

Spheroids of mesenchymal stem cells (MSCs) and chondrocytes and lung endothelial cells were utilized to fabricate scaffold-free tracheal transplant. After implantation in the rat model, the matured spheroids displayed excellent vasculogenesis, chondrogenesis, and mechanical strength. FDM technique was used to fabricate a glomerular structure for kidneys using human iPSCs and hydrogel and a hollow porous network using poly(lactic-co-glycolic acid (PLGA)/PCL/tumor-associated endothelial cells (TECs) for the urethra.

In in-situ bioprinting, the tissue is directly printed on the specific defect or wound site in the body for regenerative and reparative therapy. This method provides a well-defined structure and reduces the gap between host-implant interfaces. In-situ bioprinting is better than in vitro bioprinting techniques as the patients body, as a natural bioreactor, provides a natural microenvironment.

Several studies have evaluated this technique for tissue regeneration. For instance, PE/SE method was used for skin tissue regeneration in pigs and mice using fibrin/collagen/HA and human fibroblast cells. Skin-laden sheets of consistent composition, thickness, and width were formed upon rapid crosslinking of biomaterial. PE/SE technique was also used for neural tissue regeneration in mice using agarose/CMC/alginate and human iPSCs.

In vitro models provide significant assistance in understanding the mechanism of therapeutics and disease pathophysiology. Recently, in vitro models of human tissues and organs were engineered using 3DBP technology for safety assessment and drug testing.

In the 3DBP of organs and tissues, biomaterials play a crucial role in maintaining cellular viability, providing support, and long-term acceptance. Specifically, bioinks must possess unique properties, such as cell growth promotion and structural stability, that can be optimized for clinical use. Additionally, bioinks must be compatible with printers for high-precision rapid prototyping.

Bioinks fulfilling all of these requirements are yet to be identified. Moreover, managing the time during the bioprinting of the constructs is another major challenge, as the time required to fabricate them is often more than the survival time of cells. A bioreactor platform that supports organoid growth and provides time for tissue remodeling can be used to overcome this challenge. Ethical challenges and issues are also a hurdle since fabricating internal tissues/organs can lead to liability and biosafety concerns.

In the future, 3DBP can provide novel solutions to engineer organs/tissues and revolutionize modern healthcare and medicine if these challenges can be addressed.

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Jain, P., Kathuria, H., Dubey, N. Advances in 3D bioprinting of tissues/organs for regenerative medicine and in-vitro models. Biomaterials 2022. https://www.sciencedirect.com/science/article/abs/pii/S0142961222002794?via%3Dihub

Disclaimer: The views expressed here are those of the author expressed in their private capacity and do not necessarily represent the views of AZoM.com Limited T/A AZoNetwork the owner and operator of this website. This disclaimer forms part of the Terms and conditions of use of this website.

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What New Advances are there in 3D Bioprinting Tissues? - AZoM

Cardiac Stem Cells Comments Off on What New Advances are there in 3D Bioprinting Tissues? – AZoM | June 30th, 2022