Unlike other CAR T-cell therapies, clinical success was not associated with significant complications from therapy, said Dr. Jonathan Serody. This means this treatment should be available to patients in a clinic setting and would not require patients to be hospitalized, which is critical in our current environment.

Results from the parallel phase 1 and phase 2 studies also demonstrated that the CAR T-cell therapy was safe and did not produce any serious or severe side effects.

Researchers from the UNC Lineberger Comprehensive Cancer Center and Baylor College of Medicine administered anti-CD30 CAR T cells to 41 patients with relapsed or refractory Hodgkin lymphoma. All patients underwent lymphodepletion with bendamustine alone, bendamustine and fludarabine, or cyclophosphamide and fludarabine prior to the anti-CD30 CAR T-cell therapy.

Measuring safety was the primary goal of the two parallel studies.

The overall response rate, or the percentage of partial or complete responses to therapy, among 37 evaluable patients was 62%. Thirty-four of the patients received fludarabine-based lymphodepletion 17 of which received it with bendamustine, and the other half received it with cyclophosphamide. Two of these patients were considered to be complete response at infusion and maintained the response, so they were not included in final analysis.

The overall response rate among the remaining patients was 72%, with 59% of patients achieving a complete response. After a median follow-up of 533 days, researchers identified the one-year progression free survival rate to be 36% and the one-year overall survival rate to be 94%.

This is particularly exciting because the majority of these patients had lymphomas that had not responded well to other powerful new therapies, said senior study author Dr. Barbara Savoldo, professor in the Department of Microbiology and Immunology at the UNC School of Medicine, in a press release.Patients within the study had received a median of seven previous lines of therapy that included checkpoint inhibitors and autologous or allogeneic stem cell therapies, therapies known to be powerful but also tend to come with a host of side effects.

However, treatment with the anti-CD30 CART cells demonstrated a favorable safety profile. Although 10 patients developed cytokine release syndrome, all cases were considered minor.

Patients who received fludarabine-containing lymphodepletion were the only participants in the study to have a response to the anti-CD30 CAR T-cell therapy.

Although CD30 CAR T (cells) showed modest activity in (Hodgkin lymphoma) when infused without lymphodepletion, robust clinical responses were achieved when these cells were infused in hosts lymphodepleted with fludarabine-containing regimens, the authors wrote.

The activity of this new therapy is quite remarkable and while we need to confirm these findings in a larger study, this treatment potentially offers a new approach for patients who currently have very limited options to treat their cancer, said Dr. Jonathan Serody, director of the bone marrow transplant and cellular therapy program at UNC Lineberger Comprehensive Cancer Center, in the release. Additionally, unlike other CAR T-cell therapies, clinical success was not associated with significant complications from therapy. This means this treatment should be available to patients in a clinic setting and would not require patients to be hospitalized, which is critical in our current environment.

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Jakafi may offer a survival benefit for patients with myelofibrosis and an increased number of circulating blasts, a recent study found.

While the presence of circulation blasts in the blood is considered an important factor in patient prognosis, the impact of bone marrow blasts on survival is not as well defined. To better understand the connection between the amount of blasts found in the blood and bone marrow together, all in regard to patient prognosis, researchers performed a retrospective analysis of 1,316 patients with myelofibrosis, a type of myeloproliferative neoplasm (MPN).

These patients (median age, 66 years), who all presented to the University of Texas MD Anderson Cancer Center in Houston, Texas, from July 1984 and 2018, had to have available circulation blasts in the blood and bone marrow percentages to be included in the analysis. Survival was noted as the time from the date of referral to the date of last follow-up or death, whichever came first. The median follow-up was 27 months.

Among the total, 700 (53%) had 0% circulation blasts in the blood and less than 5% had bone marrow blasts. Of the remaining patients who had 1% or greater circulation blasts in the blood, the range was as follows:

The researchers also found that higher percentages of circulating blasts in the blood had a negative correlation with hemoglobin and platelets, but a positive correlation with white blood cells, age and the presence of symptoms, among other factors.

Out of the total group, 523 patients (44%) received the JAK1/JAK2 inhibitor Jakafi. The authors noted that patients who received this treatment and also had 10% or less blasts, regardless of whether they were in the blood or bone marrow, saw a superior overall survival rate compared to those with similar disease features who did not receive Jakafi.

The studys authors went on to conclude that patients who have circulating blasts in the blood of 4% or more have an unfavorable prognosis; however, Jakafi offers a significant survival benefit to patients with circulating blasts in the blood of 10% or less, making a combination approach to treatment vital in improving the outcomes of patients with myelofibrosis.

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Poverty, Government apathy and Covid-19 induced-lockdown restricting travel proved fatal for little Kishan, a 11-year-old boy suffering from Aplastic anemia, a life-threatening blood disorder condition in which the bone marrow and stem cells do not produce enough blood cells

Facing severe financial constraints and waiting timely medical aid, first at Safdarjung Hospital and then AIIMS, both Government hospitals in Delhi, Kishans life was cut short in March this year amid Covid-19 pandemic.

However, Kishans is not a lone case. Dr Nita Radhakrishnan, paediatric haemato-oncologist at Super Speciality Paediatric Hospital, Noida, Uttar Pradesh says that as the deadly Coronavirus captured the attention of the nation in the most unprecedented manner, the non-Covid patients particularly those with the Aplastic anemia have suffered the most in the crisis.

She gave instances of her two teenage patients who succumbed to blood disorder in the Covid catastrophe. Manish (name change), a 17-year-old was suffering with on-and-off fever, gum bleeding, and melena for three months, he came to us in December last year just when Coronavirus had started spreading its tentacles from China to other parts of the world.

The boy was diagnosed with severe Aplastic anemia and was recommended requisite treatment like regular hospital visit for red cell transfusion before he could be given bone marrow transplant (BMT), a life saving treatment.

However, while the family was not able to visit our hospital in Noida due to the covid-lockdown, no blood products were available at the hospital near to the patients locality. In want of blood, Manish could not survive more days.

13-year-old Suresh (name change) too faced similar fate. While Government funds could not be sanctioned for his BMT in time the boy could not visit the Noida hospital for further follow-up due to travel restrictions. Two weeks later, Suresh died due to hemorrhage at his native place, lamented the doctor.

These are just two reported cases from the NCR hospital located near the countrys capital. Several have gone unreported. The Government has no policy nor any long-term plan for such patients.

The prognosis of severe aplastic anemia in our country is dismal. The incidence of 46 per million population of childhood aplastic anemia in India and other Asian countries is higher than what is observed in the West, explains Dr Radhakrishnan. The scenario is gloomy for the patients afflicted with the disease as they need blood transfusion almost every 20 days.

A significant proportion of patients of aplastic anemia (around 30 per cent) die before any definitive treatment is initiated. A study by AIIMS based on a recent series of patients follow-up showed that out of 1501 patients diagnosed over last seven years, only 303 ie 20 per cent received the definitive treatment modalities through either BMT or IST with ATG and cyclosporine, says Dr Radhakrishnan in her case report Aplastic anemia: Non-COVID casualties in the Covid-19 era, published in the latest edition of Indian Journal of Palliative Care.

The doctors have sought urgent intervention. Dr Radhakrishnan says that as we await the peak of Covid-19 in our country and possibly secondary and tertiary waves thereafter, patients with aplastic anemia who are the sickest among all hematological illnesses would benefit greatly from urgent intervention from the Government to ensure timely treatment.

Those suffering with Aplastic anemia, there is mostly delay in diagnosis, delay in initiation of treatment due to monetary constraints, non-inclusion of the disease under government schemes such as Ayushman Bharat and NHM and delay in sanction of money from other Government schemes such as Rashtriya Arogya Nidhi, Chief Minister and Prime Ministers relief fund often due to lack of proper documents, she added.

Delay means, risk of contracting fungal infections and increase in drug-resistant bacterial infections increase which further hamper the treatment, point out Dr Ravi Shankar and Dr Savitri Singh in the study.

Though the Union Health Ministry, after few days of lockdown period, issued directions for continuing treatment for essential health services including reproductive and maternal health services, newborn care, severe malnutrition, and NCDs including cancer care, palliative care, dialysis, and care of disabled, unfortunately those with Aplastic anemia got ignored.

This despite of the fact that these patients are at the highest risk of death following a break in the treatment of few weeks, notes Dr Radhakrishnan.

Because of the closure of offices and absence of staff, during the lockdown period, there was delay in sanction of usual grants due to the lockdown of offices and inability in generating documents such as income certificate from the tehsils.

For instance, Suresh and Manish, both our patients received the Government grant after around 34 months of applying for the same. But both had died before they could reach the hospital for treatment, lamented the hematologist.

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Covid-19 Impact: Patients with aplastic anemia at receiving end - Daily Pioneer

Bone Marrow Stem Cells Comments Off on Covid-19 Impact: Patients with aplastic anemia at receiving end – Daily Pioneer | August 13th, 2020

INTRODUCTION

The ability to regenerate complex body parts varies considerably in the animal kingdom. While planarian and hydra are able to regenerate their entire bodies, many avian and mammalian species mostly stop at the wound healing stage without a reparative regeneration process (1). This disparity may result from complexity differences among organisms by nature, yet it leaves us the hope that we may learn from highly regenerative species to improve our own regenerative potential.

Zebrafish is known for its ability to regenerate multiple complex body structures (2). Among regenerable tissues, the caudal fin serves as a great model due to its faithful and rapid regeneration, ease of manipulation, and relatively low complexity. A key step in regeneration is the formation of the blastema, a layer of proliferative and undifferentiated cells that accumulates between the wound site and the wound epidermis following initial wound closure. This step occurs in response to appendage loss and is one of the key features that separates regenerative systems from nonregenerative systems. At later stages of regeneration, the blastema further proliferates and differentiates to regenerate the missing complex structures.

However, the molecular signatures of blastemal cell state transitions during regeneration in zebrafish remain elusive. The state of a cell can be represented by its collective gene expression profile, which has only been measured in bulk for all genes or in specific lineages of cells for a subset of genes during caudal fin regeneration. Prior work has shown that both proliferation of progenitors and dedifferentiation of adult lineage cells contribute to the blastema (38). Progenitors respond to injury cue and proliferate as in normal development. Cells derived from mature adult lineages, however, lose their lineage-specific markers while obtaining progenitor-like markers when they proliferate. Neither type of cell gains multipotency, but rather, they proliferate and regenerate with lineage restrictions. The limited resolution and throughput of these approaches have prevented a more systematic understanding of blastema cells. The advent of single-cell transcriptomic technologies promises to reveal signals masked at the bulk tissue level (9), granting us an opportunity to define and monitor cellular state transition in regenerating fin at an unprecedented resolution.

In this study, we generated single-cell transcriptomic maps of regenerating fin tissue. These maps allowed us to separate the contribution from different cell types and track the transcriptomic dynamics in cell state transitions during regeneration. By comparing with the profiles obtained from uninjured fin tissue, we identified cell types involved in regeneration. We demonstrated the activation of cell cyclerelated programs shared across cell types as well as cell typespecific programs. Furthermore, we defined the heterogeneity in both epithelial and blastemal populations and their functional relations to the regeneration process.

To better understand cell type involvement in fin regeneration, we characterized single-cell transcriptional landscapes for both preinjury and regenerating caudal fin tissues using the 10x Genomics platform (see Materials and Methods and table S1) (9). We sampled regenerating fins from 1, 2, and 4 days post-amputation (dpa) time points to interrogate the stages of blastema formation, outgrowth, and maintenance (Fig. 1A). Fin samples were collected from multiple fish to control for individual variation while at the same position along the proximal-distal axis to avoid positional effects. To establish the transcriptional ground states for each cell type in the fin tissue, we first focused on cells collected from the preinjury time point. Via an unsupervised clustering of 4134 cells, we identified epithelial cells (epcam and cdh1), hematopoietic cells (mpeg1.1 and cxcr3.2), and mesenchymal cells (msx1b and twist1a) (fig. S1, A and B) (1014). Epithelial cells are from three transcriptionally distinct subgroups, representing the superficial (krt4), intermediate (tp63), and basal layers (tp63 and krtt1c19e) of the epithelium (fig. S1, A and B) (15, 16).

(A) General experimental design. Zebrafish caudal fin tissues at preinjury and 1/2/4 dpa stages were collected. (B) Clustering assignments for caudal fin cells collected from each stage. Uniform Manifold Approximation and Projection (UMAP) axes were calculated from the integrated cells dataset as in (C). (C) Clustering assignments for caudal fin cells collected from both preinjury and regenerating stages. Cells were plotted on UMAP axes. Color coding is the same as in (E). (D) Percentage distribution of the major cell types captured in caudal fin, grouped by their stage of collection. Color coding is the same as in (E). (E) Differential expressions of the key marker genes by the identified major cell types. Color gradient: normalized relative expression level. Dot size: percentage of cells in the cluster that express the specified gene.

To determine whether the same cell types existed in the regenerating stages, we performed analysis using two different approaches: (i) Cells from each stage were clustered independently, and (ii) cells from both uninjured fins and injured fins were integrated through the anchoring approach (see Materials and Methods; Fig. 1, B, C, and E; and table S2) (17). For both approaches, we regressed out cell cycle effects before principal components analysis (PCA). Agreement between cluster assignments was measured using Hubert and Arabies adjusted Rand index (ARI). An average ARI of 0.86 (preinjury, 0.86; 1 dpa, 0.85; 2 dpa, 0.90; and 4 dpa, 0.83) indicated that clustering results generated using the two approaches were highly consistent. Cell types identified in the preinjury cells presented consistently across all regenerating stages, suggesting that regenerating fins contain the same cell types as the preinjury fins.

New regenerates are built up by the proliferation and migration of cells located at a number of fin segments away from the amputation plane (2). In response to injury cues, these cells gained the ability to detach from local tissue, enter cell cycle, and migrate toward the wound site while undergoing transcriptional reprogramming. We computationally separated S phase, G2-M phase, and G1-phase cells based on the expression level of cell cyclerelated genes and performed clustering analysis using only S phase cells (see Materials and Methods and fig. S2A). In this cycling cell population, we identified epithelial, mesenchymal, and hematopoietic cell groups as before (Fig. 2, A to C, and table S3). Our data support a model in which cells likely keep their original identities during proliferation.

(A) Cell type clustering of S phase cells plotted onto UMAP axes calculated by S phase cell only. Cells are colored by the general cell types merged from major cells types in Fig. 1B. (B) Stage distribution of S phase cells. Cells were plotted on the same UMAP axes as in (A) and colored by stage when the cells were collected. (C) Relative expression levels of the top 30 differentially expressed genes from each cluster of only S phase cells. (D) Venn diagrams of numbers of genes shared between the cell cycleactivated genetic programs. Left, included all genes; right, included only cell cyclerelated genes (see Materials and Methods).

Next, we asked whether different regenerating cell types exhibited similar or distinct cell cycle regulations. To this end, we identified genes up-regulated in S phase cells compared to G1 phase cells in each cell type, respectively (logFC, >0.25; minimum percentage, >10%). Of the 1098 differentially expressed genes, 161 were shared across all three groups of comparisons (Fig. 2D and table S4). Of these shared genes, at least 54 genes were related to cell cycle regulation, underscoring a shared program governing cell cycle reentry (criteria described in Materials and Methods). In contrast, hundreds of genes differentially highly expressed in S phase exhibited cell typespecific pattern, of which dozens were related to cell cycle (Fig. 2D). We next evaluated the degree of conservation of these enriched genes by asking what fraction did not have human orthologs that had been curated in the Metascape database (18). Twenty-five percent of genes in the epithelial cellspecific group had no human ortholog, whereas all shared groups had at most 15% genes without a human ortholog, suggesting that enriched genes shared by cell types were more evolutionarily conserved (fig. S2C).

Some cell typespecific S-G1 enriched genes were also expressed in a cell typespecific manner regardless of their cell cycle phases: For example, psmb8a and psmb9a shared similar epithelial-hematopoietic enrichments (fig. S2D). The human homologs of these genes (PSMB8 and PSMB9) encode 5i and 1i subunits of the immunoproteasome (19). Together with 2i and PA28 subunits of the proteasome, they turn the proteasome into immunoproteasome and take part in immune response (20). Immunoproteasome digests peptides more efficiently, promoting antigen presentation by a major histocompatibility complex (MHC) class I molecule. Although they did not pass the differential expression criteria in the S-G1 comparison, zebrafish psmb10, psme1, and psme2 shared a differential expression signature similar to that of psmb8a and psmb9a, suggesting that zebrafish might use the same group of subunits for the assembly of immunoproteasomes that might help increase immune responses during regeneration, especially in epithelial and hematopoietic cells (fig. S2, D and E). In addition, we found three genes that shared the same expression signature with the immunoproteasome subunits (psmb13a, psmb12, and psma6l) (fig. S2E) without known human or mouse homologs, suggesting that they might form zebrafish-specific proteasomes with functional relevance to regeneration (19).

Consistent with current knowledge, we observed three transcriptionally distinct subgroups in the preinjury epcam+ epithelial cells, representing the superficial, intermediate, and basal layers of the adult zebrafish epithelium (Fig. 3A and fig. S1B) (15, 16). By integrating cells from all stages during regeneration, we found clusters of cells that corresponded to all three layers of the epithelium after injury (Fig. 1, B and C). In addition, we captured a rare agr2+ population (referred to as mucosal-like epithelium herein) that was too small to be clustered by itself in the preinjury stage (Fig. 1E). These cells shared general epithelial features with the other epithelial layers but exhibited higher expression of a unique set of 200 genes. We examined the expression distribution of the orthologs of these genes in human tissues (The Human Protein Atlas, http://proteinatlas.org/) (21). Among the top 30 genes with human orthologs, 11 showed enriched expressions in proximal digestive or gastrointestinal tract and another 11 in bone marrow of blood lineages, suggesting that this population is analogous to cells in the mucosa in mammalian systems (table S2). In zebrafish, agr2 is required for the differentiation of the mucosal-producing goblet cells in the intestinal epithelium (22). To confirm the cell typespecific expression pattern of this gene in the fin tissue, we performed in situ hybridization on agr2 in both uninjured and regenerating fin tissues (see Materials and Methods). agr2 transcripts are scattered within the epithelium regardless of the sample collection stage and reflect a round morphology of the cell expressing it (fig. S3, A, C, E, and G to I). A proportion of agr2+ cells overlap with positive dark blue staining of Alcian blue in serial sections, suggesting that these cells are mucous cells that are known to exist in the caudal fin epithelium (fig. S3, B, D, and F) (23).

(A) Diagram of the stratified adult zebrafish epithelium. (B) Differential expressions of claudin family and keratin family genes in epithelial subgroups shown as a dot plot. Known epithelial markers krt4, fn1b, tp63, and krtt1c19e were included for comparison. Cells were first grouped by major cell types and then separated into preinjury and regenerating stages. Darkness of dot color: relative expression level. Dot size: percentage of cells in the cluster that express the specified gene. (C) In situ hybridization targeting krt1-19d, cldna, cldn1, and krt4 of 4-dpa fin tissues. Brown dots indicate positive RNA signals from target genes, while pale blue blocks represent hematoxylin-stained cell nuclei. Zoomed-in views are presented. Original images can be found in fig. S4. All epithelial layers are above the black dotted lines. (D) Clustering assignment of epithelial cells plotted on UMAP axes calculated with only epithelial cells. Cells are colored by their epithelial layer identity as in (A). (E) The same UMAP visualization as in (D), with cells colored by stage of collection. Arrows connect the groups of comparison, with a direction from preinjury stage to regenerating stages (1, 2, and 4 dpa). Numbers next to the green triangle: number of genes up-regulated in regenerating stage. Numbers next to the red triangle: number of genes down-regulated in regenerating stage. (F) Clustered GO enrichment for genes up-regulated in regenerating basal, intermediate, and superficial epithelial cells comparing to their preinjury counterparts. GTPase, guanosine triphosphatase; ER, endoplasmic reticulum; PKN, protein kinases N; snRNP, small nuclear ribonucleoprotein.

Although the same three-layer classification of epithelial cells could be defined when cells from regenerating stages were integrated with the preinjury cells, the expression of the commonly used layer-specific marker genes changed dramatically during regeneration: Superficial epithelial marker krt4 expanded into basal and intermediate layers of the epithelium, the intermediate layer marker fn1b was also highly expressed in the basal layer, and the basal epithelial marker krtt1c19e was barely detectable in the postinjury cell populations (Fig. 3B) (15, 16). To better understand the molecular features of the epithelial populations, we identified genes significantly more highly expressed in epithelial cells than in hematopoietic and mesenchymal cells and found that cell-cell junction genes ranked high in the list. Among these, genes from the claudin and keratin families were detected at a ratio 20-fold higher than that in randomly selected detectable genes (2 test, P value of <0.0001). We focused on expression patterns of all claudin and keratin genes in zebrafish and found that cldne, cldnf, krt1-19d, and krt17 labeled the superficial cluster; cldnh labeled the mucosal-like cluster; cldna, krt93, and krt94 labeled the intermediate cluster; and cldn1 and cldni labeled the basal cluster (Fig. 3B). Claudin genes are expressed in a tissue-specific manner in zebrafish and are generally considered to be the proteins responsible for regulating the paracellular permeability in the vertebrate epithelium (24). Their differential expression signature in both uninjured and regenerating tissues suggests that they might play important roles in maintaining the permeability in each epithelial population. On the other hand, the expression of keratin genes displayed less restriction across the three layers relative to claudin genes but stronger dependence on regenerating states (Fig. 3B). The differential expression signature suggests that they might perform epithelial subtyperelated function in regeneration. To verify their expression pattern, we performed RNA in situ hybridization targeting the known marker krt4 and new candidates, including krt1-19d, cldna, and cldn1 (Fig. 3C) as well as cldne, krt94, and cldni (fig. S4, A to H). Comparing with the known marker krt4, these genes exhibited more restricted expression patterns in epithelial layers, better representing the molecular signatures of different epithelial populations in the fin tissue regardless of regeneration status (Fig. 3, B and C).

The three epithelial layers were present across the regeneration stages albeit with varying proportions (Fig. 1D). The proportion of basal epithelial cells peaked at 2 dpa, reaching up to 42%, whereas the superficial layer epithelial cells decreased from 27 to 6% at 2 dpa (the coefficient of variations of cell proportions between biological replicates is below 15%). The observed compositional change of the two epithelial populations is consistent with a previous finding that the initial migration of superficial layer cells to the new regenerates is followed by replenishment by basal epithelial cells (25). This basal replenishment was also reflected in the two-dimensional Uniform Manifold Approximation and Projection (UMAP) calculation from only epithelial cells, in which preinjury cells were separated by their respective layers, whereas regenerating cells were closer in the projection space (Fig. 3, D and E). Superficial layer cells from before and after injury stages were in juxtaposition to each other, consistent with our knowledge that this layer of epithelial cells directly migrates to and covers the wound site (25). On the other hand, basal layer cells from before and after injury stages were more distantly separated, suggesting more dramatic changes between resting and regenerating basal epithelial cells.

To understand the mechanisms of epithelium regeneration, we compared the transcriptome between preinjury and regenerating cells for the three epithelial layers. Basal layer cells up-regulated 1271 genes and down-regulated 198 genes during regeneration; both were the highest numbers across all comparisons (numbers of differentially expressed genes were from Wilcoxon rank sum test, adjusted P value of < 0.01; Fig. 3E). We performed gene ontology (GO) enrichment analysis on genes up-regulated in the regenerating stage by layer and found both common and layer-specific programs associated with regeneration (18). All three layers were enriched for oxidative phosphorylation (dre00190), proteasome (dre03050), and cell redox homeostasis (GO:0045454). While basal and intermediate layer cells could be regulated by Rho guanosine triphosphatasemediated Wnt signaling for extracellular matrix organization and actin filament depolymerization, respectively (R-DRE-195258, R-DRE-5625740, R-DRE-195721, GO:0030198, and GO:0030042), superficial layer cells showed enrichment mainly for general transcriptional and translational regulations (Fig. 3F). When comparing the expression profiles between regenerating superficial epithelial and basal epithelial, we saw enrichment for antigen presentation and apoptosis features in the superficial layer (table S5). In addition, the superficial layer contained the lowest proportion of cells in S phase or G2-M phase, further supporting that superficial layer epithelium was most likely maintained by migration and proliferation from other layers (fig. S2B).

Subcluster identification within regenerating basal epithelial cells revealed two subgroups that represented different functionalities during regeneration, one labeled by distally distributed fgf24, while the other by proximally distributed lef1 (fig. S5, A to C) (26, 27). We compared expression profiles between group I (distal) and group II (proximal) cells and found that their suggested functionalities were consistent with their expected roles in regeneration: The distal subgroup (or distal wound epidermis) up-regulated genes associated with extracellular matrix degradation, and the proximal subgroup (or proximal wound epidermis) up-regulated genes associated with organization of extracellular matrix, skeletal system development, and negative regulation of locomotion (fig. S5, D and E). In addition, the increase of proximal cell proportion was accompanied by the decrease of distal cell proportion, suggesting that basal layer epithelium become gradually active in promoting blastema proliferation and differentiation during the initial regeneration process (fig. S5C). To confirm the distribution of these cells, we performed RNA in situ hybridization targeting two candidate genes, stmn1b and sema3b, one from each cluster. The expression of stmn1b was first observed at the basal layer of the wound epidermis at 1 dpa but diminished as regeneration proceeded (fig. S4, I to K). On the contrary, sema3b showed expression at later stages and was enriched in the relatively proximal portion of the basal layer epithelium (fig. S4, L to N). The expression dynamics of these two genes matched the predicted proportion changes of the two clusters (fig. S5C). While sema3b was more restricted to the basal layer, stmn1b showed low expression levels in the intermediate layer as well, potentially suggesting that this subpopulation could be labeling cells transitioning from the basal layer to the other layers of epithelium.

We next performed subcluster analysis within the hematopoietic cluster and found four subpopulations (Fig. 4, A to C and table S6). The first three populations were enriched for the macrophage marker mpeg1.1, with the cluster H1 being M1-like (lgals2+ and lcp1+) and the cluster H3 M2-like (ctsc+ and lgmn+) (Fig. 4D) (12). We speculated that the cluster H2 represented a transition state between M1-like and M2-like or a state before the macrophages differentiate toward M1-like or M2-like. From 1 to 4 dpa, the proportion of M1-like macrophages remained at a constant level, while that of M2-like macrophages expanded (Fig. 4B), potentially suggesting a shift in the function of macrophages in the new regenerates from pro-inflammatory toward anti-inflammatory as regeneration proceeded. Macrophages are important for proper blastema proliferation (28). The change in the proportions of M1/M2-like macrophage in our data matched with that observed in the larvae fin, suggesting that the adults followed a similar rule for immune cell recruitment after injury.

(A) Subcluster assignments of the hematopoietic cells. Cells were plotted on UMAP axes. The same color code is used for (B) to (D). (B) Proportion of subgroups of hematopoietic cells. (C) Expression enrichment of the top 30 differentially expressed genes in the four subclusters within hematopoietic cluster shown as a heatmap. (D) Expression distribution of genes associated with macrophage activation grouped by subclusters. Expression levels were log normalized by Seurat. y axis: cluster identity. z axis: cell density. (E) Expressions of pigment cell markers gch2 and mlpha in the hematopoietic population.

The cluster H4 enriched for genes including mlpha and gch2, both well-characterized markers for the chromatophore lineages in zebrafish (Fig. 4E) (29). Chromatophores are derived from neural crest lineage, yet here, they clustered with macrophages that were from hematopoietic lineage. One possibility is that this clustering result could be driven by features related to antigen presentation via MHC class II, a feature of pigment cells based on studies using human melanocytes (30). The proportion of this cluster decreased as regeneration started, agreeing with the known pattern of fin stripe recovery after amputation (Fig. 4B) (31).

To understand the component and function of the cells in the mesenchymal cell cluster before and during fin regeneration, we focused on genes enriched in this cluster and found previously identified blastema marker genes that are required for fin regeneration, including the muscle segment homeobox family members msx1b and msx3 and the insulin-like growth factor signaling ligand igf2b (logFC, >0.25; minimum percentage, >25%; and adjusted P value of <1 105, as listed in table S1) (2, 13). The mesenchymal cluster expressed these genes nearly exclusively, confirming their blastema identity in regenerating stages (fig. S6A). In addition, we found key genes involved in zebrafish bone development and regeneration: twist1a, the transcription factor that controls the skeletal development by regulating the expression of runx2 (14); cx43, the gap junction protein required for building the fin ray up to the right length; and hapln1a and serpinh1b, two genes downstream of cx43 (32, 33). By performing conserved marker analysis using Seurat, we found that msx1b and twist1a were also among the markers conserved across all stages, underscoring shared features that existed between regenerating and preinjury mesenchymal cells (maximum P values across stages: 4.72 1010 and 2.84 109 for msx1b and twist1a, respectively). This theme of building and supporting bone tissues in mesenchymal cells was not only reflected by a handful of genes: GO analysis of all the detected up-regulated genes in this cluster revealed significant enrichment of genes associated with GO terms, including fin regeneration (GO:0031101) and skeletal system development (GO:0001501) (fig. S6B). When more stringent criteria for differential expression were used, genes were also significantly enriched for GO terms, including skeletal system morphogenesis (GO:0048705) and extracellular matrix organization (GO:0030198) (fig. S6C).

Previous work has shown that blastema comprises bone cells and non-bone cells but has not defined the cell types and the regeneration process of each type (23, 34, 35). To better understand the regeneration process by cell type, we performed clustering analysis within the mesenchymal cluster and identified nine distinct subgroups (Fig. 5A and fig. S6D). Of the two preinjury subgroups, M-2 represented the mature bone lineage, which was enriched for expressions of bglap, mgp, and sost (fig. S6E) (36, 37). Comparing to M-2, cluster M-1 presented low expression levels of bglap, mgp, and sost and high expression levels of a group of other genes, including fhl1a, fhl2a, and tagln (fig. S6E). Mammalian orthologs of these genes are required for chondrogenesis and osteogenesis, leading us to speculate that cluster M-1 could represent the supporting non-bone cell lineage in the preinjury state (38, 39).

(A) Subclustering assignments of mesenchymal cells shown on UMAP axes. Cells are colored by their cluster assignments and connected by Slingshot-reconstructed trajectories. Lineage 1: 1-2-3-4; lineage 2: 1-2-3-5-6; lineage 3: 1-2-3-5-7-8; lineage 4: 1-2-3-5-9. (B) By-lineage highlighting of mesenchymal cells. Cells with colors other than gray represent the cells included in each corresponding lineage in (A). (C) Expression distribution of genes labeling cell lineages and cell states in mesenchymal cells. Gene feature plots were connected by estimated lineages using the same lineage color code as in (A). (D to G) In situ hybridization targeting the tnfaip6 gene in (D) preinjury, (E) 1-dpa, and [(F) and (G)] 4-dpa fin tissues. Brown dots indicate positive RNA signals from target genes, while pale blue blocks represent hematoxylin-stained cell nuclei. A zoomed-in view for the region inside the focused rectangle is provided within (D). (G) Zoomed-in view for the region highlighted by a rectangle in (F). Dotted lines indicate the amputation plane. All scale bars, 100 m.

The remaining seven populations came from regenerates. Pseudotime analysis via Slingshot (40) suggested that these subgroups formed four trajectories, all initiated from the tnfaip6+ cluster (M-3), which was composed mainly of 1-dpa cells (Fig. 5, B and C, and fig. S6D). tnfaip6 was ranked top by an adjusted P value in the differentially expressed genes labeling the regeneration initiation cluster and was also expressed exclusively in the mesenchymal cluster (Fig. 5C and fig. S6A). The mammalian ortholog of this gene is required for proliferation and proper differentiation of mesenchymal stem cells (MSCs) and balances the mineralization via osteogenesis inhibitions (41). The expression of tnfaip6 in the postinjury zebrafish fin suggested that it could also be required in the early stages of regeneration for promoting mesenchymal proliferation. To confirm the expression pattern of tnfaip6, we performed RNA in situ hybridization for uninjured and regenerating fin tissues targeting this gene (Fig. 5, D and E). In the uninjured fin, tnfaip6 was expressed in a segmental pattern, presumably enriching at joints between bone segments. At 1 dpa, tnfaip6 was expressed not only near the bony rays but also in the cavity, showing a general activation in the mesenchymal population. As regeneration proceeded from 1 to 4 dpa, mesenchymal cells divided into cdh11+ (M-4) and tph1b+ (M-5) branches, with the latter further divided into mmp13a+ (M-6), tagln+ (M-7), and vcanb+ (M-9) branches (Fig. 5C and fig. S6D). The mmp13+ (M-6) cluster maintained a high-level tnfaip6 expression, whereas all other branches had a lower but detectable tnfaip6 expression. This was consistent with the observation we made from in situ hybridization at 4 dpa targeting tnfaip6: the broad expression in the mesenchymal population and segmental enrichments similar to that in the uninjured fin (Fig. 5, F and G).

The four trajectories initiated from the tnfaip6+ cluster revealed four putative lineages representing bone and non-bone cells in the blastema. cdh11+ lineage 1 specifically expressed runx2 and osterix/sp7, which are the key transcription factors regulating osteogenesis (fig. S6E) (42). Mammalian ortholog of cdh11 could induce Sp7-dependent bone and cartilage formation in vivo, suggesting that the cdh11+ branch in the blastema represented the regenerating osteoblasts (43). Genes highly expressed at the end of this lineage (M-4) compared to the initiation point (M-3) were associated with bone mineralization and skeletal system development, further supporting their bone cell identity (table S7).

Mesenchymal cells outside the osteoblast branch shared enrichment for tph1b and aldh1a2 expressions at 2 dpa, followed by and1 expression at 4 dpa (Fig. 5C and fig. S6F). These three genes had been suggested to label joint fibroblasts, fibroblast-derived blastema cells, and actinotrichia-forming cells in the blastema, respectively (34, 35, 44). However, their expression signatures implied that instead of labeling separate populations in the blastema, they might be labeling different states of the same non-osteoblastic cells at the early stage of fin regeneration.

Upon 4 dpa, these non-osteoblastic cells diverged into three groups (Fig. 5C and fig. S6D). To understand this separation, we performed differential expression analysis for each branch between cells at the end of the lineage tree (lineage 1, M-4; lineage 2, M-6; lineage 3, M-7 and M-8; and lineage 4, M-9) and cells in the initiation cluster (M-3). Genes highly expressed at the lineage end points were included for GO analysis for functional predictions (logFC, >0.25; minimum percentage of >25%; and adjusted P value of <0.01). These three lineages were also associated with skeletal system development or extracellular matrix organizations as were the bone cell lineage; however, the association was driven by a nearly completely different set of genes (table S7). Unlike the osteoblast lineage, none of these three non-bone cell lineages showed enrichment for bone mineralization, suggesting that these cells might indirectly contribute to bone formation. In lineage 2, top differentially expressed genes mmp13a and ogn both have mammalian orthologs that are associated with bone formation (Fig. 5C and fig. S6F) (45, 46). In addition, this lineage presented up-regulation of DLX family genes, especially dlx5a, suggesting the reactivation of fin outgrowthrelated developmental programs during regeneration (fig. S6F and table S7) (47). Lineages 3 and 4 both enriched for estrogen response and expressed the retinoic acid (RA) synthesis gene aldh1a2. However, only lineage 3 displayed up-regulation of the RA-degrading enzyme cyp26b1 (fig. S6F and table S7). The cyp26b1high-aldh1a2low pattern helped to reduce RA levels in the blastema, promoting redifferentiation of the osteoblasts (44). The differentiation-promoting signature was also reflected in the enrichment of genes, including col6a1 and tagln, whose mammalian orthologs are essential for bone formation (fig. S6F and table S7) (39, 48). These genes were also enriched in the preinjury non-bone cell population, suggesting a connection between this subset of the non-bone cells and their preinjury counterparts (Fig. 5C and fig. S6F). Top up-regulated genes in lineage 4, on the other hand, were main contributors of the extracellular matrix, including and1/2, loxa, and vcanb (35, 49, 50). Enriched expression of these genes suggested that this lineage could be responsible for creating and organizing the fibrous environment. Together, the various non-osteoblastic cells could potentially work collaboratively with the osteoblasts in creating the environment for bone tissue regeneration.

Genes that had been suggested to label progenitors contributing to fin regeneration (mmp9 and cxcl12a) and several orthologs of known mammalian MSC markers (lrrc15, prrx1a/b, and pdgfra) (6, 7, 51, 52) were expressed almost exclusively in the mesenchymal cluster (fig. S6A). Consistent with the observations made in the lineage-tracing study, the mmp9 expression was associated with the regenerating bone cell lineage (lineage 1; Fig. 5B and fig. S6E) (7). However, mmp9 was detected only in a small portion of the mesenchymal cells and was highly expressed in the basal epithelium cells at similar proportions. On the other hand, we observed coenrichment of cxcl12a (previously known as sdf-1) and orthologs of the known mammalian MSC markers in the preinjury population (fig. S6E). cxcl12a-expressing cells in zebrafish were found to carry osteogenic, adipogenic, and chondrogenic characteristics in vitro like MSCs would do and contributed to the mesenchyme of the newly developing bony rays during fin regeneration (6, 53). The coenrichment pattern suggested that some of the preinjury cxcl12a-expressing cells could be MSCs in the fin tissue, which contribute to fin regeneration.

Zebrafish caudal fin is a unique regeneration system to model the injury response and regeneration of vertebrate appendages despite being a simple structure without muscular and adipose tissues. Major components of the regenerating caudal fin are epithelial cells covering the wound site and blastemal cells producing the connective tissue and bone matrices. Early studies established that actively proliferating blastema is the key to regeneration. Formed by cell migration and proliferation, this layer of cells continues in outgrowth and differentiation, rebuilding the complex body structure. Despite efforts in understanding its importance, basic questions regarding the formation of blastema remained: (i) Which type of cells contributes to the blastema and (ii) how do they shape the regeneration process?

Using single-cell transcriptomes, we defined cell types in both preinjury and postinjury fin tissues. Although regenerating cells were drastically different from their preinjury counterparts, both stage-specific and integrated clustering analysis revealed the same major cell type compositions in the fin tissues regardless of their time of collection. Common cell types detected include epithelial cells from all three layers, hematopoietic cells, and mesenchymal cells. Our data lay a foundation for lineage-targeted analysis to investigate the role of epithelial layers and subtypes in fin regeneration.

For each cell type to be a consistent component in the regenerated fin, cell cycle entry is required. We found that both common and unique cell cycle programs activated in the regenerating fin, with the shared ones appearing to be more evolutionarily conserved than the unique ones. Among the genes showing cell typespecific S phase enrichment, several immunoproteasome subunits also showed a clear cell typespecific expression. We speculated that the increasing level of immunoproteasome subunits in epithelial and hematopoietic cells specifically might accelerate antigen processing and presentation, which could be important for immune cell recruitment and tumor necrosis factorinduced blastemal proliferation (54).

Epithelial cells were the most abundant cell type in the profiled fins and could be clustered into four different subgroups, including the three layers in the adult fish epithelium and the mucosal-like cells within the intermediate layer. However, markers labeling these layers did not perform well in separating cell groups when only regenerating cells were considered. An unbiased differential expression test suggested that some members of the krt and cldn families were expressed in specific layers more consistently throughout regeneration. RNA in situ hybridization targeting cldne, krt1-19d, cldna, krt94, cldni, and cldn1 confirmed their exclusive layer-specific expression pattern, underscoring their potential to serve as markers for the distinct epithelial layers during regeneration. Our epithelium-specific analysis suggested that basal layer epithelial cells proliferate and could be the main source for replenishing the other two layers of the epithelium, similar to findings in a previous study based on genetic lineage tracing in zebrafish and echoing findings made using the axolotl limb regeneration model (25, 55). We observed higher apoptosis and lower proliferation features in the superficial epithelial layer compared to the other layers. At the same time, we observed transition patterns in gene expression, connecting the basal to the intermediate and the superficial layer during regeneration.

The behavior of mucosal-like cells during regeneration had been rarely reported for zebrafish in literature. We found in this study that this group of cells was an integral part of the regeneration process. Enrichment of foxp1b in this population and enrichment of foxp4 in basal and intermediate epithelial cells supported that zebrafish foxp homologs could be involved in regulating agr2 expression as does the Fox family in mice and, furthermore, the mucin production in the epithelium during regeneration (Fig. 1E) (56). The protein encoded by amphibian homologs of agr2, nAG (from newts) and aAG (from axolotl), are necessary and sufficient for salamander limb regeneration (57, 58). They are expressed in both dermal glands and the nerve sheaththe pattern of which has also been recovered from single-cell RNA sequencing (scRNA-seq) analysis (55). Regeneration deficiencies caused by denervation before amputation can be rescued by the ectopic expression of nAG. Although we do not have data supporting the nerve sheath expression pattern, as shown for the amphibian models, we hypothesize that agr2 could similarly mediate neuronal signals in zebrafish during regeneration.

Macrophages are critical players in the zebrafish caudal fin regeneration (28, 54). We observed subgroups of the mpeg1.1+ macrophage population in the regenerating fin tissue, resembling M1 and M2 macrophages in mammalian systems. However, we were not able to recover other immune cell population in the hematopoietic cells. This could potentially be due to the systematic bias against certain cell types during tissue dissociation and droplet incorporation in the microfluidic device. The same bias might also explain why we were not able to recover some other known players in the regenerating fin tissue, including neurons and endothelial cells (4). Increasing the number of cells sampled for scRNA-seq or performing scRNA-seq on sorted hematopoietic lineage cells would help to better understand the involvement of these populations in the regeneration process.

The expression profiles of mesenchymal cells captured from the postinjury stages resembled those of blastema in histology studies. We found four connected but distinct lineages representing both bone and non-bone cells in the blastema. All four lineages initiated from one cluster mostly consisted of 1-dpa cells and enriched for the tnfaip6 expression. A similar scenario has been observed in the axolotl limb regeneration model. By using scRNA-seq on a lineage-labeled axolotl model, Gerber et al. (58) found that connective tissue cells funnel into a progenitor state at initiation. Whether the cluster identified in our study represented a shared cell origin for the blastema or a shared state across mesenchymal cell types in the initial blastema-formation stage requires further investigation. High proportion of epithelial population in the fins could also hamper the discovery of relatively rare population with multipotency. Finer dissection before single-cell profiling might help in future study designs in capturing these populations.

While the bone cell lineage has been well studied in the regenerating fin, non-bone cells had been labeled by different markers and given different names and their intercorrelations left to be clarified. We found that tph1b, aldh1a2, and and1/and2 genes were shared among the non-bone cell lineages and could be labeling states instead of types of blastemal cells during regeneration. Meanwhile, differential analysis revealed similar enrichment for bone formation in all lineages yet distinct associations with reactivation of developmental programs, RA signaling, and collagen metabolism, underscoring their collaborative and complementary roles in the regeneration process.

Our scRNA-seq data also provided more details about the fish system we are working with. For all sample collections, we used the transgenic strain Tg(sp7:EGFP)b1212, which specifically labels osteoblast lineage in the fish (59). It was reported that green fluorescence signal could be detected in the fish skin after 72 hours post-fertilization. This ectopic expression, however, does not interfere with confocal imaging of skeletal structures of fish at any stage due to the fact that they lie in different planes of focus. What these cells are and why they expressed the transgene were unclear. In this study, we obtained a holistic view of the transgene expression pattern in the fin region regardless of whether that was associated with the cell type of interest, i.e., osteoblasts in this context. Unsupervised clustering on the expression profiles from single fin cells suggested that green fluorescent protein (GFP) is not only expressed in the mesenchymal but also highly enriched in the superficial layer epithelium (table S2). A closer examination of this classic reporter gene construct revealed that the regulatory region of sp7 used for the construction of the transgene did not exactly represent the endogenous sp7 regulatory region. Tg(sp7:EGFP)b1212 was generated from bacterial artificial chromosome transgenesis using CH73-243G6 as the backbone, which did not contain the first exon of sp7 according to the annotation of the current genome assembly (chr6:58630884-58720045 and GRCz10), leading to the usage of a regulatory sequence different from the endogenous version. Whether this usage difference contributed to the ectopic expression pattern of the transgene requires further study. This finding points to the potential of using single-cellbased approaches in reporter line validation and more thorough analysis of the transgene behavior.

All zebrafish were used in accordance with protocol no. 20190041 approved by the Washington University Institutional Animal Care and Use Committee. Wild-type and Tg(sp7:EGFP) strains are maintained under standard husbandry in the Washington University Fish Facility, with the system water temperature at 28.5C and a day-night cycle controlled as 14-hour light/10-hour dark. For fin amputation, we anesthetized 1-year-old fish with MS-222 (0.16 g/liter) in the system water and then removed the distal half of their caudal fin with sterilized razor blades. The fish were then sent back to circulating water system for recovery. We collected regenerating fin tissue from 39 fish by doing secondary fin amputation at the primary cutting plane with the same anesthesia and recovery procedures.

Collected fin tissues were digested by Accumax (Innovative Cell Technologies), filtered through 40-m cell strainers, and washed with 1 Dulbeccos phosphate-buffered saline (DPBS)0.04% bovine serum albumin to generate single-cell suspensions. Libraries were constructed from these cell suspensions following the instruction of the Chromium Single Cell Gene Expression Solution 3 v2 (10x Genomics) and were subsequently sequenced on HiSeq2500 (Illumina) with read lengths of 26 + 75 (Read1 + Read2). Raw reads were processed by Cell Ranger (10x Genomics) with default parameters for read tagging, alignment to zebrafish reference genome (GRCz10), and feature counting based on Ensembl release 91 (cellranger count). EGFP sequence was added into the reference genome as a separate chromosome for mapping reads from the reporter gene.

We performed unsupervised clustering using Seurat v3.0 following the procedure of normalization (SCTransform), highly variable gene detection, dimensional reduction (principal components analysis), and cells clustering (Louvain clustering at resolutions from 0.1 to 0.6) (17). For integrating the four stages in finding conserved cell types, we used the anchoring approach provided by Seurat v3. Cell clustering was based on the top principal components that account for most of the cell-cell variances. The same set of principal components was used in UMAP calculation for visualization as well.

We found differentially expressed genes in each cluster by comparing the expression profiles of them with those of the rest of the cells using Wilcoxon rank sumbased approach with the criteria of log fold change more than 0.25 and a minimum cell percentage of 0.25. The same criteria were applied to all pairwise comparisons, unless stated otherwise. We made functional connections between the list of differentially expressed genes and the type of cell that they most likely represent by testing for GO term enrichment (18) and manual curation by searching The Zebrafish Information Network database and PubMed. Certain cell clusters were taken as independent samples for secondary clustering following the same unsupervised clustering procedures.

We calculated the by-cell average expression level of a set of S phase or G2-M phase markers suggested by Seurat that are detected in our zebrafish dataset and normalized by subtracting aggregated expression of control genes. Although G1 phase cells are also within cell cycle, they are hardly separable from G0 cells. To avoid false-positive labeling for active cycling cells, we set stringent thresholds and only included cells with |S.score G2M.score| > 0.1 in the S or G2-M group, while cells with both S.score and G2M.score below zero as G1. Other cells were not included in this part of the analysis. Differentially expressed genes were also identified by Wilcoxon rank sumbased approach. These differentially expressed genes were considered to be cell cycle related if they were in the list of genes associated with R-DRE-1640170 Cell Cycle and/or cycling marker genes used for cell cycle phase score calculations.

We collected uninjured and regenerating fin tissues from casper (nacrew2/w2;roya9/a9) fish and fixed in 4% paraformaldehyde overnight (60). Fixed tissues were subsequently submerged in 10% sucrose in 1 PBS, 20% sucrose in 1 PBS, and 30% sucrose in 1 PBS for 4 hours each. After sucrose exchange, tissues were embedded in Optimal Cutting Temperature (O.C.T.) compound (Fisher Healthcare Tissue-Plus) and snap frozen on dry ice. The frozen tissue blocks were then processed into 15-m sections on a Leica CM1950 cryostat. We performed RNA in situ hybridization targeting krt4, cldne, krt1-19d, cldna, krt94, cldni, cldn1, agr2, sema3b, stmn1b, and tnfaip6 for mRNA detection using an RNAscope kit (Advanced Cell Diagnostics, Hayward, CA, USA). Alcian blue/periodic acidSchiff (PAS) staining was subsequently performed on the same section or separately on a consecutive serial section following the manufacturers protocol (Newcomer Supply). Microscopic images were taken by ZEISS Axio Observer.

Cell trajectories were constructed using Slingshot v1.3.1 (40). Through initial subclustering and cell type identifications, we found one subcluster with high epcam expression, potentially a doublet cell contamination from the major cell type classifications. We removed this group of cells from all downstream analysis within the mesenchymal cluster. We used UMAP embedding and subclustering assignments as input for the Slingshot calculation.

We performed nonparametric Wilcoxon rank sum test to identify differentially expressed genes across cell groups as implemented in Seurat. P values were adjusted by all features in the dataset using Bonferroni correction.

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Cellular diversity of the regenerating caudal fin - Science Advances

Bone Marrow Stem Cells Comments Off on Cellular diversity of the regenerating caudal fin – Science Advances | August 13th, 2020

According to latest research report on Global Stem Cell Banking Market report provides information related to market size, production, CAGR, gross margin, growth rate, emerging trends, price, and other important factors. Focusing on the key momentum and restraining factors in this market, the report also provides a complete study of future trends and developments in the market.

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In terms of geography, this research report covers almost all major regions around the world such as North America, Europe, South America, Middle East, Africa, and the Asia Pacific. Europe and North America are expected to increase over the next few years. Stem Cell Banking markets in the Asia-Pacific region are expected to experience significant growth during the forecast period. Advanced technology and innovation are the most important characteristics of North America and the main reason why the United States dominates the world market. The Stem Cell Banking market in South America is also expected to expand in the near future.

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Stem Cell Banking Market Applications, Types and Future Outlook Report 2020-2025 - Express Journal

Bone Marrow Stem Cells Comments Off on Stem Cell Banking Market Applications, Types and Future Outlook Report 2020-2025 – Express Journal | August 12th, 2020

TEL AVIV, Israel, Aug. 12, 2020 /PRNewswire/ -- Cellect Biotechnology Ltd. (NASDAQ: APOP), a developer of innovative technology which enables the functional selection of stem cells, today reported financial and operating results for the second quarter ended June 30, 2020. The Company's six-month progress includes the development of several strategic initiatives, including growth-oriented opportunities in pain management and COVID-19 related therapeutics.

"Despite the COVID-19 pandemic business disruptions and the near-term delays to completing and commencing our clinical programs in Israel and the U.S., respectively, we acted swiftly over the past few months to leverage our sought-after technology to create several long-term business initiatives to enhance our value," commented Dr. Shai Yarkoni, Chief Executive Officer. "In addition to pursuing a potential merger with a global leader in the high growth medical-grade cannabis market, which is being delayed due to COVID-19, we have either initiated or are contemplating other business development activities that will greatly benefit from our innovation, technology and know-how. I believe each of these opportunities represents meaningful catalysts for Cellect in multi-billion-dollar markets, subject to resolution of the COVID-19 pandemic and return to normal course of business."

Notwithstanding the continued delays due to COVID-19, the Company remains focused on the following operational and clinical objectives:

The Company's cash and cash equivalents totaled $7 million as of June 30, 2020, which includes the approximately $1.5 million (gross before expenses)resulting from several investors exercising certain warrants that were issued in February 2019.

SecondQuarter 2020 Financial Results:

*For the convenience of the reader, the amounts above have been translated from NIS into U.S. dollars, at the representative rate of exchange on June 30, 2020 (U.S. $1 = NIS 3.466).

About Cellect Biotechnology Ltd.

Cellect Biotechnology (APOP) has developed a breakthrough technology, for the selection of stem cells from any given tissue, that aims to improve a variety of stem cell-based therapies.

The Company's technology is expected to provide researchers, clinical community and pharma companies with the tools to rapidly isolate stem cells in quantity and quality allowing stem cell-based treatments and procedures in a wide variety of applications in regenerative medicine. The Company's current clinical trial is aimed at bone marrow transplantations in cancer treatment.

Forward Looking Statements

This press release contains forward-looking statements about the Company's expectations, beliefs and intentions. Forward-looking statements can be identified by the use of forward-looking words such as "believe", "expect", "intend", "plan", "may", "should", "could", "might", "seek", "target", "will", "project", "forecast", "continue" or "anticipate" or their negatives or variations of these words or other comparable words or by the fact that these statements do not relate strictly to historical matters. For example, forward-looking statements are used in this press release when we discuss Cellect's expectations regarding timing of the commencement of its planned U.S. clinical trial and its plan to reduce operating costs. These forward-looking statements and their implications are based on the current expectations of the management of the Company only and are subject to a number of factors and uncertainties that could cause actual results to differ materially from those described in the forward-looking statements. In addition, historical results or conclusions from scientific research and clinical studies do not guarantee that future results would suggest similar conclusions or that historical results referred to herein would be interpreted similarly in light of additional research or otherwise. The following factors, among others, could cause actual results to differ materially from those described in the forward-looking statements: the Company's history of losses and needs for additional capital to fund its operations and its inability to obtain additional capital on acceptable terms, or at all; the Company's ability to continue as a going concern; uncertainties of cash flows and inability to meet working capital needs; the Company's ability to obtain regulatory approvals; the Company's ability to obtain favorable pre-clinical and clinical trial results; the Company's technology may not be validated and its methods may not be accepted by the scientific community; difficulties enrolling patients in the Company's clinical trials; the ability to timely source adequate supply of FasL; risks resulting from unforeseen side effects; the Company's ability to establish and maintain strategic partnerships and other corporate collaborations; the scope of protection the Company is able to establish and maintain for intellectual property rights and its ability to operate its business without infringing the intellectual property rights of others; competitive companies, technologies and the Company's industry; unforeseen scientific difficulties may develop with the Company's technology; the Company's ability to retain or attract key employees whose knowledge is essential to the development of its products; and the Company's ability to pursue any strategic transaction or that any transaction, if pursued, will be completed. Any forward-looking statement in this press release speaks only as of the date of this press release. The Company undertakes no obligation to publicly update or review any forward-looking statement, whether as a result of new information, future developments or otherwise, except as may be required by any applicable securities laws. More detailed information about the risks and uncertainties affecting the Company is contained under the heading "Risk Factors" in Cellect Biotechnology Ltd.'s Annual Report on Form 20-F for the fiscal year ended December 31, 2019 filed with the U.S. Securities and Exchange Commission, or SEC, which is available on the SEC's website, http://www.sec.gov, and in the Company's periodic filings with the SEC.

Cellect Biotechnology Ltd.

Consolidated Statement of Operation

Convenience

translation

Six months

ended

Six months ended

Three months ended

June 30,

June 30,

June 30,

2020

2020

2019

2020

2019

Unaudited

Unaudited

U.S. dollars

NIS

(In thousands, except share and per

share data)

Research and development expenses

837

2,901

7,086

1,364

3,564

General and administrative expenses

1,356

4,703

5,064

2,116

2,709

Operating loss

2,193

7,604

12,150

3,480

6,273

Financial expenses (income) due to warrants exercisable into shares

1,098

3,807

(7,111)

4,697

(5,919)

Other financial expenses (income), net

(15)

(55)

880

627

462

Total comprehensive loss

3,276

11,356

5,919

8,804

816

Loss per share:

Basic and diluted loss per share

0.010

0.034

0.029

0.024

0.004

Weighted average number of shares outstanding used to compute basic and diluted loss per share

338,182,275

338,182,275

200,942,871

365,428,101

224,087,799

Cellect Biotechnology Ltd.

Consolidated Balance Sheet Data

Convenience

translation

June 30,

June 30,

December 31,

2020

2020

2019

Unaudited

Unaudited

Audited

U.S. dollars

NIS

(In thousands, except share and per

share data)

CURRENT ASSETS:

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Cellect Biotechnology Reports Second Quarter Financial and Operating Results; First Half 2020 Strategic Developments Create Long-Term Revenue...

Bone Marrow Stem Cells Comments Off on Cellect Biotechnology Reports Second Quarter Financial and Operating Results; First Half 2020 Strategic Developments Create Long-Term Revenue… | August 12th, 2020

With the help of a huge 66M Series A round last week, the German startup T-knife is developing cancer T-cell immunotherapies with the help of genetically modified mice. However, this is just one of several cancer T-cell therapy startups making advances this year, with other innovations including off-the-shelf treatments and a potential universal cancer therapy.

The rise of Chimeric Antigen Receptor (CAR) T-cell immunotherapy was a major step forward in the treatment of cancer. CAR T-cell therapy consists of bioengineering a patients immune T cells to produce proteins called CARs. These proteins recognize targets on the surface of cancer cells, letting the T-cells destroy them. However, CAR T-cell therapy is also limited against solid tumors since many cancer targets lie within the cancer cells, beyond the reach of the CAR proteins.

In the last few months, European startups have been making advances in T-cell receptor (TCR) T-cell immunotherapies, which could be better than CAR T-cells at hunting down solid tumors. This is because the protein that is genetically modified on TCR T cells the TCR can recognize targets hidden inside cancer cells by scanning a protein on the cell surface called human leukocyte antigen (HLA).

Last week, the Berlin-based T-knife brought TCR T-cell therapies into the spotlight with a huge 66M Series A round. With the proceeds, the startup aims to take a radical approach to developing TCR T-cell therapies.

While most TCR T-cell therapy developers tweak existing human TCRs in their cell therapies, T-knife sources its cancer-hunting TCRs from mice. The firm genetically modifies mice to produce fully humanized T-cell receptors and injects them with human tumor antigens. The immune system of the mice then reacts to the cancer antigens and produces a variety of T-cell receptors. After picking the best cancer-seeking T-cell receptors from the mouse immune system, T-knife then expresses them in the patients T cells to produce the cell therapy.

The mouse immune system is not tolerant of human tumor antigens it sees them like a virus or a pathogen. Thus we can generate a strong immune response in the mice when we immunize them with human tumor antigens, Elisa Kieback, CEO and co-founder of T-knife, told me.

According to Kieback, the companys mouse-derived TCRs can latch onto cancer antigens more strongly and specifically than those of established TCR T-cell therapy biotechs such as Immatics and Adaptimmune. We are letting the mice select the best TCR via a very natural in vivo selection mechanism which means they are less likely to have off-target reactivity, she said.

T-knife exited stealth mode with the Series A round, which was led by the investment firms Versant Ventures and RA Capital Management. The company has already initiated the clinical development of a myeloma treatment and plans to sponsor a solid tumor trial in late 2021.

One drawback of cell therapies based on genetically modifying the patients own T cells is that the process is complex, costly, and must be tailored to each patient. To get around this issue, several European startups have been developing TCR T-cell therapies that use donor immune cells in an off-the-shelf fashion, cutting the costs of the therapy.

One such company is the Norwegian startup Zelluna Immunotherapy, which raised 7.5M in equity funding and grants in June. The company aims to develop a TCR T-cell therapy based on cancer-hunting immune cells called natural killer cells. The company sees these cells as well suited for making off-the-shelf therapies since they have a lower risk of attacking the patients healthy tissue than T cells and are faster at killing cancer cells.

Another off-the-shelf TCR T-cell therapy in the works is being developed by the Dutch biotech Gadeta, which appointed a new CEO in April. It is working with the US company Kite Pharma to engineer T cells that produce TCRs from a rare type of T cell called gamma delta T cells. The TCRs from gamma delta T cells are better at recognizing stress signals on cancer cells than those of the more common type of T cells, called alpha beta T cells.

Gadetas platform combines the key features ofalpha beta T cells, such as the high proliferation and memory capacity, with the anti-tumor specificity and activity of selectedgamma delta receptors, Marco Londei, the companys new CEO, told me. This novel T cell platform is perfectly placed for possible allogeneic off-the-shelf use.

Gadeta is currently preparing to enter phase I testing for the treatment of multiple myeloma.

TC Biopharm has also hinted at promising progress with its own off-the-shelf cancer cell immunotherapy. The Scottish startup collects gamma delta T cells from young, healthy donors and makes them produce CAR proteins like a CAR T-cell therapy.

In some patients, the innate ability to hunt and kill cells is compromised either because of the cancer itself, other pathologies or age, Michael Leek, CEO of TC BioPharm, explained.

This is no ordinary CAR T-cell therapy, however. TC BioPharm also uses the gamma delta T cells TCRs as a safety catch to avoid destroying healthy cells that happen to show a cancer target. The CAR protein recognizes a cancer target on the cell surface, but the gamma delta TCR only allows the cell therapy to kill cells that show signs of stress from cancer. This could make it much safer than current CAR T-cell therapies.

TC BioPharm initiated a phase I clinical trial for the treatment of the blood cancer acute myeloid leukemia last year. The trial has progressed well; all qualifying patients saw a marked response to treatment with reduction of their tumor burden, Leek told me. We hope to progress this therapy to market around 2021-22.

In addition to cancer, TC BioPharm has also joined a growing list of immuno-oncology companies testing the potential of its technology for the treatment of Covid-19, launching a phase I trial in July.

Though TCR T-cell therapies can target more types of cancer than CAR T-cell therapies, they still tend to be specific to particular types of cancers, and ineffective against others. One cancer entity is oftentimes much more heterogeneous than initially thought, Kai Pinkernell, CMO of Munich-based Medigene, told me. Could such a therapy target more than one cancer type?

In June, Medigene initiated a phase I clinical trial of a TCR T-cell therapy candidate for a diverse range of blood cancers. The treatment is designed to hit a target that they all have in common called HA-1. The trial is testing the treatment in patients that recently received a bone marrow stem cell transplant, but whose blood cancer has relapsed.

[Our therapy] would improve the current gold-standard approach, being stem cell transplantation. Interestingly, this could work in many different diseases that were the reason for the transplant, Pinkernell explained.

Another TCR T-cell therapy player aims to go even further with widening the range of treatments. In January, the London-based Ervaxx recently rebranded as Enara Bio entered a partnership agreement with the University of Cardiff to overcome a common limitation of TCR therapies: the HLA molecules that TCRs scan vary widely between patients, so TCR T-cell therapies need to be personalized to different patients.

To get around this obstacle, Enara Bio and a research group led by Andrew Sewell, Professor of Immunology at Cardiff University, are developing a type of TCR T-cell therapy that doesnt scan HLA, but rather a protein called MR1, which is the same from patient to patient and is found on a wide range of cancer cells.

We have various T-cell receptors that respond to most cancers without the need for a specific human leukocyte antigen that we are exploring, Sewell told me.

By accessing a wide range of cancers and patients, this cancer immunotherapy could work universally with no need for personalization. The team aims to test the therapy in humans at the end of this year.

While a universal cancer therapy is an intriguing concept, Pinkernell thinks that we should be cautious in our expectations of seeing such a therapy. The timing of the drug in the therapy of a cancer, or best window of application is not easy to find, he said.

T-knifes Kieback echoed the skepticism. For now, rather highly tumor-, target-, and patient-specific therapies will be required and emerge, she said. Londei of Gadeta agreed and pointed out the complexity of cancer disease development. Key challenges are understanding how tumors escape immunotherapies and how to find combination therapies to overcome this problem, for different types of tumors, he added.

Sewell has a slightly more optimistic take. I think it is a bit strong to say that there is potential for universal therapies, but we can definitely build T cells that recognize most cancers from all individuals. I feel that there is a prospect for immunotherapy to be successfully treating most cancers within the next 25 years.

Part of the reason for the unclear potential of TCR T-cell therapy is that it is at an early stage in the clinical pipeline. The most advanced TCR T-cell therapy programs havent yet gone beyond phase II, such as that of Adaptimmunes lead candidate. However, the size of T-knifes recent Series A round demonstrates that investors are interested in the future of the technology, so its going to be worth keeping an eye on the TCR T-cell startup scene in the coming years.

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Stem Cell Therapy Market is expected to reach 202.77 billion by 2026 from XX billion in 2018 at CAGR of XX %.REQUEST FOR FREE SAMPLE REPORT:https://www.maximizemarketresearch.com/request-sample/522

Stands for use of stem cells to treat or prevent disease or condition.Bone marrow transplant and some therapies derived from umbilical cord blood are mainly used in stem cell therapy. Advancement, in order to establish new sources for stem cells, and to apply stem-cell treatments for neurodegenerative diseases and conditions such as diabetes, heart disease, and other conditions, are increased in recent years.

The report study has analyzed revenue impact of covid-19 pandemic on the sales revenue of market leaders, market followers and disrupters in the report and same is reflected in our analysis.

Stem Cell Therapy Market Researchers are making efforts to discover novel methods to create human stem cells. This will increase the demand as well as supply for stem cell production and potential investigation in disease management. Increasing investment & research grants for developing safe and effective stem cell therapy products, the growing patient base for target diseases, concentrated product pipelines, increasing approval of the new clinical trials, rapid technological advancement in genomics, and the rising awareness about the stem cell are expected to drive the growth of the Stem Cell Therapy solutions market during the forecast period.

However, improper infrastructure, insufficient storage systems, nascent technology in underdeveloped economies, Ethical issues related to an embryonic stem cell, low patient acceptance rate, Difficulty in the preservation of stem cell are expected to restrain the market growth. North America is expected to be the largest growing region by 2026; the reason behind that is extensive funding by Government. However, Emerging countries like India, china, Korea have low growth rate as compared to Developed regions in 2017 but increase in awareness about stem cell therapy will lead the Asia Pacific to generate a significant level of revenue by 2026.

Key Highlights of Stem Cell Therapy Market report

Detailed quantitative analysis of the current and future trends from 2017 to 2026, which helps to identify the prevailing market opportunities.Comprehensive analysis of factors instrumental in changing the market scenario, rising prospective opportunities, market shares, core competencies in terms of market development, growth strategies and identification of key companies that can influence this market on a global and regional scale.Assessment of Market definition along with the identification of key drivers, restraints opportunities and challenges for this market during the forecast period.Complete analysis of micro-markets with respect to individual growth trends, prospects, and contributions to the overall Stem Cell Therapy Solutions market.Stem Cell Therapy market analysis and comprehensive segmentation with respect to the Application, End users, Treatment, and geography to assist in strategic business planning.Stem Cell Therapy market analysis and forecast for five major geographies-North America, Europe, Asia Pacific, Middle East & Africa, Latin America, and their key regions.For company profiles, 2017 has been considered as the base year. In cases, wherein information was unavailable for the base year, the years prior to it have been considered.

Research Methodology:

The market is estimated by triangulation of data points obtained from various sources and feeding them into a simulation model created individually for each market. The data points are obtained from paid and unpaid sources along with paid primary interviews with key opinion leaders (KOLs) in the market. KOLs from both, demand and supply side were considered while conducting interviews to get an unbiased idea of the market. This exercise was done at a country level to get a fair idea of the market in countries considered for this study. Later this country-specific data was accumulated to come up with regional numbers and then arrive at a global market value for the stem cell therapy market.Key Players in the Stem Cell Therapy Market are:

Chiesi Farmaceutici S.P.A Are:Gamida CellReNeuron Group, plcOsiris Therapeutics, Inc.Stem Cells, Inc.Vericel Corporation.Mesoblast, Ltd.

Key Target Audience:

Stem Cell Associations and OrganizationsGovernment Research Boards and OrganizationsResearch and consulting firmsStem Cell Therapy Market InvestorsHealthcare Service Providers (including Hospitals and Diagnostic Centers)Stem Cell Therapeutic Product Manufacturing OrganizationsResearch LabsClinical research organizations (CROs)Stem Cell Therapy Marketing PlayersPharmaceutical Product Manufacturing CompaniesScope of the Stem Cell Therapy Market Report:

Stem Cell Therapy market research report categorizes the Stem Cell Therapy market based on Application, End users, Treatment, and geography (region wise). Market size by value is estimated and forecasted with the revenues of leading companies operating in the Stem Cell Therapy market with key developments in companies and market trends.Stem Cell Therapy Market, By Treatments:

Allogeneic Stem Cell TherapyAutologous Stem Cell Therapy

Stem Cell Therapy Market, By End Users:

HospitalsAmbulatory Surgical Centers

Stem Cell Therapy Market, By Application:

OncologyCentral Nervous System DiseasesEye DiseasesMusculoskeletal DiseasesWound & InjuriesMetabolic DisordersCardiovascular DisordersImmune System DisordersStem Cell Therapy Market, By Geography:

North AmericaEuropeAsia PacificMiddle East & AfricaLatin America

Available Customization:

With the given market data, Maximize Market Research offers customization of report and scope of the report as per the requirement

Regional Analysis:

Breakdown of the North America stem cell therapy marketBreakdown of the Europe stem cell therapy marketBreakdown of the Asia Pacific stem cell therapy marketBreakdown of the Middle East & Africa stem cell therapy marketBreakdown of the Latin America stem cell therapy market

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Latest released the research study on Global Orthopedic Regenerative Medicine Market, offers a detailed overview of the factors influencing the global business scope. Orthopedic Regenerative Medicine Market research report shows the latest market insights, current situation analysis with upcoming trends and breakdown of the products and services. The report provides key statistics on the market status, size, share, growth factors of the Orthopedic Regenerative Medicine. The study covers emerging players data, including: competitive landscape, sales, revenue and global market share of top manufacturers are Curasan, Inc., Carmell Therapeutics Corporation, Anika Therapeutics, Inc., Conatus Pharmaceuticals Inc., Histogen Inc., Royal Biologics, Ortho Regenerative Technologies, Inc., Swiss Biomed Orthopaedics AG, Osiris Therapeutics, Inc., and Octane Medical Inc.

Definition:

Orthopedic Regenerative Medicine strategy sends messages to the customers or subscribers in predefined schedule. However, other forms of media can also be used in Orthopedic Regenerative Medicine. It is the most common form of marketing as multiple messages can be sent in low costs. Orthopedic Regenerative Medicine is used to achieve business objectives such as increasing sales, maintaining communications with customers while saving the business time. Moreover, the users can personalize each of the email messages and increase conversion rate.

Market Drivers

Market Trend

Opportunities

Challenges

Detailed Segmentation:

By Procedure Cell TherapyTissue EngineeringBy Cell TypeInduced Pluripotent Stem Cells (iPSCs)Adult Stem CellsTissue Specific Progenitor Stem Cells (TSPSCs),Mesenchymal Stem Cells (MSCs)Umbilical Cord Stem Cells (UCSCs)Bone Marrow Stem Cells (BMSCs)By SourceBone MarrowUmbilical Cord BloodAdipose TissueAllograftsAmniotic FluidBy ApplicationsTendons RepairCartilage RepairBone RepairLigament RepairSpine RepairOthers

Analyst at CMI have conducted special survey and have connected with opinion leaders and Industry experts from various region to minutely understand impact on growth as well as local reforms to fight the situation. A special chapter in the study presents Impact Analysis of COVID-19 on Global Orthopedic Regenerative Medicine Market along with tables and graphs related to various country and segments showcasing impact on growth trends.

o North America (United States, Canada, and Mexico)

o Europe (Germany, France, UK, Russia, and Italy)

o Asia-Pacific (China, Japan, Korea, India, and Southeast Asia)

o South America (Brazil, Argentina, Colombia)

o Middle East and Africa (Saudi Arabia, UAE, Egypt, Nigeria, and South Africa)

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Strategic Points Covered in Table of Content of Global Orthopedic Regenerative Medicine Market:

Chapter 1: Introduction, market driving force product Objective of Study and Research Scope the Orthopedic Regenerative Medicine market

Chapter 2: Exclusive Summary the basic information of the Orthopedic Regenerative Medicine Market.

Chapter 3: Displaying the Market Dynamics- Drivers, Trends and Challenges of the Orthopedic Regenerative Medicine

Chapter 4: Presenting the Orthopedic Regenerative Medicine Market Factor Analysis Porters Five Forces, Supply/Value Chain, PESTEL analysis, Market Entropy, Patent/Trademark Analysis.

Chapter 5: Displaying market size by Type, End User and Region 2014-2019

Chapter 6: Evaluating the leading manufacturers of the Orthopedic Regenerative Medicine market which consists of its Competitive Landscape, Peer Group Analysis

Chapter 7: To evaluate the market by segments, by countries and by manufacturers with revenue share and sales by key countries (2019-2027).

Chapter 8 & 9: Displaying the Appendix, Methodology and Data Source

Finally, Orthopedic Regenerative Medicine Market is a valuable source of guidance for individuals and companies in decision framework.

Data Sources & Methodology

The primary sources involves the industry experts from the Global Orthopedic Regenerative Medicine Market including the management organizations, processing organizations, analytics service providers of the industrys value chain. All primary sources were interviewed to gather and authenticate qualitative & quantitative information and determine the future prospects.

In the extensive primary research process undertaken for this study, the primary sources Postal Surveys, telephone, Online & Face-to-Face Survey were considered to obtain and verify both qualitative and quantitative aspects of this research study. When it comes to secondary sources Companys Annual reports, press Releases, Websites, Investor Presentation, Conference Call transcripts, Webinar, Journals, Regulators, National Customs and Industry Associations were given primary weight-age.

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What benefits does CMI research study is going to provide?

Definitively, this report will give you an unmistakable perspective on every single reality of the market without a need to allude to some other research report or an information source. Our report will give all of you the realities about the past, present, and eventual fate of the concerned Market.

Thanks for reading this article; you can also get individual chapter wise section or region wise report version like North America, Europe or Southeast Asia.

About Author:

Coherent Market Insights is a global market intelligence and consulting organization focused on assisting our plethora of clients achieve transformational growth by helping them make critical business decisions. We are headquartered in India, having office at global financial capital in the U.S. Our client base includes players from across all business verticals in over 150 countries worldwide. We are uniquely positioned to help businesses around the globe deliver practical and lasting results through various recommendations about operational improvements, technologies, emerging market trends and new working methods.

Mr Raj ShahCoherent Market Insights 1001 4th Ave,#3200 Seattle, WA 98154, U.S.Phone +1-206-701-6702sales@coherentmarketinsights.com

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Covid-19 Impact on Global Orthopedic Regenerative Medicine Market Rapid Growth By 2019 2027 | Curasan, Inc., Carmell Therapeutics Corporation, Anika...

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METUCHEN, N.J., Aug. 10, 2020 /PRNewswire/ --Tevogen Bio announces a joint partnership with renowned bone-marrow transplant expertNeal Flomenberg, M.D., Professor and Chair of the Department of Medical Oncology at Thomas Jefferson University, with the intent to evaluate Tevogen' s proprietary antigen-specific T cell technology as a potential treatment for COVID-19 and influenza-A patients.

This collaboration aims to harness Tevogen's proprietary immunotherapy platform and Dr. Flomenberg's expertise and research prowess to investigate potential treatments for viral infections.

Dr. Flomenberg has been at the forefront of immunogenetics and immunology for more than four decades. "Tevogen's technology resonated with me as there have been several groups who have used T cells to treat patients after bone-marrow transplants. The idea of utilizing T cell therapies to potentially treat COVID-19 and other viruses is truly remarkable," Flomenberg said. "I'm enthusiastic about moving forward with an investigation of Tevogen's technologies."

Tevogen CEO Ryan Saadi, M.D., M.P.H., is leading the new biotech's efforts. "Our work has been to pioneer T cell therapies that can be abundantly and efficiently reproduced to develop an affordable and scalable cellular treatment for the biggest global health threats, including COVID-19, influenza, and a variety of cancers. We are very excited about Dr. Flomenberg's contribution to our efforts and hope to initiate our investigational study soon."

In addition to developing its potential therapies, Tevogen is committed to organizational and manufacturing efficiency. This should allow it to engage in affordable innovation to the benefit of all patients.

About Tevogen Bio

Tevogen Bio was formed after decades of research by its contributors to concentrate and leverage their expertise, spanning multiple sectors of the health care industry, to help address some of the most common and deadly illnesses known today. The company's mission is to provide curative and preventative treatments that are affordable and scalablein order to positively impact global public health.

About Dr. Neal Flomenberg

Dr. Neal Flomenberg is the Chairman of Medical Oncology at Jefferson University in Philadelphia and also heads the Hematologic Malignancies, Blood and Marrow Transplantation (BMT) Program. Throughout his more than four decades of practice, he has maintained a longstanding interest in the immunogenetics and immunology of stem cell transplantation, with the goal of making transplantation safer and more widely available. Dr. Flomenberg developed an approach to bone-marrow transplants that uses half-matched relatives as donors, a breakthrough that assures that the majority of blood and bone-marrow cancer patients can benefit from this potentially curative treatment.

Media Contacts:

Mark Irion[emailprotected]

Katelyn Petroka [emailprotected]

SOURCE Tevogen Bio

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His name means brave in Hindi. And for four year-old Veer Gudhka that couldnt be more appropriate.

For while the bubbly little boy might look fighting fit, he actually has just months to live.

Veer suffers from a rare blood disorder called Fanconi anaemia, which results in a decreased production of all types of blood cells.

But a stem cell donor will save his life.

In a heartfelt video message, the plucky toddler asks Sunday Mirror readers: Please be my life-saver? Will you be my superhero?

And today his family are appealing to those from BAME communities to help by signing up to the Anthony Nolan stem cell register.

Mum Kirpa and dad Nirav know the odds are stacked against them getting that all-important call because they are of Indian descent.

While 69 per cent of Northern European patients find the best possible stem cell match from a stranger, this drops to just 20 per cent for those with black, Asian or ethnic minority backgrounds.

Currently only two per cent of the population is on the UK stem cell register.

And with Asians making up just six per cent of the UK population, there is a smaller pool of potential donors.

Veer was diagnosed with the blood disorder last August, after he started suffering from extreme fatigue, and was referred for tests.

Doctors said he would need a stem cell transplant within three years for a chance of survival.

They hoped to buy Veer some time by putting him on steroids to boost his blood counts. But his condition has deteriorated fast.

Recent tests at Great Ormond Street Hospital in London show he now has just three to four months to find a donor.

Kirpa and Nirav were both tested, along with Veers six-year-old sister Suhani, but none of them were a match.

A search on the global stem cell register also drew a blank.

And his dad has been trying to encourage his fellow countrymen and women in India to join the register.

They have even signed up a female battalion of the Indian Army.

Kirpa, 37, from Harrow, London, said: We just feel so scared were going to lose our cheeky, amazing little boy. To look at Veer you wouldnt know hes critically ill.

Like his name, hes been brave from the start. Hes undergone countless tests and hospital visits but has had a constant smile on his face.

"He knows he needs a superhero to step forward, but his optimism and enthusiasm are infectious and keep us all going.

She added: Going on the register is incredibly quick and donating cells if you match someone in need is painless.

You can join the Anthony Nolan stem cell register today.

Nine out of 10 people donate their stem cells through the bloodstream in a simple IV process called peripheral blood stem cell collection.

One in 10 will have their stem cells collected via the bone marrow itself, while under general anaesthetic. Doctors transplant the new, healthy cells via the patients bloodstream, where they begin to grow and create healthy red blood cells, white blood cells and platelets.

A perfect match from a donor can mean a lifelong cure.

Veers dad Nirav, 40, said: I only learned about the Anthony Nolan stem cell register two years ago and even then I assumed it would involve long and painful procedures.

We need to raise awareness to save lives in every community.

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Global Cell Therapy Technologies Marketwas valued US$ 12 billion in 2018 and is expected to reach US$ 35 billion by 2026, at CAGR of 12.14 %during forecast period.

The objective of the report is to present comprehensive assessment projections with a suitable set of assumptions and methodology. The report helps in understanding Global Cell Therapy Technologies Market dynamics, structure by identifying and analyzing the market segments and projecting the global market size. Further, the report also focuses on the competitive analysis of key players by product, price, financial position, growth strategies, and regional presence. To understand the market dynamics and by region, the report has covered the PEST analysis by region and key economies across the globe, which are supposed to have an impact on market in forecast period. PORTERs analysis, and SVOR analysis of the market as well as detailed SWOT analysis of key players has been done to analyze their strategies. The report will to address all questions of shareholders to prioritize the efforts and investment in the near future to the emerging segment in the Global Cell Therapy Technologies Market.

The report study has analyzed revenue impact of covid-19 pandemic on the sales revenue of market leaders, market followers and disrupters in the report and same is reflected in our analysis.

Global Cell Therapy Technologies Market: Overview

Cell therapy is a transplantation of live human cells to replace or repair damaged tissue and/or cells. With the help of new technologies, limitless imagination, and innovative products, many different types of cells may be used as part of a therapy or treatment for different types of diseases and conditions. Celltherapy technologies plays key role in the practice of medicine such as old fashioned bone marrow transplants is replaced by Hematopoietic stem cell transplantation, capacity of cells in drug discovery. Cell therapy overlap with different therapies like, gene therapy, tissue engineering, cancer vaccines, regenerative medicine, and drug delivery. Establishment of cell banking facilities and production, storage, and characterization of cells are increasing volumetric capabilities of the cell therapy market globally. Initiation of constructive guidelines for cell therapy manufacturing and proven effectiveness of products, these are primary growth stimulants of the market.

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Global Cell Therapy Technologies Market: Drivers and Restraints

The growth of cell therapy technologies market is highly driven by, increasing demand for clinical trials on oncology-oriented cell-based therapy, demand for advanced cell therapy instruments is increasing, owing to its affordability and sustainability, government and private organization , investing more funds in cell-based research therapy for life-style diseases such as diabetes, decrease in prices of stem cell therapies are leading to increased tendency of buyers towards cell therapy, existing companies are collaborating with research institute in order to best fit into regulatory model for cell therapies.Moreover, Healthcare practitioners uses stem cells obtained from bone marrow or blood for treatment of patients with cancer, blood disorders, and immune-related disorders and Development in cell banking facilities and resultant expansion of production, storage, and characterization of cells, these factors will drive the market of cell therapy technologies during forecast period.

On the other hand, the high cost of cell-based research and some ethical issue & legally controversial, are expected to hamper market growth of Cell Therapy Technologies during the forecast period

AJune 2016, there were around 351 companies across the U.S. that were engaged in advertising unauthorized stem cell treatments at their clinics. Such clinics boosted the revenue in this market.in August 2017, the U.S. FDA announced increased enforcement of regulations and oversight of clinics involved in practicing unapproved stem cell therapies. This might hamper the revenue generation during the forecast period; nevertheless, it will allow safe and effective use of stem cell therapies.

Global Cell Therapy Technologies Market: Segmentation Analysis

On the basis of product, the consumables segment had largest market share in 2018 and is expected to drive the cell therapy instruments market during forecast period at XX % CAGR owing to the huge demand for consumables in cell-based experiments and cancer research and increasing number of new product launches and consumables are essential for every step of cell processing. This is further expected to drive their adoption in the market. These factors will boost the market of Cell Therapy Technologies Market in upcoming years.

On the basis of process, the cell processing had largest market share in 2018 and is expected to grow at the highest CAGR during the forecast period owing to in cell processing stage,a use of cell therapy instruments and media at highest rate, mainly in culture media processing. This is a major factor will drive the market share during forecast period.

Global Cell Therapy Technologies Market: Regional Analysis

North America to held largest market share of the cell therapy technologies in 2018 and expected to grow at highest CAGR during forecast period owing to increasing R&D programs in the pharmaceutical and biotechnology industries. North America followed by Europe, Asia Pacific and Rest of the world (Row).

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Scope of Global Cell Therapy Technologies Market

Global Cell Therapy Technologies Market, by Product

Consumables Equipment Systems & SoftwareGlobal Cell Therapy Technologies Market, by Cell Type

Human Cells Animal CellsGlobal Cell Therapy Technologies Market, by Process Stages

Cell Processing Cell Preservation, Distribution, and Handling Process Monitoring and Quality ControlGlobal Cell Therapy Technologies Market, by End Users

Life Science Research Companies Research InstitutesGlobal Cell Therapy Technologies Market, by Region

North America Europe Asia Pacific Middle East & Africa South AmericaKey players operating in the Global Cell Therapy Technologies Market

Beckman Coulter, Inc. Becton Dickinson and Company GE Healthcare Lonza Merck KGaA MiltenyiBiotec STEMCELL Technologies, Inc. Terumo BCT, Inc. Thermo Fisher Scientific, Inc. Sartorius AG

MAJOR TOC OF THE REPORT

Chapter One: Cell Therapy Technologies Market Overview

Chapter Two: Manufacturers Profiles

Chapter Three: Global Cell Therapy Technologies Market Competition, by Players

Chapter Four: Global Cell Therapy Technologies Market Size by Regions

Chapter Five: North America Cell Therapy Technologies Revenue by Countries

Chapter Six: Europe Cell Therapy Technologies Revenue by Countries

Chapter Seven: Asia-Pacific Cell Therapy Technologies Revenue by Countries

Chapter Eight: South America Cell Therapy Technologies Revenue by Countries

Chapter Nine: Middle East and Africa Revenue Cell Therapy Technologies by Countries

Chapter Ten: Global Cell Therapy Technologies Market Segment by Type

Chapter Eleven: Global Cell Therapy Technologies Market Segment by Application

Chapter Twelve: Global Cell Therapy Technologies Market Size Forecast (2019-2026)

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New Delhi: Human immunity and its components have never been the topic of such breathless discussion for such a long time. But then, there has never been a time like the Covid-19 pandemic.

Between serological surveys (that check the level of antibodies against the SARS-CoV-2 virus in blood), rapid antigen tests (that test for the part of the virus that kickstarts immune mechanisms) and the quest for vaccines, the immune system is very much in.

That is also why lymphocytes (a class of white blood cells), especially the ones known as T-cells are the flavour of the season. They are probably the single most important component of the immune system; though given the perfectly synchronised working of the defence mechanism of the body, it may be a little unfair to designate any one as more important than the another.

T-cells play a plethora of roles in immunity as killer cells that can attack an infected cell and kill it along with the infecting agent, and as suppressor cells that modulate the level of functioning of other lymphocytes. They also have a starring role in the production of antibodies, a function performed by the other variant of lymphocytes called the B cells.

Latest research in Nature shows that presence of T-cells from earlier encounters with coronaviruses could have an important role to play in the bodys immune response, and therefore, a better understanding of it is crucial for the development of a vaccine.

The published data discussed here indicate that patients with severe COVID-19 can have either insufficient or excessive T cell responses. It is possible, therefore, that disease might occur in different patients at either end of this immune response spectrum, in one case from virus-mediated pathology and in the other case from T cell-driven immunopathology.

However, it is unclear why some patients respond too little and some patients too much, and whether the strength of the T cell response in the peripheral blood reflects the T cell response intensity in the respiratory tract and other SARS-CoV-2-infected organs, wrote the researchers from the University of Pennsylvania. They called for more research on the topic.

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Turns out, antibodies may or may not last, but T-cells are the new superheroes with the potential to possibly save the planet.

Also read: T Cells the unsung immune warriors that takeover after coronavirus antibodies wane

Immunity is of two kinds innate and acquired.

The defence mechanisms that the body is born with is known an innate immunity. This includes something as simple as the ability of the skin to prevent inner, more vulnerable tissues, from coming in contact with the external environment.

Acquired immunity, as the name suggests, is something that develops over time through exposure to pathogens or disease causing agents like virus and bacteria. Acquired immunity kicks in either through antibodies (this is known as humoral immunity) or through cells programmed to destroy invading organisms by causing the dissolution of the very cells that have been infected.

White blood cells (WBC) play a crucial role in immunity. There are five different kinds of WBCs eosinophil, basophil, neutrophil, monocyte and lymphocyte. Among these, the most important are lymphocytes, which include the T lymphocytes and the B lymphocytes. However, the others also have important roles to play as supporting cast. For the present discussion, we are concentrating on lymphocytes.

Also read: Immunity boosters are a myth why you shouldnt believe claims that promise to fight Covid

Structurally, under a microscope, very little differentiates a T-lymphocyte from a B lymphocyte. Both varieties are formed in the bone marrow from stem cells, get trained in different organs and then lodge themselves in the lymph nodes from where they are deployed when the occasion arises.

The training is important. It teaches the cells not to start attacking the bodys own cells. T-cells get trained antenatally (during pregnancy) and for some time after that in the thymus, a small gland present between the lungs only till puberty. B cells are trained in the foetal liver and bone marrow.

When a pathogen invades, specific chemicals unique to it (often proteins or complex carbohydrates) activate the bodys immune system. This activator, which is a unique feature of the invading pathogen, is the antigen. This is what the rapid antigen test looks for.

When an antigen has been detected, the T-cells troop out of the lymph node in an activated form and travel to the affected areas to take on the infection. The activated cells, called the Killer T cells, attach themselves to the membrane of the infected cell and with help of cytotoxic chemicals, kill the cell and destroy the invader with it. This is cell-mediated immunity. It is the basis of what happens when transplanted organs are rejected.

The thymus training teaches T-cells to ignore the antigens that are present within the body and not attack them. When that lesson is forgotten, because of genetic or environmental reasons, an autoimmune disorder is triggered.

Antigens set in motion a different pathway in the B lymphocytes. These enlarge and start duplicating very rapidly to form many clones, all of which, on maturity, start producing antibodies. The whole process happens very fast.

Antibodies are protein molecules that are present in the plasma, the matrix of the blood in which the cells float. Not all T-cells though turn into cytotoxic killers. Some become what are known as helper T cells, to go and further activate B lymphocytes to produce antibodies. In fact, without these helper cells, the antibody output is not quite sufficient to combat the invading particle.

Antibodies can directly kill the invader using a number of different mechanisms at their disposal. They can also activate a set of proteins present in the blood plasma that in turn can attack the invader using their own pathways.

Once the infection has been tackled, some of the B lymphocytes are tucked away with information about how this was done. These are memory cells that remain dormant until the next invasion happens. These ensure that when an infection recurs, the response is expedited, magnified and is longer lasting. This is the principle behind vaccination to teach the body to identify and combat a pathogen so that when a future infection happens, the response is stronger.

Also read:An Oxford immunologist breaks down how the universitys vaccine works against Covid-19

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T cells, B cells and the range of the human bodys immune response A simple decoder - ThePrint

Bone Marrow Stem Cells Comments Off on T cells, B cells and the range of the human bodys immune response A simple decoder – ThePrint | August 10th, 2020

Global Multiple Myeloma Treatment Marketsize was valued US$ XX Mn. in 2019 and the total revenue is expected to grow at 11.34% from 2019 to 2027, reaching nearly US$ XX Mn.

The report study has analyzed the revenue impact of COVID -19 pandemic on the sales revenue of market leaders, market followers, and market disrupters in the report, and the same is reflected in our analysis.

Multiple myeloma, also known as Kahlers disease, is a type of blood cancer of plasma cells that are found in the bone marrow. Multiple myeloma causes cancer cells to accrue in the bone marrow, where they attack the strong blood cells.

Multiple myeloma treatments have developed significantly above the last decade. New multiple myeloma treatments have provided efficient survival rates between myeloma patients. It has been also observed that the future drug pipeline of multiple myeloma is promising, biological drugs and stem cell-based therapies are likely to fuel the multiple myeloma treatment market in the upcoming years. On the other hand, the costs of radiotherapeutic equipment implementation, a limited number of target patients population, strict legal regulations are expected to hamper the market growth. Likewise, the MMR report contains a detailed study of factors that will drive and restrain the growth of the multiple myeloma treatment market globally.

Multiple Myeloma accounts for approximately 2.5% of the cancer-related deaths globally and is the second most major type of blood cancer next to Hodgkins Lymphoma. According to the World Cancer Research Fund, in 2018, above 159500 cases of multiple myeloma were diagnosed with the condition, where the occurrence rate among women and men was found in the ratio 1.2:1. The onset of the disease occurs after the age of 60. In recent times, the age of onset is drastically decreasing. In the year 2001, only two medications were available for treating multiple myeloma but now in 2020, 18 medicines are available. Moreover, there are over 25 FDA-approved drugs for treating multiple myeloma with therapeutics such as pomalidomide, carfilzomib, panobinostat, and ixazomib. The availability of new medications has given new hope for better treatments and better results and thus affecting the growth of the market as well. However, the survival of patients with a limited response while receiving treatment with primary immunodeficiency therapy remains poor and is one of the major challenges.

The MMR report covers the segments in the multiple myeloma treatment market such as type and application. By application, the hospital is expected to continue to hold the largest XX.85% share in multiple myeloma treatments market thanks to growing specialist doctors providing the best chance of long term survival.

North Americas multiple myeloma treatments market was valued at US$ XX.26 Mn. in 2019 and is expected to reach a value of US$ XX.13 Mn. by 2027, with a CAGR of 9.3%. The number of patients in the U.S is growing YoY with nearly 14600 new cases diagnosed annually. In 2017 alone there were approximately 142000 patients diagnosed for multiple myeloma.

Europe and the South African population are prone to develop multiple myeloma when compared with Asian economies. Though, the population in the APAC region outwits Europe and Africa. Further, growing the adoption rate of novel therapies, coupled with the support from the government along with non-government organizations and improving the survival of multiple myeloma patients.

The research study includes the profiles of leading players operating in the global multiple myeloma treatment market. Eli Lilly Company acquired ARMO Biosciences to develop immunotherapies for the treatment of cancer, hypercholesterolemia, inflammatory, and fibrosis diseases.

The objective of the report is to present a comprehensive analysis of the Global Multiple Myeloma Treatment Market including all the stakeholders of the industry. The past and current status of the industry with forecasted market size and trends are presented in the report with the analysis of complicated data in simple language. The report covers all the aspects of the industry with a dedicated study of key players that includes market leaders, followers, and new entrants. PORTER, SVOR, PESTEL analysis with the potential impact of micro-economic factors of the market has been presented in the report. External as well as internal factors that are supposed to affect the business positively or negatively have been analyzed, which will give a clear futuristic view of the industry to the decision-makers.The report also helps in understanding Global Multiple Myeloma Treatment Market dynamics, structure by analyzing the market segments and projects the Global Multiple Myeloma Treatment Market size. Clear representation of competitive analysis of key players by Application, price, financial position, Product portfolio, growth strategies, and regional presence in the Global Multiple Myeloma Treatment Market make the report investors guide.Scope of the Global Multiple Myeloma Treatment Market

Global Multiple Myeloma Treatment Market, by Applications

Hospitals Clinics Cancer Treatment and Rehabilitation CentersGlobal Multiple Myeloma Treatment Market, by Type

Proteasome Inhibitors Immunomodulatory Agents (IMiDs) Histone Deacetylase (HDAC) Inhibitors Immunotherapy Cytotoxic ChemotherapyGlobal Multiple Myeloma Treatment Market, by Region

Asia Pacific North America Europe South America Middle East & AfricaKey players operating in Global Multiple Myeloma Treatment Market

Celgene Corporation Janssen Biotech, Inc. Bristol-Myers Squibb Company Novartis AG Cellectar Biosciences Inc. Millennium Pharmaceuticals Amgen, Inc. bbVie Genzyme Corporation Juno Therapeutics Eli Lilly and Company Glenmark Pharma

Global Multiple Myeloma Treatment Market Request For View Sample Report Page : @https://www.maximizemarketresearch.com/request-sample/65671About Us:

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Global Multiple Myeloma Treatment Market-Industry Analysis and forecast 2019 2027: By Application, Type, and Region. - Good Night, Good Hockey

Bone Marrow Stem Cells Comments Off on Global Multiple Myeloma Treatment Market-Industry Analysis and forecast 2019 2027: By Application, Type, and Region. – Good Night, Good Hockey | August 10th, 2020

Cell Therapy Industry Report focuses on Market Influence Factors, Growth Drivers, Restraints, Trends and Opportunities so that Market Players can face any challenges and take advantage of Lucrative Prospects available in the Global Cell Therapy market.

The Covid-19 (coronavirus) pandemic is impacting society and the overall economy across the world. The impact of this pandemic is growing day by day as well as affecting the supply chain. The COVID-19 crisis is creating uncertainty in the stock market, massive slowing of supply chain, falling business confidence, and increasing panic among the customer segments. The overall effect of the pandemic is impacting the production process of several industries including Medical Device, Pharmaceutical, Healthcare and many more. Trade barriers are further restraining the demand- supply outlook. As government of different regions have already announced total lockdown and temporarily shutdown of industries, the overall production process being adversely affected; thus, hinder the overall Cell Therapy Market globally. This report on Cell Therapy Market provides the analysis on impact on Covid-19 on various business segments and country markets. The report also showcase market trends and forecast to 2027, factoring the impact of Covid -19 Situation.

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The Emerging Players in the Cell Therapy Market includes Kolon TissueGene, Inc., MEDIPOST, JCR Pharmaceuticals Co. Ltd., Stemedica Cell Technologies, Inc., Osiris Therapeutics, Inc., NuVasive, Inc., Fibrocell Science, Inc., Vericel Corporation, Cells for Cells, Celgene Corporation, etc.

Cell Therapy Market Definitions and Overview:

Cell therapy (CT) is the process of transplanting human cells to replace or repair damaged tissue or cells. Various methods can be used to carry out cell therapy. For instance, hematopoietic stem cell transplantation, also known as bone marrow transplant, is the most widely used cell therapy. It is used to treat a variety of blood cancers and blood-related conditions.

Cell therapy market is expected to grow due to factors such as increasing the biotechnology industry, rising healthcare expenditure, growing incidences of chronic diseases, and others. The market is expected to have growth opportunities in the emerging region as they are developing their genetic sectors rapidly.

The research provides answers to the following key questions:

Competitive scenario:

The study assesses factors such as segmentation, description, and applications of Cell Therapy industries. It derives accurate insights to give a holistic view of the dynamic features of the business, including shares, profit generation, thereby directing focus on the critical aspects of the business.

Scope of the Report

The research on the Cell Therapy market focuses on mining out valuable data on investment pockets, growth opportunities, and major market vendors to help clients understand their competitors methodologies. The research also segments the Cell Therapy market on the basis of end user, product type, application, and demography for the forecast period 20212027. Comprehensive analysis of critical aspects such as impacting factors and competitive landscape are showcased with the help of vital resources, such as charts, tables, and infographics.

Cell Therapy Market Segmented by Region/Country: North America, Europe, Asia Pacific, Middle East & Africa, and Central & South America

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All-inclusive evaluation of the parent market

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Cell Therapy Market: Study Navigating the Future Growth Outlook | Osiris Therapeutics, NuVasive, Vericel Corporation - Chelanpress

Bone Marrow Stem Cells Comments Off on Cell Therapy Market: Study Navigating the Future Growth Outlook | Osiris Therapeutics, NuVasive, Vericel Corporation – Chelanpress | August 10th, 2020

Overview

We are a clinical stage biopharmaceutical company focused on the discovery,development and commercialization of drugs for the treatment of cancer. We aredeveloping proprietary drugs independently and through research and developmentcollaborations. Our core objective is to leverage our proprietary phospholipiddrug conjugate (PDC) delivery platform to develop PDCs that are designed tospecifically target cancer cells and deliver improved efficacy and better safetyas a result of fewer off-target effects. Our PDC platform possesses thepotential for the discovery and development of the next generation ofcancer-targeting treatments, and we plan to develop PDCs both independently andthrough research and development collaborations. The COVID-19 pandemic hascreated uncertainties in the expected timelines for clinical stagebiopharmaceutical companies such as us, and because of such uncertainties, it isdifficult for us to accurately predict expected outcomes at this time. We havenot yet experienced any significant impacts as a result of the pandemic and havecontinued to enroll patients in our clinical trials. However, COVID-19 mayimpact our future ability to recruit patients for clinical trials, obtainadequate supply of CLR 131 and obtain additional financing.

Our lead PDC therapeutic, CLR 131 is a small-molecule PDC designed to providetargeted delivery of iodine-131 directly to cancer cells, while limitingexposure to healthy cells. We believe this profile differentiates CLR 131 frommany traditional on-market treatment options. CLR 131 is the company's leadproduct candidate and is currently being evaluated in a Phase 2 study inrelapsed/refractory (r/r) B-cell malignancies, including multiple myeloma (MM),chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL),lymphoplasmacytic lymphoma/Waldenstrom's macroglobulinemia (LPL/WM), marginalzone lymphoma (MZL), mantle cell lymphoma (MCL), and diffuse large B-celllymphoma (DLBCL).CLR 131 is also being evaluated in a Phase 1 dose escalationstudy in pediatric solid tumors and lymphoma. The U.S. Food and DrugAdministration ("FDA") granted CLR 131 Fast Track Designation for both r/r MMand r/r DLBCL and Orphan Drug Designation (ODD) of MM, LPL/WM, neuroblastoma,rhabdomyosarcoma, Ewing's sarcoma and osteosarcoma. CLR 131 was also grantedRare Pediatric Disease Designation (RPDD) for the treatment of neuroblastoma,rhabdomyosarcoma, Ewing's sarcoma and osteosarcoma. Most recently, the EuropeanCommission granted an ODD for r/r MM.

Our product pipeline also includes one preclinical PDC chemotherapeutic program(CLR 1900) and several partnered PDC assets. The CLR 1900 Series is beingtargeted for solid tumors with a payload that inhibits mitosis (cell division) avalidated pathway for treating cancers.

We have leveraged our PDC platform to establish four collaborations featuringfive unique payloads and mechanisms of action. Through research and developmentcollaborations, our strategy is to generate near-term capital, supplementinternal resources, gain access to novel molecules or payloads, accelerateproduct candidate development and broaden our proprietary and partnered productpipelines.

Our PDC platform provides selective delivery of a diverse range of oncologicpayloads to cancerous cells, whether a hematologic cancer or solid tumor, aprimary tumor, or a metastatic tumor and cancer stem cells. The PDC platform'smechanism of entry does not rely upon specific cell surface epitopes or antigensas are required by other targeted delivery platforms. Our PDC platform takesadvantage of a metabolic pathway utilized by all tumor cell types in all stagesof the tumor cycle. Tumor cells modify specific regions on the cell surface as aresult of the utilization of this metabolic pathway. Our PDCs bind to theseregions and directly enter the intracellular compartment. This mechanism allowsthe PDC molecules to accumulate over time, which enhances drug efficacy, and toavoid the specialized highly acidic cellular compartment known as lysosomes,which allows a PDC to deliver molecules that previously could not be delivered.Additionally, molecules targeting specific cell surface epitopes face challengesin completely eliminating a tumor because the targeted antigens are limited inthe total number on the cell surface, have longer cycling time frominternalization to being present on the cell surface again and available forbinding and are not present on all of the tumor cells in any cancer. This meansa subpopulation of tumor cells always exist that cannot be targeted by therapiestargeting specific surface epitopes. In addition to the benefits provided by themechanism of entry, PDCs offer the ability to conjugate payload molecules innumerous ways, thereby increasing the types of molecules selectively deliveredvia the PDC.

The PDC platform features include the capacity to link with almost any molecule,provide a significant increase in targeted oncologic payload delivery and theability to target all types of tumor cells. As a result, we believe that we cangenerate PDCs to treat a broad range of cancers with the potential to improvethe therapeutic index of oncologic drug payloads, enhance or maintain efficacywhile also reducing adverse events by minimizing drug delivery to healthy cells,and increasing delivery to cancerous cells and cancer stem cells.

We employ a drug discovery and development approach that allows us toefficiently design, research and advance drug candidates. Our iterative processallows us to rapidly and systematically produce multiple generations ofincrementally improved targeted drug candidates.

In June 2020, the European Medicines Agency (EMA) granted us Small andMedium-Sized Enterprise status by the EMA's Micro, Small and Medium-sizedEnterprise office. SME status allows us to participate in significant financialincentives that include a 90% to 100% EMA fee reduction for scientific advice,clinical study protocol design, endpoints and statistical considerations,quality inspections of facilities and fee waivers for selective EMA pre andpost-authorization regulatory filings, including orphan drug and PRIMEdesignations. We are also eligible to obtain EMA certification of quality andmanufacturing data prior to review of clinical data. Other financial incentivesinclude EMA-provided translational services of all regulatory documents requiredfor market authorization, further reducing the financial burden of the marketauthorization process.

A description of our PDC product candidates follows:

Our lead PDC therapeutic, CLR 131 is a small-molecule, PDC designed to providetargeted delivery of iodine-131 directly to cancer cells, while limitingexposure to healthy cells. We believe this profile differentiates CLR 131 frommany traditional on-market treatments and treatments in development. CLR 131 iscurrently being evaluated in a Phase 2 study in r/r B-cell lymphomas, and twoPhase 1 dose-escalating clinical studies, one in r/r MM and one in r/r pediatricsolid tumors and lymphoma. The initial Investigational New Drug (IND)application was accepted by the FDA in March 2014 with multiple INDs submittedsince that time. Initiated in March 2017, the primary goal of the Phase 2 studyis to assess the compound's efficacy in a broad range of hematologic cancers.The Phase 1 study is designed to assess the compound's safety and tolerabilityin patients with r/r MM (to determine maximum tolerated dose) and was initiatedin April 2015. The FDA previously accepted our IND application for a Phase 1open-label, dose escalating study to evaluate the safety and tolerability of asingle intravenous administration of CLR 131 in up to 30 children andadolescents with cancers including neuroblastoma, sarcomas, lymphomas (includingHodgkin's lymphoma) and malignant brain tumors. This study was initiated duringthe first quarter of 2019. These cancer types were selected for clinical,regulatory and commercial rationales, including the radiosensitive nature andcontinued unmet medical need in the r/r setting, and the rare diseasedeterminations made by the FDA based upon the current definition within theOrphan Drug Act.

In December 2014, the FDA granted ODD for CLR 131 for the treatment of MM.Multiple myeloma is an incurable cancer of the plasma cells and is the secondmost common form of hematologic cancers. In 2018, the FDA granted ODD and RPDDfor CLR 131 for the treatment of neuroblastoma, rhabdomyosarcoma, Ewing'ssarcoma and osteosarcoma. The FDA may award priority review vouchers to sponsorsof rare pediatric disease products that meet its specified criteria. The keycriteria to receiving a priority review voucher is that the disease beingtreated is life-threatening and that it primarily effects individuals under theage of 18. Under this program, a sponsor who receives an approval for a drug orbiologic for a rare pediatric disease can receive a priority review voucher thatcan be redeemed to receive a priority review of a subsequent marketingapplication for a different product. Additionally, these priority reviewvouchers can be exchanged or sold to other companies for them to use thevoucher. In May 2019, the FDA granted Fast Track designation for CLR 131 for thetreatment of multiple myeloma in July 2019 for the treatment of DLBCL, inSeptember, CLR 131 received Orphan Drug Designation from the European Union forMultiple Myeloma, and in January 2020, the FDA granted Orphan Drug Designationfor CLR 131 in lymphoplasmacytic lymphoma (LPL).

Phase 2 Study in Patients with r/r select B-cell Malignancies

In February 2020, we announced positive data from our Phase 2 CLOVER-1 study inpatients with relapsed/refractory B-cell lymphomas. Relapsed/Refractory MM andnon-Hodgkin lymphoma (NHL) patients were treated with three different doses(<50mCi, ~50mCi and ~75mCi total body dose (TBD). The <50mCi total body dose wasa deliberately planned sub-therapeutic dose. CLR 131 achieved the primaryendpoint for the study. Patients with r/r MM who received the highest dose ofCLR 131 showed a 42.8% overall response rate (ORR). Those who received ~50mCiTBD had a 26.3% ORR with a combined rate of 34.5% ORR (n=33) while maintaining awell-tolerated safety profile. Patients in the studies were elderly with amedian age of 70, and heavily pre-treated, with a median of five prior lines oftreatment (range: 3 to 17), which included immunomodulatory drugs, proteasomeinhibitors and CD38 antibodies for the majority of patients. Additionally, amajority of the patients (53%) were quad refractory or greater and 44% of alltreated multiple myeloma patients were triple class refractory. 100% of allevaluable patients (n=43) achieved clinical benefit (primary outcome measure) asdefined by having stable disease or better. 85.7% of multiple myeloma patientsreceiving the higher total body dose levels of CLR 131 experienced tumorreduction. The 75mCi TBD demonstrated positive activity in both high-riskpatients and triple class refractory patients with a 50% and 33% ORR,respectively.

Patients with r/r NHL who received ~50mCi TBD and the ~75mCi TBD had a 42% and43% ORR, respectively and a combined rate of 42%. These patients were alsoheavily pre-treated, having a median of three prior lines of treatment (range, 1to 9) with the majority of patients being refractory to rituximab and/oribrutinib. The patients had a median age of 70 with a range of 51 to 86. Allpatients had bone marrow involvement with an average of 23%. In addition tothese findings, subtype assessments were completed in the r/r B-cell NHLpatients. Patients with DLBCL demonstrated a 30% ORR with one patient achievinga complete response (CR), which continues at nearly 24 months post-treatment.The ORR for CLL/SLL/MZL patients was 33%. Current data from our Phase 2 CLOVER-1clinical study show that four LPL/WM patients demonstrated 100% ORR with onepatient achieving a CR which continues at nearly 27 months post-treatment. Thismay represent an important improvement in the treatment of relapsed/refractoryLPL/WM as we believe no approved or late-stage development treatments forsecond- and third-line patients have reported a CR. LPL/WM is a rare, indolentand incurable form of NHL that is composed of a patient population in need ofnew and better treatment options.

The most frequently reported adverse events in r/r MM patients were cytopenias,which followed a predictable course and timeline. The frequency of adverseevents have not increased as doses were increased and the profile of cytopeniasremains consistent. Importantly, these cytopenias have had a predictable patternto initiation, nadir and recovery and are treatable. The most common grade ?3events at the highest dose (75mCi TBD) were hematologic toxicities includingthrombocytopenia (65%), neutropenia (41%), leukopenia (30%), anemia (24%) andlymphopenia (35%). No patients experienced cardiotoxicities, neurologicaltoxicities, infusion site reactions, peripheral neuropathy, allergic reactions,cytokine release syndrome, keratopathy, renal toxicities, or changes in liverenzymes. The safety and tolerability profile in patients with r/r NHL wassimilar to r/r MM patients except for fewer cytopenias of any grade. Based uponCLR 131 being well tolerated across all dose groups and the observed responserate, especially in difficult to treat patients such as high risk and tripleclass refractory or penta-refractory, and corroborating data showing thepotential to further improve upon current ORRs and durability of thoseresponses, the study has been expanded to test a two-cycle dosing optimizationregimen of CLR 131.

In July 2016, we were awarded a $2,000,000National Cancer Institute (NCI)Fast-Track Small Business Innovation Research grant to further advance theclinical development of CLR 131. The funds are supporting the Phase 2 studyinitiated in March 2017 to define the clinical benefits of CLR 131 in r/r MM andother niche hematologic malignancies with unmet clinical need. These nichehematologic malignancies include Chronic Lymphocytic Leukemia, Small LymphocyticLymphoma, Marginal Zone Lymphoma, Lymphoplasmacytic Lymphoma and DLBCL. Thestudy is being conducted in approximately 10 U.S. cancer centers in patientswith orphan-designated relapse or refractory hematologic cancers. The study'sprimary endpoint is clinical benefit response (CBR), with additional endpointsof ORR, progression free survival (PFS,) median Overall Survival (mOS) and othermarkers of efficacy following a single 25.0 mCi/m2 dose of CLR 131, with theoption for a second 25.0 mCi/m2dose approximately 75-180 days later. Based onthe performance results from Cohort 5 of our Phase 1 study in patients with r/rMM, reviewed below, we have modified the dosing regimen of this study to afractionated dose of 15.625 mCi/m2 administered on day 1 and day 8.

In May 2020, we announced that the FDA granted Fast Track Designation for CLR131 in LPL/WM in patients having received two prior treatment regimens or more.

Phase 1 Study in Patients with r/r Multiple Myeloma

In February 2020, we announced the successful completion of our Phase 1 doseescalation study. Data from the study demonstrated that CLR 131 was safe andtolerated at total body dose of approximately 90mCi in r/r MM. The Phase 1multicenter, open-label, dose-escalation study was designed to evaluate thesafety and tolerability of CLR 131 administered as a 30-minute I.V. infusion,either as a single bolus dose or as two fractionated doses. The r/r multiplemyeloma patients in this study received single cycle doses ranging fromapproximately 20mCi to 90mCi total body dose. To date, an independent DataMonitoring Committee determined that all doses have been safe and well-toleratedby patients.

CLR 131 in combination with dexamethasone is currently under investigation inadult patients with r/r MM. Patients must have been refractory to or relapsedfrom at least one proteasome inhibitor and at least one immunomodulatory agent.The clinical study is a standard three-plus-three dose escalation safety studyto determine the maximum tolerable dose. Multiple myeloma is an incurable cancerof the plasma cells and is the second most common form of hematologic cancers.Secondary objectives include the evaluation of therapeutic activity by assessingsurrogate efficacy markers, which include M protein, free light chain (FLC), PFSand OS. All patients have been heavily pretreated with an average of five priorlines of therapy. CLR 131 was deemed by an Independent Data Monitoring Committee(IDMC) to be safe and tolerable up to its planned maximum single, bolus dose of31.25 mCi/m2. The four single dose cohorts examined were: 12.5 mCi/m2(~25mCiTBD), 18.75 mCi/m2 (~37.5mCi TBD), 25 mCi/m2(~50mCi TBD), and 31.25mCi/m2(~62.5mCi TBD), all in combination with low dose dexamethasone (40 mgweekly). Of the five patients in the first cohort, four achieved stable diseaseand one patient progressed at Day 15 after administration and was taken off thestudy. Of the five patients admitted to the second cohort, all five achievedstable disease however one patient progressed at Day 41 after administration andwas taken off the study. Four patients were enrolled to the third cohort and allachieved stable disease. In September 2017, we announced results for cohort 4,showing that a single infusion up to 30-minutes of 31.25mCi/m2 of CLR 131 wassafe and tolerated by the three patients in the cohort. Additionally, all threepatients experienced CBR with one patient achieving a partial response (PR). Weuse the International Myeloma Working Group (IMWG) definitions of response,which involve monitoring the surrogate markers of efficacy, M protein and FLC.The IMWG defines a PR as a greater than or equal to 50% decrease in FLC levels(for patients in whom M protein is unmeasurable) or 50% or greater decrease in Mprotein. The patient experiencing a PR had an 82% reduction in FLC. This patientdid not produce M protein, had received seven prior lines of treatment includingradiation, stem cell transplantation and multiple triple combination treatmentsincluding one with daratumumab that was not tolerated. One patient experiencingstable disease attained a 44% reduction in M protein. In January 2019, weannounced that the pooled mOS data from the first four cohorts was 22.0 months.In late 2018, we modified this study to evaluate a fractionated dosing strategyto potentially increase efficacy and decrease adverse events.

Following the determination that all prior dosing cohorts were safe andtolerated, we initiated a cohort 7 utilizing a 40mCi/m2 fractionated doseadministered 20mCi/m2 (~40mCi TBD) on days 1 and day 8. Cohort 7 was the highestpre-planned dose cohort and subjects have completed the evaluation period. Finalstudy report and study close-out will be completed later this year.

In May 2019, we announced that the FDA granted Fast Track Designation for CLR131 in fourth line or later r/r MM. CLR 131 is our small-moleculeradiotherapeutic PDC designed to deliver cytotoxic radiation directly andselectively to cancer cells and cancer stem cells. It is currently beingevaluated in our ongoing CLOVER-1 Phase 2 clinical study in patients withrelapsed or refractory multiple myeloma and other select B-cell lymphomas.

Phase 1 Study in r/r Pediatric Patients with select Solid tumors, Lymphomas andMalignant Brain Tumors

In December 2017 the Division of Oncology at the FDA accepted our IND and studydesign for the Phase 1 study of CLR 131 in children and adolescents with selectrare and orphan designated cancers. This study was initiated during the firstquarter of 2019. In December 2017, we filed an IND application for r/r pediatricpatients with select solid tumors, lymphomas and malignant brain tumors. ThePhase 1 clinical study of CLR 131 is an open-label, sequential-group,dose-escalation study evaluating the safety and tolerability of intravenousadministration of CLR 131 in up to 30 children and adolescents with cancersincluding neuroblastoma, sarcomas, lymphomas (including Hodgkin's lymphoma) andmalignant brain tumors. Secondary objectives of the study are to identify therecommended Phase 2 dose of CLR 131 and to determine preliminary antitumoractivity (treatment response) of CLR 131 in children and adolescents. In 2018,the FDA granted OD and RPDD for CLR 131 for the treatment of neuroblastoma,rhabdomyosarcoma, Ewing's sarcoma and osteosarcoma. Should any of theseindications reach approval, the RPDD would enable us to receive a priorityreview voucher. Priority review vouchers can be used by the sponsor to receivepriority review for a future New Drug Application ("NDA") or Biologic LicenseApplication ("BLA") submission, which would reduce the FDA review time from 12months to six months. Currently, these vouchers can also be transferred or soldto another entity.

Phase 1 Study in r/r Head and Neck Cancer

In August 2016, the University of Wisconsin Carbone Cancer Center ("UWCCC") wasawarded a five-year Specialized Programs of Research Excellence ("SPORE") grantof $12,000,000 from the National Cancer Institute and the National Institute ofDental and Craniofacial Research to improve treatments and outcomes for head andneck cancer, HNC, patients. HNC is the sixth most common cancer across the worldwith approximately 56,000 new patients diagnosed every year in the U.S. As a keycomponent of this grant, the UWCCC researchers completed testing of CLR 131 invarious animal HNC models and initiated the first human clinical trial enrollingup to 30 patients combining CLR 131 and external beam radiation with recurrentHNC in Q4 2019. This clinical trial was suspended due to the COVID-19 pandemicbut has now been reopened for enrolment.

We believe our PDC platform has potential to provide targeted delivery of adiverse range of oncologic payloads, as exemplified by the product candidateslisted below, that may result in improvements upon current standard of care("SOC") for the treatment of a broad range of human cancers:

Research and development expense. Research and development expense consist ofcosts incurred in identifying, developing and testing, and manufacturing productcandidates, which primarily include salaries and related expenses for personnel,cost of manufacturing materials and contract manufacturing fees paid to contractmanufacturers and contract research organizations, fees paid to medicalinstitutions for clinical trials, and costs to secure intellectual property. TheCompany analyzes its research and development expenses based on four categoriesas follows: clinical project costs, preclinical project costs, manufacturing andrelated costs, and general research and development costs that are not allocatedto the functional project costs, including personnel costs, facility costs,related overhead costs and patent costs.

General and administrative expense. General and administrative expense consistsprimarily of salaries and other related costs for personnel in executive,finance and administrative functions. Other costs include insurance, costs forpublic company activities, investor relations, directors' fees and professionalfees for legal and accounting services.

Three Months Ended June 30, 2020 and 2019

Research and Development. Research and development expense for the three monthsended June 30, 2020 was approximately $2,465,000 compared to approximately$1,810,000 for the three months ended June 30, 2019.

The following table is an approximate comparison summary of research anddevelopment costs for the three months ended June 30, 2020 and June 30, 2019:

General research and development costs 1,018,000 384,000 634,000

The overall increase in research and development expense of $655,000, or 36%,was primarily a result of increased general research and development costsresulting from increased personnel related costs and in clinical project costs.Manufacturing and related costs decreased due to a decrease in materialsproduction processes and related costs. Pre-clinical study costs were relativelyconsistent.

General and administrative. General and administrative expense for the threemonths ended June 30, 2020 was approximately $1,157,000, compared toapproximately $1,391,000 in the three months ended June 30, 2019. The decreaseof approximately $234,000, or 17%, was primarily a result of lower stock-basedcompensation expense.

Six Months Ended June 30, 2020 and 2019

Research and Development. Research and development expense for the six monthsended June 30, 2020 was approximately $5,082,000 compared to approximately$4,118,000 for the six months ended June 30, 2019.

The following table is a comparison summary of research and development costsfor the six months ended June 30, 2020 and June 30, 2019:

General research and development costs 1,779,000 914,000 865,000

The overall increase in research and development expense of approximately$964,000, or 23%, was primarily a result of increased general research anddevelopment costs resulting from increased personnel related costs and inclinical project costs. Manufacturing and related costs decreased due to adecrease in materials production processes and related costs. Pre-clinical studycosts were relatively consistent.

General and Administrative. General and administrative expense for the sixmonths ended June 30, 2020 was approximately $2,499,000, compared toapproximately $2,712,000 in the six months ended June 30, 2019. The decrease ofapproximately $213,000, or 8%, was primarily a result of lower stock-basedcompensation expense.

Liquidity and Capital Resources

As of June 30, 2020, we had cash and cash equivalents of approximately$22,450,000 compared to $10,615,000 as of December 31, 2019. This increase wasdue primarily to the approximately $18,300,000 of net proceeds received inconnection with the June 5, 2020 public offering. Net cash used in operatingactivities during the six months ended June 30, 2020 was approximately$6,562,000.

Our cash requirements have historically been for our research and developmentactivities, finance and administrative costs, capital expenditures and overallworking capital. We have experienced negative operating cash flows sinceinception and have funded our operations primarily from sales of common stockand other securities. As of June 30, 2020, we had an accumulated deficit ofapproximately $119,251,000.

We believe that the cash balance is adequate to fund our basic budgetedoperations for at least 12 months from the filing of these financial statements.However, our future results of operations involve significant risks anduncertainties. Our ability to execute our operating plan beyond that timedepends on our ability to obtain additional funding via the sale of equityand/or debt securities, a strategic transaction or otherwise. We plan toactively pursue all available financing alternatives; however, there can be noassurance that we will obtain the necessary funding. Other than theuncertainties regarding our ability to obtain additional funding, there arecurrently no known trends, demands, commitments, events or uncertainties thatare likely to materially affect our liquidity. Because we have had recurringlosses and negative cash flows from operating activities, and in light of ourexpected expenditures, the report of our independent auditors with respect tothe financial statements as of December 31, 2019 and for the year ended December31, 2019 contains an explanatory paragraph as to the potential inability tocontinue as a going concern. This opinion indicated at that time, thatsubstantial doubt existed regarding our ability to remain in business.

Edgar Online, source Glimpses

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CRISPR is a catchy acronym that originally described a naturally occurring gene editing tool, derived from a bacterial defense mechanism against viruses. Its the name on everybodys lips in the intersecting realms of science, medicine, ethics, and politics. From the moment of its discovery, CRISPR-Cas9 looked like a miraculous solution to all of the problems that gene editing efforts have experienced over decades of trial and error. This revolutionary new gene editing technique has opened the doors to both massive scientific progress and ethical controversy. Now more than ever, were seeing that CRISPR still has massive kinks to work out. Can we ever fully understand the social and scientific implications of gene editing, and should we use it in humans before we learn how to properly harness it?

What is gene editing?

The 20th century saw genetic scientists increasingly focus their pursuits on the sub-microscopic. As science delved deeper into the human body in an attempt to uncover the molecular minutiae of life, the possibility of reaching into the cell and manipulating its genetic material began to look more and more real. Even by the 1950s, evidence had been mounting for decades that deoxyribonucleic acid (DNA), an unassuming molecule residing in a central cellular compartment called the nucleus, was the physical genetic material that passed information from parent to child. Finally, in 1953, landmark work by Kings College biochemist Rosalind Franklin allowed Cambridge researchers to reveal the structure of DNA and confirm its role in heredity once and for all.

Starting from a hesitant foundation, molecular genetics exploded in both scope and popularity over subsequent decades. With the secrets of heredity increasingly out in the open, human ambition demanded that we try to bend DNA to our willand now we can. These days, targeted gene editing techniques revolve around artificially-engineered molecular tools known as nucleases, whose earliest use was in 1996not even 50 years after the discovery of DNAs structure. Engineered nucleases are often described as molecular scissors. Fundamentally, they have two main parts: one part that finds and grabs onto the target DNA within a cell, and one part that snips a piece out of that DNA.

How CRISPR works

CRISPR is similar to other directed nucleases, but its much better at its job. The CRISPR part is secondary to the systems gene editing applications; the truly important discovery, which Jennifer Doudna made in 2012, was a protein that she called CRISPR-associated protein 9, or Cas9. This protein is the nuclease tool, the pair of molecular scissors that finds, sticks to, and snips target DNAand its more accurate than anything weve ever seen before.

In bacteria, CRISPR is a section of the genome that acts as an immune memory, storing little snippets of different viruses genetic material as DNA after failed infections, like trophies. When a once-active virus attempts to invade a bacterium, the mobile helper Cas9 copies down the relevant snippet from CRISPR in the form of ribonucleic acid, or RNA. RNA is a molecule thats virtually identical to DNA, except for one extra oxygen atom. Because of this property, the RNA sequence that Cas9 holds can pair exactly, nucleotide by nucleotide, with the viral targets DNA, making it extremely efficient at finding that DNA. With a freshly transcribed RNA guide, the bacterium can deploy Cas9 to findand cut outthe corresponding section of viral genetic material, rendering the attacker harmless.

The existence of CRISPR in bacteria was old news by 2012, but Doudnas discovery of Cas9s function was revolutionary. With a little creativity and ingenuity, such a simple and accurate nuclease can be modified to be much more than just a pair of scissors. Using synthetic RNA guides and certain tweaks, Cas9 can be used to remove specific genes, cause new insertions to genomes, tag DNA sequences with fluorescent probes, and much more.

The possibilities seem endless.What if we could go into the body of a human affected by a hereditary disease and change that persons DNA to cure them? What if we could modify reproductive germ cells in human bodies (which give rise to sperm and eggs), or make targeted genetic edits in the very first cell of an embryo? Nine months of division and multiplication later, that cell would give rise to a human being whose very nature has been deliberately tweakedand their childrens nature, and their childrens. With the accuracy and accessibility of the CRISPR/Cas9 system, these ideas arent hypotheticals. In 2019, CRISPR edits in bone marrow stem cells were successfully used to cure sickle cell anemia in a Mississippi woman. Beta thalassaemia, another genetic disease of the blood, has also been treated this way. In 2018, Chinese scientist He Jiankui even claimed that he had conferred HIV immunity upon twin girls using embryonic editing.

CRISPRs complications

At first glance, CRISPR looks like a miraclebut it isnt perfect. What if some cells were affected by edits, but others werent, creating a strange genetic mosaic in a human body? What if, in trying to modify a specific gene, we accidentally hit a different section of DNA nearby? What if we got the right gene, but it also affected a different part of the body that we didnt know about?

These problems arent hypotheticals either. So-called mosaicism and off-target editing are huge concerns among CRISPR scientists. Mosaicism is of particular concern in embryonic editing. Though CRISPR injections are carried out when an embryo is single-celled, CRISPR doesnt always appear to work until after several rounds of cell divisionand it doesnt work in every cell. If not all the cells in the body are affected by gene editing that is intended to eliminate a genetic disease, the disease could remain in the body. It may be possible to combat mosaicism with faster gene editing (so that cells dont replicate before theyve had a chance to become CRISPR-modified), altering sperm and egg cells before they meet to form an embryo, and developing more precise CRISPR gene editing which is in itself a challenge, thanks to off-target editing.

In nature, a little bit of off-target editing could actually make the CRISPR-Cas9 defense system stronger with the principle of redundancy. Flexibility in the form of imprecision could allow a bacterium to neutralize viruses whose exact genetic sequences have not yet been encountered: viruses related to, but not identical to, previous attackers. In clinical and therapeutic applications, on the other hand, precision is everything. And unfortunately, as time passes, CRISPRs level of precision seems further and further off. Preprints released just this year reveal that the frequency and magnitude of CRISPRs off-target edits in human cells may be worse than we had previously known. Large proportions of cells with massive unwanted DNA deletions, losses of entire chromosomes in experimental embryos, and shuffling of genetic sequences were observed.

Of course, not only do scientists need to avoid off-target edits, but they also need to know when such undesired edits have occurred. Off-target effects can be detected by genome sequencing and computer prediction tools, but theres no perfect way to do it yetthere may still be editing misses that were, well, missing. Off-target edits themselves could be minimized by altering the RNA transcript that Cas9 carries to make it more accurate, altering Cas9 itself, or reducing the actual amount of Cas9 protein released into the cell (though this could also reduce on-target effects). Replacing Cas9 itself with other Cas variants, like smaller and more easily deliverable CasX and CasY proteins, is a promising possibility for more efficient editing, but these candidates still run into many of the same problems as Cas9. More strategies are constantly being discovered, proposed, and explored, but were still nowhere near perfect.

Perhaps most importantly, even barring any purely technical problems, is that humans remain in sheer ignorance of much of the extent and consequences of pleiotropy, a phenomenon where a genes presence or deletion has more than one effect in the human body. Even genes whose function we think we know well might have totally unexpected additional functions. On the other side of the coin, we dont have a comprehensive understanding of how many different genetic contributors there are to any given trait or disease, much less where they lie in the genome. We dont understand the way that thousands of variations across the entire genome contribute to appearance, personality, and health. Assuming that some genes are good and others are bad is morally dangerous, and scientifically reprehensible. In reality, we are not ready for genetic determinism, and may never be.

A great responsibility

Humanity has discovered a great power, but we all know what comes with great power. Questions of which edits are necessary for health (is mild Harlequin syndrome a disease or a cosmetic concern?), whether edits are ethical (should autism and homosexuality be considered curable conditions?), and the possibility of designer babies, among others, are pertinent and require thorough discussion. We also need to realize that making these types of changes isnt our decision until we can get CRISPR right, and understand the genome well enough to target particular phenotypes. Though most scientists are aware of the difficulties of CRISPR and its use is generally tightly regulated, some scientistsand laypeopleare less careful. He Jiankuis apparent miracle HIV cure led to his arrest and imprisonment for unapproved and unethical practice. Its no great surprise that his work likely fell prey to off-target effects and mosaicism; even if he got it right, his intended change could alter cognitive function, and who knows what else?

Non-scientists are getting involved too: in 2018, self-proclaimed biohacker Josiah Zayner publicly injected his own arm with what he claimed was muscle-enhancing CRISPR. Though Zayner is one of the most vocal, hes not the only one of his kind. Quieter biohackers, untrained people without a scientific background or a good understanding of how CRISPR can go wrong, are attempting to edit themselves and even their pets.

Laypeople have an unquestionable place in science: the scientific discipline needs fresh perspectives and creativity that stuffy academics cant offer. CRISPR is still in its infancy, though. Before we know much, much more about its capabilities and consequences, there can be no place for black market gene editing kits, rogue scientists altering human embryonic and germline DNA, or basement geneticists injecting Cas9 into their dogs. Who can say what effects these interventions might have, not just on edited individuals, but on the futures of entire species?

Some say that gene editing is an act of hubris, destined to backfire spectacularly and horrendously. Others believe that its our responsibility to use CRISPR to improve lives. Which of these opinions is true depends on how science walks a narrow tightrope, though Im inclined to agree with the latterand add that our responsibility is not just to master gene editing, but to make clear and public its many faults and failings. The truth, in all its complexity, needs to overcome pop sciences oversimplification and sensationalism. Promising new advances and techniques are on the horizon, but we have a long way to go. Gene editing is no joke; humanity is playing with fire. With an incredibly accurate and accessible nuclease making its way into labs and garages across the world (while its flaws continue to be uncovered year by year), it is more important than ever for the world to understand and discuss the long-reaching consequences and responsible use of gene editing technology. CRISPR is not a miracle, but gene editing may very well be the future of humanityand its on us to keep it under control.

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Brazilian researchers announced that a 36-year-old man in Brazil is HIV-free after receiving a cocktail of antiviral drugs.

If true, this unidentified case, detailed at the medical conference AIDS 2020, would be the first instance of long-term remission from HIV without a stem cell or bone marrow transplant.

But the researchers peers are sceptical, since anti-retroviral therapy, which is used to queel HIV and prevent it from developing into AIDS, has been the standard treatment for all HIV-positive people since the treatment was invented in 1995.

There will be a lot of buzz, a lot of controversy about this part everyones going to be sceptical, HIV researcher Dr. Steve Deeks told the New York Times. Am I sceptical? Of course. Am I intrigued? Absolutely.

According to the research team at the Federal University of So Paulo, the man was diagnosed with HIV in 2012 and began taking the typical antiretroviral drugs.

In 2016, he joined a clinical trial where he was given three additional drugs, including maraviroc and nicotinamide, for 11 months, in an aggressive treatment designed to flush the virus out of his body.

The man returned to the standard anti-retroviral therapy after the trial ended, and stopped taking all anti-retroviral drugs in March 2019. Every three weeks since March 2019, his blood has been tested.

The fact that he tested negative for HIV is not remarkable in itself anyone religiously taking anti-retroviral therapy for more than six months will reach an undetectable viral load.

But in this case, the researchers said they found no trace of dormant HIV-infected cells in his system.These latent cells can become active as soon as treatment stops, making people sick again.

The researchers announced that virus-detecting blood tests did not show any remaining traces of HIV in the mans blood. The man also did not show any signs of having antibodies to the virus.

Prior to this, just two people had been cured of HIV.

First was the Berlin Patient, an American man named Timothy Ray Brown, who received a bone marrow transplant in 2007 in Berlin, Germany.

Brown had leukemia, and required a bone marrow transplant to survive. His doctors sought bone marrow from someone with an HIV-resistant gene. Post-transplant, Brown suffered a series of health issues, he needed to be put in a medically induced coma, and nearly died. But not only was his cancer gone, so was his HIV. He is still alive today, with no HIV, and no need for the anti-retroviral therapy that HIV-positive people must take habitually.

In 2019, the London Patient, a man named Adam Castillejo, became the second person ever to enter long-term remission from HIV. Castillejo, who was treated in London, England, had two bone marrow transplants. His recovery process was less intense, assuaging scientists concerns that Brown had only been cured because of the massive destruction to his immune system, which also rid him of HIV.

Deeks said that independent lab results will be needed to confirm these results. The Brazilian research team has offered to send the mans blood samples to other labs.

When HIV enters the body, it inserts genetic material into the DNA of its hosts immune cells. This forces the cells to make copies of the virus. Some active HIV-infected cells are created, and some latent HIV-infected cells are created. These cells are infected with HIV but are not actively producing new HIV, according to the NIH.

But there is a difference between testing negative for HIV, as some people do after taking medication that makes their HIV undetectable, and having zero traces of HIV in your RNA or DNA. In the first instance the virus is controlled within the body, but in the second instance it is entirely removed from the body.

Many researchers have announced they have cured HIV in their patients, only for the disease to return a short while later.

A baby in Mississippi stopped taking antiretroviral medication at 18 months, researchers eagerly announced that the virus was gone, and then two years later, in 2014, researchers detected HIV in the child again. In 2013, two Boston patients received bone marrow transplants, and headlines declared that they had been cured, only for the virus to resurface again.

The So Paulo Patient has gone 66 weeks without showing signs of the virus.

Read more:

Case of HIV patient in remission raises hopes for future AIDS cure

Doctors say experimental treatment may have rid man of HIV

There is no virus there that we can measure. Second HIV patient in remission becomes new hope for a cure

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Scientists say a man with HIV is the first to reach long-term remission without a bone marrow transplant, but their peers are sceptical - Business...

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FT819 CAR T-cell Product Candidate Derived from Clonal Master iPSC Line with Novel CD19-specific 1XX CAR Integrated into TRAC Locus

Phase 1 Clinical Study will Evaluate FT819 for Patients with Advanced B-cell Leukemias and Lymphomas

SAN DIEGO, July 09, 2020 (GLOBE NEWSWIRE) -- Fate Therapeutics, Inc. (NASDAQ: FATE), a clinical-stage biopharmaceutical company dedicated to the development of programmed cellular immunotherapies for cancer and immune disorders, announced today that the U.S. Food and Drug Administration (FDA) has cleared the Companys Investigational New Drug (IND) application for FT819, an off-the-shelf allogeneic chimeric antigen receptor (CAR) T-cell therapy targeting CD19+ malignancies. FT819 is the first-ever CAR T-cell therapy derived from a clonal master induced pluripotent stem cell (iPSC) line, and is engineered with several first-of-kind features designed to improve the safety and efficacy of CAR T-cell therapy. The Company plans to initiateclinical investigation of FT819for the treatment of patients with relapsed / refractory B-cell malignancies, including chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), and non-Hodgkin lymphoma (NHL).

The clearance of our IND application for FT819 is a ground-breaking milestone in the field of cell-based cancer immunotherapy. Our unique ability to produce CAR T cells from a clonal master engineered iPSC line creates a pathway for more patients to gain timely access to therapies with curative potential, said Scott Wolchko, President and Chief Executive Officer of Fate Therapeutics. Four years ago, we first set out under our partnership with Memorial Sloan Kettering led by Dr. Michel Sadelain to improve on the revolutionary success of patient-derived CAR T-cell therapy and bring an off-the-shelf paradigm to patients, and we are very excited to advance FT819 into clinical development.

FT819 was designed to specifically address several limitations associated with the current generation of patient- and donor-derived CAR T-cell therapies. Under a collaboration with Memorial Sloan Kettering Cancer Center (MSK) led by Michel Sadelain, M.D., Ph.D., Director, Center for Cell Engineering, and Head, Gene Expression and Gene Transfer Laboratory at MSK, the Company incorporated several first-of-kind features into FT819 including:

The multi-center Phase 1 clinical trial of FT819 is designed to determine the maximum tolerated dose of FT819 and assess its safety and clinical activity in up to 297 adult patients across three types of B-cell malignancies (CLL, ALL, and NHL). Each indication will enroll independently and evaluate three dose-escalating treatment regimens: Regimen A as a single dose of FT819; Regimen B as a single dose of FT819 with IL-2 cytokine support; and Regimen C as three fractionated doses of FT819. For each indication and regimen, dose-expansion cohorts of up to 15 patients may be enrolled to further evaluate the clinical activity of FT819.

At the American Association for Cancer Research (AACR) Virtual 2020 Meeting, the Company presented preclinical data demonstrating FT819 is comprised of CD8 T cells with uniform 1XX CAR expression and complete elimination of endogenous TCR expression. Additionally, data from functional assessments showed FT819 has antigen-specific cytolytic activity in vitro against CD19-expressing leukemia and lymphoma cell lines that is comparable to that of healthy donor-derived CAR T cells, and persists and maintains tumor clearance in the bone marrow in an in vivo disseminated xenograft model of lymphoblastic leukemia.

Fate Therapeutics has an exclusive license for all human therapeutic use to U.S. Patent No. 10,370,452 pursuant to its license agreement with MSK1, which patent covers compositions and uses of effector T cells expressing a CAR, where such T cells are derived from a pluripotent stem cell including an iPSC. In addition to the patent rights licensed from MSK, the Company owns an extensive intellectual property portfolio that broadly covers compositions and methods for the genome editing of iPSCs using CRISPR and other nucleases, including the use of CRISPR to insert a CAR in the TRAC locus for endogenous transcriptional control.

1 Fate Therapeutics haslicensedintellectual propertyfrom MSK on which Dr. Sadelain is aninventor.As a result of the licensing arrangement, MSK has financial interests related to Fate Therapeutics.

About Fate Therapeutics iPSC Product PlatformThe Companys proprietary induced pluripotent stem cell (iPSC) product platform enables mass production of off-the-shelf, engineered, homogeneous cell products that can be administered with multiple doses to deliver more effective pharmacologic activity, including in combination with cycles of other cancer treatments. Human iPSCs possess the unique dual properties of unlimited self-renewal and differentiation potential into all cell types of the body. The Companys first-of-kind approach involves engineering human iPSCs in a one-time genetic modification event and selecting a single engineered iPSC for maintenance as a clonal master iPSC line. Analogous to master cell lines used to manufacture biopharmaceutical drug products such as monoclonal antibodies, clonal master iPSC lines are a renewable source for manufacturing cell therapy products which are well-defined and uniform in composition, can be mass produced at significant scale in a cost-effective manner, and can be delivered off-the-shelf for patient treatment. As a result, the Companys platform is uniquely capable of overcoming numerous limitations associated with the production of cell therapies using patient- or donor-sourced cells, which is logistically complex and expensive and is subject to batch-to-batch and cell-to-cell variability that can affect clinical safety and efficacy. Fate Therapeutics iPSC product platform is supported by an intellectual property portfolio of over 300 issued patents and 150 pending patent applications.

About Fate Therapeutics, Inc.Fate Therapeutics is a clinical-stage biopharmaceutical company dedicated to the development of first-in-class cellular immunotherapies for cancer and immune disorders. The Company has established a leadership position in the clinical development and manufacture of universal, off-the-shelf cell products using its proprietary induced pluripotent stem cell (iPSC) product platform. The Companys immuno-oncology product candidates include natural killer (NK) cell and T-cell cancer immunotherapies, which are designed to synergize with well-established cancer therapies, including immune checkpoint inhibitors and monoclonal antibodies, and to target tumor-associated antigens with chimeric antigen receptors (CARs). The Companys immuno-regulatory product candidates include ProTmune, a pharmacologically modulated, donor cell graft that is currently being evaluated in a Phase 2 clinical trial for the prevention of graft-versus-host disease, and a myeloid-derived suppressor cell immunotherapy for promoting immune tolerance in patients with immune disorders. Fate Therapeutics is headquartered in San Diego, CA. For more information, please visit http://www.fatetherapeutics.com.

Forward-Looking StatementsThis release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995 including statements regarding the advancement of and plans related to the Company's product candidates and clinical studies, the Companys progress, plans and timelines for the clinical investigation of its product candidates, the therapeutic potential of the Companys product candidates including FT819, and the Companys clinical development strategy for FT819. These and any other forward-looking statements in this release are based on management's current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to, the risk of difficulties or delay in the initiation of any planned clinical studies, or in the enrollment or evaluation of subjects in any ongoing or future clinical studies, the risk that the Company may cease or delay preclinical or clinical development of any of its product candidates for a variety of reasons (including requirements that may be imposed by regulatory authorities on the initiation or conduct of clinical trials or to support regulatory approval, difficulties in manufacturing or supplying the Companys product candidates for clinical testing, and any adverse events or other negative results that may be observed during preclinical or clinical development), the risk that results observed in preclinical studies of FT819 may not be replicated in ongoing or future clinical trials or studies, and the risk that FT819 may not produce therapeutic benefits or may cause other unanticipated adverse effects. For a discussion of other risks and uncertainties, and other important factors, any of which could cause the Companys actual results to differ from those contained in the forward-looking statements, see the risks and uncertainties detailed in the Companys periodic filings with the Securities and Exchange Commission, including but not limited to the Companys most recently filed periodic report, and from time to time in the Companys press releases and other investor communications.Fate Therapeutics is providing the information in this release as of this date and does not undertake any obligation to update any forward-looking statements contained in this release as a result of new information, future events or otherwise.

Contact:Christina TartagliaStern Investor Relations, Inc.212.362.1200christina@sternir.com

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By David Bautz, PhD

NASDAQ:BCLI

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Business Update

KOL Event for Alzheimers Program

On July 8, 2020, BrainStorm Cell Therapeutics, Inc. (NASDAQ:BCLI) conducted a Key Opinion Leader (KOL) webinar to discuss the companys upcoming Phase 2a clinical trial of NurOwn in patients with Alzheimers Disease (AD). The event included presentations by two of the lead investigators for the upcoming trial, Dr. Philip Scheltens, Professor of Cognitive Neurology and Director of the Alzheimer Centre at VU University Medical Center in Amsterdam, Netherlands, and Dr. Bruno Dubois, Professor of Neurology at the Neurological Institute of the Salptrire University Hospital in Paris, France. The presentation can be found here.

The companys Phase 2a trial (BCT-201-EU) is expected to enroll approximately 40 patients with prodromal to mild AD. It will be taking place at medical centers in France and the Netherlands. To be eligible for the trial, patients must have been diagnosed with prodromal to mild dementia at least six months prior to enrollment. In addition, patients must score between 20-30 on the Mini-Mental State Exam (MMSE) and have a Clinical Dementia Rating (CDR) global score of 0.5-1.0. The MMSE is a series of questions that are designed to assess a patients mental skills, with the maximum score being 30 points and a score of 20-24 suggesting mild dementia. The CDR is a scale used to characterize six domains of cognitive and functional performance with a score of 0.5 suggesting very mild dementia and a score of 1.0 suggesting mild dementia.

The primary objective of the trial is to assess the safety and tolerability of three intrathecal injections of NurOwn in AD patients. Following bone marrow aspiration during a 10-week run-in period, patients will be treated three times with NurOwn, with eight weeks between treatments. Follow-up visits will occur 12 and 26 weeks following the final injection of NurOwn for a total trial length of 52 weeks. The following figure gives an overview of the trial design.

Cerebrospinal fluid (CSF) and serum will be collected prior to treatment and again at Weeks 0, 8, and 16 to assess changes in various neurotropic, neurodegenerative, and inflammatory factors (e.g., VEGF, HGF, NfL, NfH, MCP-1, IL-6), markers associated with amyloid deposition (e.g., a40, a42), and markers of tau protein levels (e.g., p-tau, t-tau). Additional clinical outcome measures will be analyzed through administration of the following tests:

Clinical Dementia Rating ScaledSum of Boxes (CDR-SB)

Free and Cued Selective Reminding Test (FCSRT)

Neuropsychological Test Battery (NTB)

Delis-Kaplan Executive Function System (D-KEFS) subtests

Mini Mental State Examination(MMSE)

AmsterdamInstrumentalActivitiesofDailyLivingQuestionnaire-ShortVersion(A-IADL-Q-SV)

Alzheimers Disease

Alzheimers disease (AD) is the most common form of dementia in older adults. The disease is named after Dr. Alois Alzheimer, who identified the first case in a 50-year-old woman named Auguste Deter in 1902. Dr. Alzheimer followed her case until her death in 1906, at which point he first publicly reported on it (Alzheimer, 1907).

After Ms. Deters death, Dr. Alzheimer examined her brain and found many abnormal clumps (now known as amyloid plaques) and tangled bundles of fibers (now known as neurofibrillary tangles). Over the next five years, 11 similar cases were reported in the medical literature, with some of them already using the term Alzheimers disease (Berchtold et al., 1998).

The most common early symptom of AD is a gradually worsening ability to remember new information. This is due to neurons associated with forming new memories dying off first. As neurons in other parts of the brain die, individuals experience different symptoms, which include:

Memory loss that disrupts daily life

Inability to plan or solve problems

Difficulty completing familiar tasks

Confusion with location and time

Difficulty with visual images and spatial relationships

Problems with words in speaking or writing

Withdrawal from social activities

Changes in mood, including apathy and depression

Each person progresses through AD at a different rate, and little is known about how or why there is such a marked variation, thus predicting how it will affect someone is quite difficult. One thing that is common to everyone diagnosed with AD is that his or her cognitive and functional abilities will gradually decline. As the disease progresses symptoms can include confusion, irritability, aggression, mood swings, and long-term memory loss. In the final advanced stage of the disease, people need help with the basic activities of living (e.g., bathing, dressing, eating, and using the restroom), they lose the ability to communicate, fail to recognize loved ones, and eventually become bed bound and reliant on round-the-clock care (Frstl et al., 1999). The inability to move makes them more prone to infections, including pneumonia, which are often a contributing factor to the death of those with AD.

Competing Theories for the Cause of Alzheimers

The root cause of Alzheimers is still unknown; however, it is likely to involve a number of different factors as opposed to being due to one single cause. These factors are likely a combination of genetic, environmental, and lifestyle. There are a number of hypotheses that exist to explain the cause of the disease, with the two dominant hypotheses focused on amyloid and tau.

Amyloid hypothesis: This hypothesis proposes that extracellular beta-amyloid deposits are the fundamental cause of the disease (Hardy et al., 1991). Beta-amyloid is a fragment of the larger protein amyloid precursor protein (APP), mutations of which are known to cause FAD. Several lines of evidence support the amyloid hypothesis: 1) the location of APP is on chromosome 21, while those with Down Syndrome (trisomy 21) almost all show signs of AD by 40 years of age (Lott et al., 2005); 2) APOE4 is a major genetic risk factor for AD, and while apolipoproteins enhance the breakdown of beta-amyloid, some isoforms are less capable of performing this task than others, leading to more beta-amyloid buildup on the brain (Polvikoski et al., 1995); 3) mice that harbor a mutant form of APP develop amyloid plaques and Alzheimers-like pathology (Games et al., 1995). Lastly, amyloid plaques are readily identifiable by microscopy in the brains of AD patients (Tiraboschi et al., 2004). While the brains of many older individuals develop some plaques, the brains of AD patients show severe pathological changes specifically within the temporal neocortex (Bouras et al., 1994).

Tau hypothesis: Tau is a protein located mainly within the axonal compartment of neurons and is an important element in microtubule stabilization and neurite outgrowth. In AD, a proportion of tau protein becomes abnormally phosphorylated, dissociates from axonal microtubules, and accumulates in paired helical filaments inside the neuron (Goedert et al., 1991). When this occurs, the microtubules disintegrate causing the collapse of the neurons transport system (Igbal et al., 2005). Just as with beta-amyloid plaques, tau tangles are readily observable in the brains of those affected by AD.

In addition to amyloid and tau, inflammation has been an underappreciated and often overlooked mediator in patients with AD (Akiyama et al., 2000). A multitude of inflammatory markers are found in AD patients brains and a number of studies have shown a link between chronic inflammation and an increased risk of developing AD (Walker et al., 2017; Tao et al., 2018). Thus, a treatment such as NurOwn that can decrease inflammatory mediators could prove beneficial in AD patients.

On Track to Repot Topline Data from Phase 3 ALS Trial in 4Q20

On July 2, 2020, BrainStorm announced that all doses have been administered in the pivotal Phase 3 trial ofrecen NurOwn in patients with amyotrophic lateral sclerosis (ALS) and that it remains on track to report topline data in the fourth quarter of 2020.

The ongoing randomized, double blind, placebo controlled, multi-dose Phase 3 clinical trial is testing the ability of NurOwn to alter disease progression as measured by the ALSFRS-R (NCT03280056). Cells were extracted once from each patient prior to treatment, with all administrations of NurOwn derived from the same extraction of cells due to a cryopreservation process the company developed for long-term storage of mesenchymal stem cells (MSC). Just as with the companys prior studies, there was a 3-month run-in period prior to the first treatment with two additional NurOwn treatments occurring two and four months following the first treatment. The company is focusing the trial on faster-progressing ALS patients since those patients demonstrated superior outcomes in the Phase 2 trial of NurOwn.

BrainStorm Joins Russell 2000 and Russell 3000; Granted SME Status by EMA

On June 23, 2020, BrainStorm announced that its shares would be included in the Russell 2000 Index and the Russell 3000 Index. The annual reconstitution of the Russell indexes is done to capture the 4,000 largest U.S. stocks by market capitalization.

On June 15, 2020, BrainStorm announced that the company has been granted Small and Medium-Sized Enterprise (SME) status by the European Medicines Agency (EMA). SME status allows the company to participate in a number of financial incentives including a 90-100% reduction in the EMA fee for scientific advice, clinical study protocol design, endpoints and statistical considerations, quality inspections of facilities, and fee waivers for selective EMA pre- and post-authorization regulatory filings, including Orphan Drug and PRIME designations.

Conclusion

Were excited about the potential for NurOwn in AD and we look forward to the initiation of the Phase 2a trial later in 2020. We have recently made a few changes to our model, including the inclusion of NurOwn in AD and lowering of the discount rate from 20% to 15% for all indications. We model for the company to file for approval of NurOwn in AD in 2026 and to be granted approval in 2027. We currently estimate peak sales of over $2 billion for NurOwn in AD in both the U.S. and E.U. Using a 25% probability of approval leads to an NPV of $113 million. Combined with the NPV for NurOwn in ALS ($700 million) and MS ($41 million) along with the companys current cash position and potential cash from warrants leads to a valuation for the company of a bit less than $900 million. Dividing by the companys current fully diluted share count of 35.7 million leads to a valuation of $25 per share.

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BCLI: KOL Event Gives Overview of the use of NurOwn in Alzheimer's Disease; Raising Valuation to $25/Share - Zacks Small Cap Research

Bone Marrow Stem Cells Comments Off on BCLI: KOL Event Gives Overview of the use of NurOwn in Alzheimer’s Disease; Raising Valuation to $25/Share – Zacks Small Cap Research | July 10th, 2020