For more in-depth learning, we recommend Different Approaches in our Patient Education program.

The challenges of gene and cell therapists can be divided into three broad categories based on disease, development of therapy, and funding.

Challenges based on the disease characteristics: Disease symptoms of most genetic diseases, such as Fabrys, hemophilia, cystic fibrosis, muscular dystrophy, Huntingtons, and lysosomal storage diseases are caused by distinct mutations in single genes. Other diseases with a hereditary predisposition, such as Parkinsons disease, Alzheimers disease, cancer, and dystonia may be caused by variations/mutations in several different genes combined with environmental causes. Note that there are many susceptible genes and additional mutations yet to be discovered. Gene replacement therapy for single gene defects is the most conceptually straightforward. However, even then the gene therapy agent may not equally reduce symptoms in patients with the same disease caused by different mutations, and even the samemutationcan be associated with different degrees of disease severity. Gene therapists often screen their patients to determine the type of mutation causing the disease before enrollment into a clinical trial.

The mutated gene may cause symptoms in more than one cell type. Cystic fibrosis, for example, affects lung cells and the digestive tract, so the gene therapy agent may need to replace the defective gene or compensate for its consequences in more than one tissue for maximum benefit. Alternatively, cell therapy can utilizestem cellswith the potential to mature into the multiple cell types to replace defective cells in different tissues.

In diseases like muscular dystrophy, for example, the high number of cells in muscles throughout the body that need to be corrected in order to substantially improve the symptoms makes delivery of genes and cells a challenging problem.

Some diseases, like cancer, are caused by mutations in multiple genes. Although different types of cancers have some common mutations, every tumor from a single type of cancer does not contain the same mutations. This phenomenon complicates the choice of a single gene therapy tactic and has led to the use of combination therapies and cell elimination strategies. For more information on gene and cell therapy strategies to treat cancer, please refer to the Cancer and Immunotherapy summary in the Disease Treatment section.

Disease models in animals do not completely mimic the human diseases and viralvectorsmay infect various species differently. The testing of vectors in animal models often resemble the responses obtained in humans, but the larger size of humans in comparison to rodents presents additional challenges in the efficiency of delivery and penetration of tissue.Gene therapy, cell therapy, and oligonucleotide-based therapy agents are often tested in larger animal models, including rabbit, dog, pig and nonhuman primate models. Testing human cell therapy in animal models is complicated by immune rejections. Furthermore, humans are a very heterogeneous population. Their immune responses to the vectors, altered cells, or cell therapy products may differ or be similar to results obtained in animal models.

Challenges in the development of gene and cell therapy agents: Scientific challenges include the development of gene therapy agents that express the gene in the relevant tissue at the appropriate level for the desired duration of time. There are a lot of issues in that once sentence, and while these issues are easy to state, each one requires extensive research to identify the best means of delivery, how to control sufficient levels or numbers of cells, and factors that influence duration of gene expression or cell survival. After the delivery modalities are determined, identification and engineering of a promoter and control elements (on/off switch and dimmer switch) that will produce the appropriate amount of protein in the target cell can be combined with the relevant gene. This gene cassette is engineered into a vector or introduced into thegenomeof a cell and the properties of the delivery vehicle are tested in different types of cells in tissue culture. Sometimes things go as planned and then studies can be moved onto examination in animal models. In most cases, the gene/cell therapy agent may need to be improved further by adding new control elements to obtain the desired responses in cells and animal models.

Furthermore, the response of the immune system needs to be considered based on the type of gene or cell therapy being undertaken. For example, in gene or cell therapy for cancer, one aim is to selectively boost the existing immune response to cancer cells. In contrast, to treat genetic diseases like hemophilia and cystic fibrosis the goal is for the therapeutic protein to be accepted as an addition to the patients immune system.

If the new gene is inserted into the patients cellularDNA, the intrinsic sequences surrounding the new gene can affect its expression and vice versa. Scientists are now examining short DNA segments that may insulate the new gene from surrounding control elements. Theoretically, these insulator sequences would also reduce the effect of vector control signals in the gene cassette on adjacent cellular genes. Studies are also focusing on means to target insertion of the new gene into safe areas of the genome, to avoid influence on surrounding genes and to reduce the risk of insertional mutagenesis.

Challenges of cell therapy include the harvesting of the appropriate cell populations and expansion or isolation of sufficient cells for one or multiple patients. Cell harvesting may require specific media to maintain the stem cells ability toself-renew and mature into the appropriate cells. Ideally extra cells are taken from the individual receiving therapy. Those additional cells can expand in culture and can be induced to becomepluripotent stem cells(iPS), thus allowing them to assume a wide variety of cell types and avoiding immune rejection by the patient. The long term benefit of stem cell administration requires that the cells be introduced into the correct target tissue and become established functioning cells within the tissue. Several approaches are being investigated to increase the number of stem cells that become established in the relevant tissue.

Another challenge is developing methods that allow manipulation of the stem cells outside the body while maintaining the ability of those cells to produce more cells that mature into the desired specialized cell type. They need to provide the correct number of specialized cells and maintain their normal control of growth and cell division, otherwise there is the risk that these new cells may grow into tumors.

Challenges in funding: In most fields, funding for basic or applied research for gene and cell therapy is available through the National Institutes of Health (NIH) and private foundations. These are usually sufficient to cover the preclinical studies that suggest a potential benefit from a particular gene and cell therapy. Moving into clinical trials remains a huge challenge as it requires additional funding for manufacturing of clinical grade reagents, formal toxicology studies in animals, preparation of extensive regulatory documents, and costs of clinical trials.Biotechnology companies and the NIH are trying to meet the demand for this large expenditure, but many promising therapies are slowed down by lack of funding for this critical next phase.

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Gene & Cell Therapy FAQs | ASGCT - American Society of Gene & Cell ...

IPS Cell Therapy Comments Off on Gene & Cell Therapy FAQs | ASGCT – American Society of Gene & Cell … | June 30th, 2022

Stem cell technology will transform medical practice. While stem cell research has already elucidated many basic disease mechanisms, the promise of stem cellbased therapies remains largely unrealized. In this review, we begin with an overview of different stem cell types. Next, we review the progress in using stem cells for regenerative therapy. Last, we discuss the risks associated with stem cellbased therapies.

There are three major types of stem cells as follows: adult stem cells (also called tissue-specific stem cells), embryonic stem (ES) cells, and induced pluripotent stem (iPS) cells.

A majority of adult stem cells are lineage-restricted cells that often reside within niches of their tissue of origin. Adult stem cells are characterized by their capacity for self-renewal and differentiation into tissue-specific cell types. Many adult tissues contain stem cells including skin, muscle, intestine, and bone marrow (Gan et al, 1997; Artlett et al, 1998; Matsuoka et al, 2001; Coulombel, 2004; Humphries et al, 2011). However, it remains unclear whether all adult organs contain stem cells. Adult stem cells are quiescent but can be induced to replicate and differentiate after tissue injury to replace cells that have died. The process by which this occurs is poorly understood. Importantly, adult stem cells are exquisitely tissue-specific in that they can only differentiate into the mature cell type of the organ within which they reside (Rinkevich et al, 2011).

Thus far, there are few accepted adult stem cellbased therapies. Hematopoietic stem cells (HSCs) can be used after myeloablation to repopulate the bone marrow in patients with hematologic disorders, potentially curing the underlying disorder (Meletis and Terpos, 2009; Terwey et al, 2009; Casper et al, 2010; Hill and Copelan, 2010; Hoff and Bruch-Gerharz, 2010; de Witte et al, 2010). HSCs are found most abundantly in the bone marrow, but can also be harvested at birth from umbilical cord blood (Broxmeyer et al, 1989). Similar to the HSCs harvested from bone marrow, cord blood stem cells are tissue-specific and can only be used to reconstitute the hematopoietic system (Forraz et al, 2002; McGuckin et al, 2003; McGuckin and Forraz, 2008). In addition to HSCs, limbal stem cells have been used for corneal replacement (Rama et al, 2010).

Mesenchymal stem cells (MSCs) are a subset of adult stem cells that may be particularly useful for stem cellbased therapies for three reasons. First, MSCs have been isolated from a variety of mesenchymal tissues, including bone marrow, muscle, circulating blood, blood vessels, and fat, thus making them abundant and readily available (Deans and Moseley, 2000; Zhang et al, 2009; Lue et al, 2010; Portmann-Lanz et al, 2010). Second, MSCs can differentiate into a wide array of cell types, including osteoblasts, chondrocytes, and adipocytes (Pittenger et al, 1999). This suggests that MSCs may have broader therapeutic applications compared to other adult stem cells. Third, MSCs exert potent paracrine effects enhancing the ability of injured tissue to repair itself. In fact, animal studies suggest that this may be the predominant mechanism by which MSCs promote tissue repair. The paracrine effects of MSC-based therapy have been shown to aid in angiogenic, antiapoptotic, and immunomodulatory processes. For instance, MSCs in culture secrete hepatocyte growth factor (HGF), insulin-like growth factor-1 (IGF-1), and vascular endothelial growth factor (VEGF) (Nagaya et al, 2005). In a rat model of myocardial ischemia, injection of human bone marrow-derived stem cells upregulated cardiac expression of VEGF, HGF, bFGF, angiopoietin-1 and angiopoietin-2, and PDGF (Yoon et al, 2005). In swine, injection of bone marrow-derived mononuclear cells into ischemic myocardium was shown to increase the expression of VEGF, enhance angiogenesis, and improve cardiac performance (Tse et al, 2007). Bone marrow-derived stem cells have also been used in a number of small clinical trials with conflicting results. In the largest of these trials (REPAIR-AMI), 204 patients with acute myocardial infarction were randomized to receive bone marrow-derived progenitor cells vs placebo 37 days after reperfusion. After 4 months, the patients that were infused with stem cells showed improvement in left ventricular function compared to control patients. At 1 year, the combined endpoint of recurrent ischemia, revascularization, or death was decreased in the group treated with stem cells (Schachinger et al, 2006).

Embryonic stem cells are derived from the inner cell mass of the developing embryo during the blastocyst stage (Thomson et al, 1998). In contrast to adult stem cells, ES cells are pluripotent and can theoretically give rise to any cell type if exposed to the proper stimuli. Thus, ES cells possess a greater therapeutic potential than adult stem cells. However, four major obstacles exist to implementing ES cells therapeutically. First, directing ES cells to differentiate into a particular cell type has proven to be challenging. Second, ES cells can potentially transform into cancerous tissue. Third, after transplantation, immunological mismatch can occur resulting in host rejection. Fourth, harvesting cells from a potentially viable embryo raises ethical concerns. At the time of this publication, there are only two ongoing clinical trials utilizing human ES-derived cells. One trial is a safety study for the use of human ES-derived oligodendrocyte precursors in patients with paraplegia (Genron based in Menlo Park, California). The other is using human ES-derived retinal pigmented epithelial cells to treat blindness resulting from macular degeneration (Advanced Cell Technology, Santa Monica, CA, USA).

In stem cell research, the most exciting recent advancement has been the development of iPS cell technology. In 2006, the laboratory of Shinya Yamanaka at the Gladstone Institute was the first to reprogram adult mouse fibroblasts into an embryonic-like cell, or iPS cell, by overexpression of four transcription factors, Oct3/4, Sox2, c-Myc, and Klf4 under ES cell culture conditions (Takahashi and Yamanaka, 2006). Yamakana's pioneering work in cellular reprogramming using adult mouse cells set the foundation for the successful creation of iPS cells from adult human cells by both his team (Takahashi et al, 2007) and a group led by James Thomson at the University of Wisconsin (Yu et al, 2007). These initial proof of concept studies were expanded upon by leading scientists such as George Daley, who created the first library of disease-specific iPS cell lines (Park et al, 2008). These seminal discoveries in the cellular reprogramming of adult cells invigorated the stem cell field and created a niche for a new avenue of stem cell research based on iPS cells and their derivatives. Since the first publication on cellular reprogramming in 2006, there has been an exponential growth in the number of publications on iPS cells.

Similar to ES cells, iPS cells are pluripotent and, thus, have tremendous therapeutic potential. As of yet, there are no clinical trials using iPS cells. However, iPS cells are already powerful tools for modeling disease processes. Prior to iPS cell technology, in vitro cell culture disease models were limited to those cell types that could be harvested from the patient without harm usually dermal fibroblasts from skin biopsies. However, mature dermal fibroblasts alone cannot recapitulate complicated disease processes involving multiple cell types. Using iPS technology, dermal fibroblasts can be de-differentiated into iPS cells. Subsequently, the iPS cells can be directed to differentiate into the cell type most beneficial for modeling a particular disease process. Advances in the production of iPS cells have found that the earliest pluripotent stage of the derivation process can be eliminated under certain circumstances. For instance, dermal fibroblasts have been directly differentiated into dopaminergic neurons by viral co-transduction of forebrain transcriptional regulators (Brn2, Myt1l, Zic1, Olig2, and Ascl1) in the presence of media containing neuronal survival factors [brain-derived neurotrophic factor, neurotrophin-3 (NT3), and glial-conditioned media] (Qiang et al, 2011). Additionally, dermal fibroblasts have been directly differentiated into cardiomyocyte-like cells using the transcription factors Gata4, Mef2c, and Tb5 (Ieda et al, 2010). Regardless of the derivation process, once the cell type of interest is generated, the phenotype central to the disease process can be readily studied. In addition, compounds can be screened for therapeutic benefit and environmental toxins can be screened as potential contributors to the disease. Thus far, iPS cells have generated valuable in vitro models for many neurodegenerative (including Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis), hematologic (including Fanconi's anemia and dyskeratosis congenital), and cardiac disorders (most notably the long QT syndrome) (Park et al, 2008). iPS cells from patients with the long QT syndrome are particularly interesting as they may provide an excellent platform for rapidly screening drugs for a common, lethal side effect (Zwi et al, 2009; Malan et al, 2011; Tiscornia et al, 2011). The development of patient-specific iPS cells for in vitro disease modeling will determine the potential for these cells to differentiate into desired cell lineages, serve as models for investigating the mechanisms underlying disease pathophysiology, and serve as tools for future preclinical drug screening and toxicology studies.

Despite substantial improvements in therapy, cardiovascular disease remains the leading cause of death in the industrialized world. Therefore, there is a particular interest in cardiovascular regenerative therapies. The potential of diverse progenitor cells to repair damaged heart tissue includes replacement (tissue transplant), restoration (activation of resident cardiac progenitor cells, paracrine effects), and regeneration (stem cell engraftment forming new myocytes) (Codina et al, 2010). It is unclear whether the heart contains resident stem cells. However, experiments show that bone marrow mononuclear cells (BMCs) can repair myocardial damage, reduce left ventricular remodeling, and improve heart function by myocardial regeneration (Hakuno et al, 2002; Amado et al, 2005; Dai et al, 2005; Schneider et al, 2008). The regenerative capacity of human heart tissue was further supported by the detection of the renewal of human cardiomyocytes (1% annually at the age of 25) by analysis of carbon-14 integration into human cardiomyocyte DNA (Bergmann et al, 2009). It is not clear whether cardiomyocyte renewal is derived from resident adult stem cells, cardiomyocyte duplication, or homing of non-myocardial progenitor cells. Bone marrow cells home to the injured myocardium as shown by Y chromosome-positive BMCs in female recipients (Deb et al, 2003). On the basis of these promising results, clinical trials in patients with ischemic heart disease have been initiated primarily using bone marrow-derived cells. However, these small trials have shown controversial results. This is likely due to a lack of standardization for cell harvesting and delivery procedures. This highlights the need for a better understanding of the basic mechanisms underlying stem cell isolation and homing prior to clinical implementation.

Although stem cells have the capacity to differentiate into neurons, oligodendrocytes, and astrocytes, novel clinical stem cellbased therapies for central and peripheral nervous system diseases have yet to be realized. It is widely hoped that transplantation of stem cells will provide effective therapy for Parkinson's disease, Alzheimer's disease, Huntington's Disease, amyloid lateral sclerosis, spinal cord injury, and stroke. Several encouraging animal studies have shown that stem cells can rescue some degree of neurological function after injury (Daniela et al, 2007; Hu et al, 2010; Shimada and Spees, 2011). Currently, a number of clinical trials have been performed and are ongoing.

Dental stem cells could potentially repair damaged tooth tissues such as dentin, periodontal ligament, and dental pulp (Gronthos et al, 2002; Ohazama et al, 2004; Jo et al, 2007; Ikeda et al, 2009; Balic et al, 2010; Volponi et al, 2010). Moreover, as the behavior of dental stem cells is similar to MSCs, dental stem cells could also be used to facilitate the repair of non-dental tissues such as bone and nerves (Huang et al, 2009; Takahashi et al, 2010). Several populations of cells with stem cell properties have been isolated from different parts of the tooth. These include cells from the pulp of both exfoliated (children's) and adult teeth, the periodontal ligament that links the tooth root with the bone, the tips of developing roots, and the tissue that surrounds the unerupted tooth (dental follicle) (Bluteau et al, 2008). These cells probably share a common lineage from neural crest cells, and all have generic mesenchymal stem cell-like properties, including expression of marker genes and differentiation into mesenchymal cells in vitro and in vivo (Bluteau et al, 2008). different cell populations do, however, differ in certain aspects of their growth rate in culture, marker gene expression, and cell differentiation. However, the extent to which these differences can be attributed to tissue of origin, function, or culture conditions remains unclear.

There are several issues determining the long-term outcome of stem cellbased therapies, including improvements in the survival, engraftment, proliferation, and regeneration of transplanted cells. The genomic and epigenetic integrity of cell lines that have been manipulated in vitro prior to transplantation play a pivotal role in the survival and clinical benefit of stem cell therapy. Although stem cells possess extensive replicative capacity, immune rejection of donor cells by the host immune system post-transplantation is a primary concern (Negro et al, 2012). Recent studies have shown that the majority of donor cell death occurs in the first hours to days after transplantation, which limits the efficacy and therapeutic potential of stem cellbased therapies (Robey et al, 2008).

Although mouse and human ES cells have traditionally been classified as being immune privileged, a recent study used in vivo, whole-animal, live cell-tracing techniques to demonstrate that human ES cells are rapidly rejected following transplantation into immunocompetent mice (Swijnenburg et al, 2008). Treatment of ES cell-derived vascular progenitor cells with inter-feron (to upregulate major histocompatibility complex (MHC) class I expression) or in vivo ablation of natural killer (NK) cells led to enhanced progenitor cell survival after transplantation into a syngeneic murine ischemic hindlimb model. This suggests that MHC class I-dependent, NK cell-mediated elimination is a major determinant of graft survivability (Ma et al, 2010). Given the risk of rejection, it is likely that initial therapeutic attempts using either ES or iPS cells will require adjunctive immunosuppressive therapy. Immunosuppressive therapy, however, puts the patient at risk of infection as well as drug-specific adverse reactions. As such, determining the mechanisms regulating donor graft tolerance by the host will be crucial for advancing the clinical application of stem cellbased therapies.

An alternative strategy to avoid immune rejection could employ so-called gene editing. Using this technique, the stem cell genome is manipulated ex vivo to correct the underlying genetic defect prior to transplantation. Additionally, stem cell immunologic markers could be manipulated to evade the host immune response. Two recent papers offer alternative methods for gene editing. Soldner et al (2011) used zinc finger nuclease to correct the genetic defect in iPS cells from patients with Parkinson's disease because of a mutation in the -Synuclein (-SYN) gene. Liu et al (2011) used helper-dependent adenoviral vectors (HDAdV) to correct the mutation in the Lamin A (LMNA) gene in iPS cells derived from patients with HutchinsonGilford Progeria (HGP), a syndrome of premature aging. Cells from patients with HGP have dysmorphic nuclei and increased levels of progerin protein. The cellular phenotype is especially pronounced in mature, differentiated cells. Using highly efficient helper-dependent adenoviral vectors containing wild-type sequences, they were able to use homologous recombination to correct two different Lamin A mutations. After genetic correction, the diseased cellular phenotype was reversed even after differentiation into mature smooth muscle cells. In addition to the potential therapeutic benefit, gene editing could generate appropriate controls for in vitro studies.

Finally, there are multiple safety and toxicity concerns regarding the transplantation, engraftment, and long-term survival of stem cells. Donor stem cells that manage to escape immune rejection may later become oncogenic because of their unlimited capacity to replicate (Amariglio et al, 2009). Thus, ES and iPS cells may need to be directed into a more mature cell type prior to transplantation to minimize this risk. Additionally, generation of ES and iPS cells harboring an inducible kill-switch may prevent uncontrolled growth of these cells and/or their derivatives. In two ongoing human trials with ES cells, both companies have provided evidence from animal studies that these cells will not form teratomas. However, this issue has not been thoroughly examined, and enrolled patients will need to be monitored closely for this potentially lethal side effect.

In addition to the previously mentioned technical issues, the use of ES cells raises social and ethical concerns. In the past, these concerns have limited federal funding and thwarted the progress of this very important research. Because funding limitations may be reinstituted in the future, ES cell technology is being less aggressively pursued and young researchers are shying away from the field.

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The benefits and risks of stem cell technology - PMC

IPS Cell Therapy Comments Off on The benefits and risks of stem cell technology – PMC | June 30th, 2022

The future of therapeutics for Parkinson disease (PD) appears to be bright, with the pipeline of clinical development featuring a vast number of investigational and varied approaches to treating the condition. This is notable because although levodopaa gold standard therapyhas provided many patients with relief from PD symptoms, there are still limitations to its abilities, and there are several needs that remain unaddressed.

In a presentation given by Rajesh Pahwa, MD, FANA, FAAN, on these emerging therapies at the2022 Advanced Therapeutics in Movement and Related Disorders (ATMRD) Congressin Washington, DC, June 17-19, four specific therapies on the horizon were highlighted that might be able to address, at least in part, some of the shortcomings of the available options.1 Pahwa, the Laverne and Joyce Rider Professor of Neurology; chief, Parkinsons Disease and Movement Disorders Division; and director, Parkinsons Foundation Center of Excellence, University of Kansas Medical Center, shared that IPX-203, apomorphine subcutaneous infusion, continuous foslevodopa/foscarbidopa infusion (also known as ABBV-591), and continuous subcutaneous liquid levodopa/carbidopa (also known as ND0612) could all enter the market within the next couple years.

If I were to predict, I would say the next four of them would definitely be in the market in the next 3 to 4 years, Pahwa said. We have had levodopa which is the gold standard for the treatment of Parkinson disease. We have had different extended forms of levodopawe had the sustained release carbidopa-levodopa that came out 30 years ago. We had the extended-release capsules that came out, about 4 to 5 years ago now. The next generation, so to speak, is IPX-203.

He said that likely, the next therapy that will become available will be subcutaneous apomorphine infusion, closely followed by foslevodopa/foscarbidopa, and then IPX-203. The Neuroderm subcutaneous liquid levodopa [ND0612] will be another few years later. The rest of themwe do not know where they'll end up with phase 3 studies, he said.

The thing is, we still don't have that perfect carbidopa-levodopa where we can say OK, we have reached the stage that this is the best one out there. But every extended-release formulation, we have made some degree of improvement over the past. The extended-release capsules were better than the sustained release because we could get immediate action. And the same thing, I think, with IPX-203. We will, hopefully, have a better improvement than we saw with the previous one, he continued.

After running through the available clinical data on these therapies, Pahwa began to look further into the future of treatment. Touching briefly on the gene therapies that have been assessedmostly unsuccessfullyin PD, he then turned to stem cell-based therapies. Speaking to the hope that patients often carry when talking about the potential of stem cell approaches, he shared that this approach can often come with difficulties, and the progress has been slow.

READ MORE: The Importance of Treatment Nuance and Novel Options in Treating Parkinson Disease

We are very early in the journey of stem cell therapies. The challenges with Parkinson are multiple. You have to figure out the source of this stem cell, the quality of stem cell, age of the patient, stage of the patient, surgical techniques used, the need to use immunosuppression therapy or not use immunosuppression therapy, Pahwa explained. We are looking at a lot of challenges that we have not completely eliminated when we talk about stem cells. But like I said, every patient really feels that the stem cell is going to be an answer to their Parkinson's disease. The challenge is, as far as being a clinician is that Parkinson's is a progressive disorder that affects multiple areas in the brain. Using stem cell therapy, can we stop this progression? Can we actually slow down the disease or cure it? Or is it really going to only focus on dopaminergic replacement? And I think those are our challenges.

These challenges as well as the promises, he explained, can also be unique to each source of stem cells that is taken with this approach. For fetal ventral mesencephalic cells or embryonic stem cells, there are a few trials ongoingthe TRANSEURO (NCT01898390), STEM-PD (NCT02452723), and NYSTEM (NCT03119636), specificallyand there have been positives with these cells, including good long-term graft survival and their indefinite expandability. But they do carry ethical concerns and can be both unpredictable and limited in terms of their supply. Additionally, tissue rejection and tumorigenesis are possible risks.

Induced pluripotent stem cells are another approach in an ongoing trial at the Center for iPS Cell Research and Application, in Kyoto, Japan. These cells, similar to the aforementioned ones, also come with the benefit of indefinite expandability, and unlike the prior mentioned, have an easily accessible source and lack the need for immunosuppressive therapy. Although, they have a high operative cost, can be time consuming to develop, and require complex procedures.

The final option, neural progenitor cells, are also being assessed in two clinical trials (NCT03309514 and NCT01329926), and offer an easy expansion and differentiation protocol, as well as a large quantity source and multipotency. But, again, they carry risks such as low graft survivability and limited proliferation, and they require invasive tissue collection.

People are surprised that we are so slow with stem cells, Pahwa said. Seven years ago, I used to say, Oh, it's going to be 5 to 10 years, and everyone was led to believe that it was all the federal governments fault that we were going so slow. But really, it takes a long time, looking at the safety of it, because all you need is one patient who have a significant complication, and this is going to be put on the backburner for a long time.

Pahwa stressed the importance of being honest with patients about the progress being made in this area, given the significant interest from the general population in stem cell approaches. He warned about patients seeking out unapproved, unregulated treatment by either traveling out of the United States, or within.

What I tell my patients is don't spend the money because a lot of people out there [are selling this idea], not only if you're talking about going to a different country, even in the US, he said. I have a patient who was walking and doing well, who had stem cells injected in her spine, and could not walk after that. It is very likely she had, some form of fibrosing meningitis or something that that affected her gait significantly. Not only there is no efficacy data, there is no safety data. So, I strongly try to discourage my patients.

But the challenge is, people who are interested in stem cells, they often don't believe you, they want to go because the person who's doing the stem cells is doing a very good job selling this product for them. I don't know how to say we can stop this from happening, and that's why I always talk about how there are very few studies going on, Pahwa said.

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The Future of Parkinson Disease Therapies and the Challenges With Stem Cell Therapies - Neurology Live

IPS Cell Therapy Comments Off on The Future of Parkinson Disease Therapies and the Challenges With Stem Cell Therapies – Neurology Live | June 20th, 2022

Since their first successful derivation in 1998, human embryonic stem cells have received almost unprecedented attention. Hailed as the next revolution for medicine, they have been described as the future of molecular biology and the biggest development since recombinant DNA.1 It has been predicted that their successful derivation will have a more profound impact on health than even the advent of anaesthesia and the development of antibiotics.2 They are set to create a whole new genre of medical therapies.3 Their potential availability has also, however, opened a Pandoras box of ethical dilemmas, ranging from ongoing issues surrounding the moral status of the human embryo to the conflicting claims of alternative stem cell sources. Although integral to ethical discourse, these dilemmas demand understanding and assessment on scientific grounds. It is our contention that the ethical debate is being hindered by failure to appreciate the subtleties of the scientific background.

Since the ethical problems accompanying destruction of human embryos are well recognised, the advantages of bypassing these by employing adult stem cells are obvious. For many, the ethical conflicts would be avoided, while all the potential benefits to patients with severe diseases would be retained. Consequently, perceived ethical problems would be resolved if it could be demonstrated that adult stem cells are superior to embryonic stem cells as therapeutic agents.

Unfortunately, resolution is far from clear, for this research field is in its infancy. Scientific uncertainty abounds, and yet societies are demanding definitive scientific answers on stem cell technology. Since the least controversial course of action would be to use adult stem cells, the pressures on scientists to emerge with evidence demonstrating that their potential is equal to, or even greater than, that of embryonic stem cells are formidable. Scientific data and interpretation have become integral to the ethical debate, perhaps in inappropriate ways.

An understanding of the most fundamental aspects of stem cell identity and function is required, from the identification of stem cells to the role of environmental factors at both the microscopic and macroscopic levels. Recognising the role of environmental factors has ramifications both clinically and ethically. Acknowledgement of these factors will provide for greater understanding of the obstacles that have to be overcome if the clinical potential of stem cells is to be realised. It will also help clarify the notions of totipotency and pluripotency, concepts central to delineating the moral value of embryonic stem cells and their parent blastocysts.

Stem cells are unspecialised cells, which have the ability to renew themselves indefinitely, and under appropriate conditions can give rise to a variety of mature cell types in the human body. Some stem cells can give rise to a wide range of mature cell types, whereas others give rise to only a few. Stem cells can be derived from a variety of sources including early embryos, fetal tissue, and some adult tissues, of which bone marrow and blood are the best known examples. Hence, there are two populations of stem cells: embryonic and adult stem cells. Of these, embryonic stem cells are derived from the inner cell mass (ICM) of the blastocyst at five to seven days after fertilisation. At this point the blastocyst has differentiated into two cell types, ICM cells (some of which will give rise to the future individual) and the surrounding trophectoderm cells (which will later form the placenta).

The distinction between embryonic and adult stem cells raises the issue of accurate identification, a prerequisite to testing the claims frequently made for the abilities of both embryonic and adult stem cells to produce a wide array of cell and tissue types. Scientifically, the problem is a fundamental one: defining stem cells solely on the basis of their structurethat is, the specific markers they carry on their outer surfaces, is inaccurate and potentially misleading. Identification mayfor example, be complicated by some stem cells expressing markers from several kinds of lineages and may be further confused by the possibility that marker expression changes throughout development.4,5 The potential for misidentification is of considerable importance for the scientific community, which has called for functional as well as structural testing.

Placing far more reliance on the functional properties of stem cells opens up a wider debate, namely, the role of the environment in an understanding of stem cell function. The ability of the structure of stem cells to change points to the existence of a dynamic relationship between stem cells and their immediate microenvironment, the stem cell niche.

The niche concept was first developed in blood cells, where proliferation, differentiation, and survival of distinct progenitor populations were found to be dependent on factors secreted by other cell types.6 This microenvironment is characterised by numerous external signals, including those derived from chemical factors, cell/cell interactions, and relationships between cells and the surrounding tissue.6 These, in their various ways, all have an impact on stem cells, affecting the precise directions in which they subsequently develop.

This microenvironment is governed by regulatory mechanisms, the molecular nature of which is complicated and elusive. Schuldiner et al,7 in their study of the effects of eight growth factors on the capacity of human embryonic stem cells to form other cell types, found that while these factors altered developmental outcome, they did not produce uniform differentiation of the stem cells. Consequently, although the structural markers and functions of stem cells appear to be dependent upon their environment, defining the nature of this environment will be far from straightforward.

An increasing awareness of the role of the niche on stem cell structure and function has led to an evolving concept of the stem cell. For instance, there is now the suggestion that stem cells should be viewed, not as undifferentiated cells, but as appropriately differentiated cells with the potential to display diverse cell types in alternative niches.8 An excellent illustration of this point is provided in a recent study by Wu et al9 where human neural stem cells were primed in a cocktail of chemical factors and then implanted into various regions of the adult rat brain. Not only did the implanted stem cells give rise to a larger number of neurons than previously reported, but most significantly they gave rise to different neuronal types depending upon the region of the brain into which they were grafted. It is possible that the distinctive nature of the local environment in each brain region instructed the neural stem cells to adopt such different fates.

Furthermore, stem cells taken out of their original niche and exposed to an entirely new environment can potentially differentiate into the cell type(s) typical of that new environment. Human neural stem cellsfor example, produced muscle cells when introduced into skeletal muscle10 and human bone marrow cells differentiated into neural cells when transplanted into a neural environment.11 The above two studies were carried out in rodents, but more recently Mezey et al12 have demonstrated that a similar scenario is possible in humans. Following bone marrow transplants in patients with various forms of cancer, bone marrow stem cells entered the brain and generated neural cell types including neurons. In many of these studies, where stem cells have been transformed into cells from different lineages, there has been some form of injury to the stem cells new environment or niche. In light of this, it is possible that various factors, signals, or chemicals normally present in damaged or disrupted tissue may play a role in governing stem cell fate.

The above findings reflect the increasing influence being attributed to environmental factors, acknowledgement of which has led to the view that stem cells are dynamic rather than static entities. This view underpins the concept of stem cell plasticity, whereby stem cells from adult sources have the ability to dedifferentiate or redifferentiate into cells from other lineages. This may blur the absolute distinction so frequently made between embryonic and adult stem cells (let alone between specific types of adult stem cells), a determinative factor in much ethical debate.

Adult stem cells include stem cells from bone marrow, blood, fat, and both fetal and adult organs. Plasticity is particularly characteristic of bone marrow. Stem cells from this source can differentiate into neural cells,11,1315 (see above for further discussion) while other research has indicated that such cells can be incorporated into skeletal muscle.16

While these reports indicate that interest in the potential of adult stem cells is justified, they should be interpreted cautiously. It would be unwise to jump to the conclusion that these studies render the use of embryonic stem cells (with destruction of human embryos) unnecessary. There are a number of reasons for this.

First, accurate identification is a prerequisite for determining the presence and extent of plasticity. For instance, although Jackson et al17 presented data to suggest that a group of muscle cells could turn into blood cells, they later found they were dealing with a subpopulation of cells that normally reside in muscle tissue.18 What is required are more rigorous standards for determining stem cell plasticity.1921 Iffor example, cardiac cells developed from stem cells are to contribute to heart function, they would have to demonstrate synchronous contraction within the heart itself. Similarly, neural cells derived from neural stem cells would have to generate electrical impulses and release and respond to chemicals normally found within the brain.19,20

A second issue concerns frequency of occurrence. Failure to replicate previous experimental work showing that blood cells are capable of differentiating into neural cells, suggests that, if transformations are occurring, they are very rare.22 Consistent with this conclusion is the work of Jackson et al,23 who demonstrated plasticity in human blood stem cells, although the change to the desired heart and blood vessel cells occurred in only 0.02% of cells. Thus, as Winston24 notes, even in apparently rich sources, the cells capable of change may be very few in number, and this may ultimately diminish their therapeutic value.

A third point of concern with clinical applications in mind, is that transformations may occur via hybrid cells, that is, by the fusion of two distinct cell types. Such spontaneous fusion was observed when embryonic stem cells were grown in the laboratory in the presence of neural cells25 or bone marrow cells.26 Such hybrids, however, show chromosomal abnormalities that may preclude them from being used in therapeutic applications.

The apparent formation of such hybrid cells may have important implications for interpretations of stem cell plasticity. Such a phenomenon presents an alternate explanation for the claims that stem cells from one tissue type are able to produce the progeny of another tissue typethat is, bone marrow into muscle, blood into brain, and vice versa. In other words, adult stem cells may not be as plastic as early reports have suggested. Thus, as pointed out by Ying et al25 future stem cell plasticity studies should ensure that any transformed cells are examined and tested to see if they display properties of both the original and the introduced cell types.

A final note of caution is that it has become clear that there is far more data to show that embryonic stem cells are capable of indefinite growth and pluripotency than adult stem cells. Mouse embryonic stem cellsfor example, have been renewing for 10 years,27 a capacity yet to be demonstrated in cells from adult sources. If adult cells have a restricted renewal potential, this will have negative implications for therapeutic applications, which rely on the ability to expand cells accurately in the laboratory in order to provide enough material for effective transplantation. Furthermore, embryonic stem cells exhibit high levels of the enzyme telomerase which indicates their immortality,28 whereas adult stem cells grown in the laboratory do not exhibit this in the same way. This property renders embryonic stem cells important in the study of cellular ageing and stem cell renewal. Work with neural stem cells from biopsies and autopsies suggests that embryonic stem cells may be easier to coax into specific cell types than adult stem cells.18

Overall, there are few confirmed reports of truly pluripotential adult human stem cells,3,29 while even apparently convincing reports30 may raise serious queries when assessed in a critical manner.3 Nearly a dozen teams have reported adult stem cell plasticity31 and it seems unlikely that random mutation or hybrid fusion can explain all these results. What is required is far more understanding of the fundamental biological issues raised by this research. Even as Winston24 outlines the advantages of embryonic stem cell researchfor example, he recognises the benefits of adult stem cells in regard to safety, possible efficacy, and accessibility. Adult sources have the added advantage of not requiring an intermediate embryo for immunocompatibility. Similarly, while the UK Department of Health32 argues that the therapeutic potential of embryonic stem cells outweighs that of adult stem cells, it acknowledges that in the long term both may be useful. The UK government reiterated this point in 2002 by stating that it wishes to advance research with stem cells from all sources.33

Scientifically, therefore, research with both adult and embryonic sources should continue, although caution should be exercised in evaluating the results. Currently, however, adult stem cells are more problematic than their embryonic counterparts. In light of this evaluation, considerable care should be employed in advocating on allegedly scientific grounds, the advantages of adult over embryonic cells as the source of replacement tissues. The impetus behind such a sentiment stems principally from a desire to protect the status of the human embryo than from any demonstrated superiority of adult stem cell sources.14,34

Confusion at this point will do nothing to advance the cause of ethical analysis, since the current state of the science and its likely future directions are integral to serious ethical assessment. In other words, it is short sighted to attempt to circumvent discussion of the moral status of the blastocyst by concentrating on the potential of adult stem cells alone. Until it is accepted that this latter approach is a cul de sac for ethical discourse, the imperatives of some ethicists will continue to come into conflict with current scientific perspectives.

It is generally asserted that totipotency denotes the ability of a cell or group of cells to give rise to a complete individual, whereas pluripotency refers to the capacity to give rise to all the cell types constituting the individualbut not the individual as a whole. Helpful as this distinction is, it is limited, in that it neither acknowledges nor emphasises the importance of environmental influences in defining these abilities.

As we have seen, embryonic stem cells are derived from the ICM of the blastocyst. These ICM cells have the capacity to form all three embryonic germ layers: endoderm, which will form the lungs, liver, and gut lining; mesoderm, which will form the bone, blood, and muscle, and ectoderm, which will form the skin, eyes, and nervous system. Outwardly, these cells appear to give rise to a complete individual and are considered by some to be totipotent.35

The claim of totipotency requires a number of conditions, however, whether this be for blastocysts or embryonic stem cells. The latter must be undifferentiated and, hence, capable of giving rise to all three germ layers, a condition that is met when embryonic stem cells are derived from the ICM of the blastocyst. In addition, there is a requirement for trophectoderm cells, which will eventually form the layers of the placenta. The extraembryonic tissues are a crucial source of signalling molecules and must function optimally for the differentiation of both embryonic somatic cells and for the establishment of germlines.36 Since both trophectoderm and ICM cells are required for successful development of the fetus, both cell types are required to establish totipotency.37 Thus, totipotency becomes a function of the immediate environment of the embryonic stem cell. If a viable fetus is to result, totipotency also requires successful implantation and development within the uterus of a woman.

In the absence of all these conditions embryonic stem cells are only pluripotent, since they are capable of creating all the cell lines of the fetus, but not the fetus itself. In the laboratory environment they are incapable of totipotency, since they have been removed from the context of the trophectoderm, let alone that of the uterus. It is inaccurate, therefore, to refer to embryonic stem cells as totipotent rather than pluripotent.38

These criteria for establishing totipotency also have ramifications for the ethical evaluation of the human blastocyst. While the blastocyst has intact trophectoderm cells and, therefore, the capacity to produce all three germ layers, plus the extraembryonic material necessary for its survival, totipotency is still dependent on the wider environmentsuccessful implantation in a uterus. Hence, blastocysts within the laboratory are only potentially totipotent, in contrast to their counterparts within the body.

A blastocyst or even a later embryo in the laboratory lacks the capacity to develop into a human individual. Unfortunately, this simple observation is frequently overlooked, and moral discussion focuses on the potential of an embryo to grow into a fully developed human without any reference to its context. Ignoring context in this manner inevitably overlooks the crucial importance of an appropriate environment necessary for the realisation of totipotency, changes to which may also alter the moral debate. Just as stem cell identity and arguably moral value depend upon the microenvironment, so too the human embryo is intimately dependent upon its wider environment.

Much opposition to the use of embryonic stem cells relies upon the argument that adult stem cells could serve as a viable source of tissues for regeneration and therapy. In the light of this, the argument continues that embryonic stem cells, with their debatable ethical credentials, should no longer feature in attempts to produce replacement tissues. This stance uses alleged scientific evidence to bolster an ethical position, and stands or falls on the strength of the scientific case.

Apart from the validity or otherwise of this approach, definitive evidence will not be forthcoming for some time (possibly years), since the scientific issues are complex on-going ones. As outlined above, the potential of adult stem cells remains a matter for debate and further experimentation. Additionally, the dynamic nature of stem cells, both embryonic and adult, points to a close interrelationship between their potential and the environment in which they are located. The possibility of cell lineage change also has to be taken into account when the suitability of different stem cell types is being advocated. From a scientific perspective none of this is surprising, and yet it fits uneasily alongside any stance that is a mixture of scientific, ethical, and political rhetoric.

The necessity of paying attention to the scientific framework of the debate, such as we are doing, has implications for other stances as well. With the advance of scientific understanding and, specifically, the advent of a genetic level of understanding, has come a tendency to view the life of an individual on the basis of DNA alone. This too, however, ignores the dependence of the embryo upon a competent environment. The context within which the embryo develops, like the niche for the stem cell, is integral to all aspects of its functioning. The environment provides nutritional requirements as well as numerous cues to ensure the healthy development of the embryo and subsequent fetus. Consequently, the preservation of DNA cannot be equated with the preservation of an individuals life, as has been suggested by McGee and Caplan.39 Adherence to such a reductionist mode of thinking is only made possible by ignoring completely the contribution of the environment. Essential as DNA is for development, it requires an appropriate context if its potential is to be realised.

From this it follows that a notion such as totipotency is a function of the environment both at the microscopic and macroscopic levels. This suggests that ethical debate cannot be reduced to potential for life, since inherent within the potential of an embryo is an assumption regarding the appropriateness of its environment. This means that the context of blastocysts and later embryos is crucial, ethically as well as scientifically and clinically.

In light of this, it is appropriate to ask whether it is useful to continue thinking of the blastocyst as an independent entity with a moral status stemming entirely from its organisation and perceived potential. We have argued that neither blastocysts nor stem cells are to be viewed in isolation from their context. Given that the claim is frequently made that moral value and status are closely associated with embryonic potential, recognition of the importance of the environment will have major implications for ethical thinking.

Butler D . France opens door to use of embryos in stem cell research. Nature2000;408:629.

Okarma TB. Human primordial stem cells. Hastings Cent Rep1999;29:30.

Committee on the Biological and Biomedical Applications of Stem Cell Research. Stem cells and the future of regenerative medicine. Washington DC: National Academy Press, 2002.

Vogel G . Cell biology. Stem cells: new excitement, persistent questions. Science2000;290:16724.

Matsuoka SY, Ebihara Y, Xu M, et al. CD34 expression on long term repopulating hematopoietic stem cells changes during developmental stages. Blood2001;97:41925.

Watt FM, Hogan BL. Out of Eden: stem cells and their niches. Science2000;287:142730.

Schuldiner MO, Yanuka O, Itskovitz-Eldor J, et al. From the cover: effects of eight growth factors on the differentiation of cells derived from human embryonic stem cells. Proc Natl Acad Sci USA2000;97:1130712.

Van der Kooy D , Weiss S. Why stem cells? Science2000;287:143941.

Wu P , Tarasenko YI, Gu Y, et al. Region specific generation of cholinergic neurons from fetal human neural stem cells grafted in adult rat. Nat Neurosci2002;5:12718.

Galli R , Borello U, Gritti A, et al. Skeletal myogenic potential of human and mouse neural stem cells. Nat Neurosci2000;3:98691.

Zhao LR, Duan WM, Reyes M, et al. Human bone marrow stem cells exhibit neural phenotypes and ameliorate neurological deficits after grafting into the ischemic brain of rats. Exp Neurol2002;174:1120.

Mezey E , Key S, Vogelsang G, et al. Transplanted bone marrow generates new neurons in human brains. Proc Natl Acad Sci USA2003;100:13649.

Brazelton TR, Rossi FM, Keshet GI, et al. From marrow to brain: expression of neuronal phenotypes in adult mice. Science2000;290:17759.

Kopen GC, Prockop DJ, Phinney DG. Marrow stromal cells migrate throughout forebrain and cerebellum, and they differentiate into astrocytes after injection into neonatal mouse brains. Proc Natl Acad Sci USA1999;96:107116.

Meyer JR. Human embryonic stem cells and respect for life. J Med Ethics2000;26:16670.

Ferrari G , Cusella-De Angelis G, Coletta M, et al. Muscle regeneration by bone marrow derived myogenic progenitors. Science1998;279:152830.

Jackson KA, Mi T, Goodell MA. Hematopoietic potential of stem cells isolated from murine skeletal muscle. Proc Natl Acad Sci USA1999;96:144826.

Vastag B . Many say adult stem cell reports overplayed. JAMA2001;286:293.

Anderson DJ, Gage FH, Weissman IL. Can stem cells cross lineage boundaries? New Eng J Med2002;346:7702.

Blau HM, Brazelton TR, Weimann JM. The evolving concept of a stem cell: entity or function? Cell2001;105:82941.

DAmour KA, Gage FH. Are somatic stem cells pluripotent or lineage restricted? Nat Med2002;8:21314.

Morshead CM, Benveniste P, Iscove NN, et al. Hematopoietic competence is a rare property of neural stem cells that may depend on genetic and epigenetic alterations. Nat Med2002;8:26873.

Jackson KA, Majka SM, Wang H, et al. Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J Clin Invest2001;107:1395402.

Winston R . Embryonic stem cell research. The case for. Nat Med2001;7:3967.

Ying QL, Nichols J, Evans EP, et al. Changing potency by spontaneous fusion. Nature2002;416:5458.

Terada N , Hamazaki T, Oka M, et al.Nature2002;416:5425.

Vogel G . Can old cells learn new tricks? Science2000;287:141819.

Pera MF. Scientific considerations relating to the ethics of the use of human embryonic stem cells in research and medicine. Reprod Fert Dev2001;13:239.

Department of Health and Human Services. Stem cells: scientific progress and future research directions. Washington DC: US government, 2001.

Zuk PA, Zhu M, Mizuno H, et al. Multilineage cells from human adipose tissue: implications for cell based therapies. Tissue Eng2001;7:21128.

Vogel G . Rat brains respond to embryonic stem cells. Science2002;295:2545.

Chief Medical Officers Expert Group. Stem cell research: medical progress with responsibility. UK: Department of Health, 2000:548.

Department of Health. Government response to the House of Lords Select Committee Report on Stem Cell Research. London: The Stationery Office, 2002:118.

Doerflinger RM. The ethics of funding embryonic stem cell research: a Catholic viewpoint. Kennedy Inst Ethics J1999;9:13750.

Wright S . Human embryonic stem cell research: science and ethics. Am Sci1999;87:35261.

Surani MA. Reprogramming of genome function through epigenetic inheritance. Nature2001;414:1228.

Jones DG, Telfer B. Before I was an embryo, I was a pre-embryo: or was I? Bioethics1995;9:3249.

Abkowitz JL. Can human hematopoietic stem cells become skin, gut, or liver cells? Nat Med2002;8:21314.

McGee G , Caplan A. The ethics and politics of small sacrifices in stem cell research. Kennedy Inst Ethics J1999;9:1518.

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As eerily relevant as 1992s Death Becomes Her is in 2022, there is an unexpected difference. Unlike Madeline (Meryl Streep) and Helen (Goldie Hawn), we arent hiding our facelifts. Instead, some of us are live streaming the whole experience. Dermal fillers and Botox are getting as common as getting a facial in your local salon.

"There has been a shift of mindset and increased acceptability of these procedures, says Dr Madhuri Agarwal of Yavana Aesthetics, Mumbai. In the next few years, the trend is going to be more innovations and better delivery mechanisms of these minimally invasive procedures that deliver long term, healthy skin.

What you want to do to look and feel good is not up for discussion. While lasers and acids are wonderful for skin texture and even tightening, a non-surgical facelift involving needles can be more effective for the latter. For example, filler that is more natural looking, because a laser isnt doing anything to make up for the lost volume.

Our bodies are dynamic and need maintenance as we age. Even, and especially, our facial skin. But with so many options of non-surgical face lifts available, it can be overwhelming to make a choice. We spoke to a few dermatologists to help break down the details of the best non-surgical facelift treatments involving needles.

Botox involves injecting a very safe neurotoxin called Botulinum to freeze muscles, and relax them, ironing out wrinkles. Wary but curious first timers can choose to start with very minute unitsthey wont erase all wrinkles but will smoothen them out enough to look a little more natural. I suggest this only when fine lines form, says Dr Kiran Sethi, a dermatologist based in Delhi and author of Skin Sense. It lasts 3-6 months, and there isnt much downtime. Its great when combined with fillers or skin boosters. Theres also been a focus on preventive Botox. If you get it done before the lines set in, you will have fewer lines as you age, explains Dr Geetika Mittal Gupta of ISAAC Luxe Clinic in Mumbai and Delhi. You will need less and less Botox as you age, because those muscles are not contracting as much. And by early I mean, when you see certain lines of ageing.

Fillers are usually injections of hyaluronic acid that add back lost volume to parts of your face. The Indian bone structure is such that our cheekbone is a little flat on the centre part of the face, explains Dr. Chytra V Anand, founder, Kosmoderma located in Chennai and Bengaluru. So most Indians, even teenagers, get dark circles and hollows. Its a loss of volume. So you have to put a filler in there. And people are accepting of that. Its not because they want to look like someone else, or they want to look younger. They just want to maintain their body and skin. The down time for fillers is usually 2-7 days, depending on how easily you bruise. And a good treatment can last anywhere between 1 and 2 years.

The vampire facial might have shocked people a few years ago, but today its one of the most popular treatments in India. Platelet-rich plasma is extracted from your blood, rich in growth hormones that renews blood flow and tissue regeneration wherever it is injected back, including your scalp. Its usually a course of 3-4 sessions, monthly, says Dr Sethi. It treats melasma, dehydration, has a mild filler effect too. And when used on the scalp, new hair growth can show in 6 months.

Theres also stem cell therapy for hair and skin rejuvenation. We take a small biopsy of the skin, splice the cells, and use the extract for regenerative therapy, says Dr Anand. It takes less time and commitment than PRP and is great for scar healing.

Its good to remember that these treatments are addictive too, says Dr Akber Aimer, Director of Aesthetic Medicine, Maya Medi Spa. You need to understand your limit. Always look for a good doctor who is experienced and talk about your problems and ask their opinions. Understand everything clearly. Your decision-making is a multi-step procedure. You need to have done proper research on the materials used and the treatment. Understand the technology. Trust your gut. And dont forget to ask for before and after pictures!

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While historically lacking in foreign investments, Japans biotech scene is thriving with global investors showing increasing interest. Here are five of the hottest Japanese private companies innovating in the healthcare space.

Japan boasts one of the highest life expectancies in the world, and, faced with a rapidly aging population, is witnessing a growing burden of chronic conditions including cardiovascular disease and type 2 diabetes. For this reason, the Japanese healthcare authorities are encouraging research into the treatment and prevention of these diseases, in addition to promoting the potential of regenerative medicine.

In addition to having a roster of healthcare giants including Takeda, Astellas Pharma and Eisai, Japan is also an Asian hotspot for biotech companies. Upcoming startups have historically been limited in foreign funding and reliant on local venture capital players such as Nippon Venture Capital, Shinsei Capital Partners, and the University of Tokyo Edge Capital Partners.

In 2021, however, the amount of foreign investment flowing into the Japanese biotech space rose to $98 million, almost triple the haul of previous years. The most prominent global backers included Newton Biocapital, F-Prime Capital, and SoftBank Group. This trend arose as the COVID-19 pandemic triggered a wave of investor enthusiasm in biotechnology around the world.

With the help of local experts, weve listed five of the hottest private biotech companies in Japan. These firms, shown in alphabetical order, have raised large funding rounds in the last two years and are developing innovative treatments for a range of conditions including cancer, cardiovascular disease and inflammatory disorders.

Source: Shutterstock

Founded: 2017

Headquarters: Fujisawa

Chordia Therapeutics derives its name from the English term chord referring to a collection of musical notes normally played in harmony. In a similar way, the company aims to work in harmony with stakeholders and collaborators to develop first-in-class small molecule treatments for cancer.

Chordias lead program is a drug that disrupts the processing of RNA in tumor cells. In a healthy cell, RNA molecules are typically transcribed from a DNA template and spliced together to guide the production of new proteins. Some cancer cells accumulate mutations in the RNA splicing machinery and become vulnerable to Chordias drugs that interfere with this process.

Chordia raised $31 million (4 billion yen) in a Series C round in May 2022. The aim of the round was to push the companys lead drug through phase I testing and fund the preclinical development of the rest of its pipeline.

This month, the company announced interim results from the phase I trial of its lead candidate, with four of the recruited patients so far showing signs of responding to the treatment.

Founded: 2015

Headquarters: Tokyo

Heart failure occurs when the heart muscle is irreparably damaged and is unable to pump blood. While this deadly condition can be treated with a heart transplant, there is a general shortage of donors available, making a pressing need for alternatives.

In June 2021, the stem cell therapy developer Heartseed raised $36.5 million (4 billion yen) in a Series C round. The mission is to provide a regenerative route to saving the heart via stem cell therapy.

In the lab, Heartseed reprograms skin cells from the patient into a type of stem cell called induced pluripotent stem cells and grows these stem cells into heart muscle cells. The company then injects the muscle cells as a small cluster, or seed, into heart tissue to repair the muscle.

The proceedings from its Series C round will allow Heartseed to take its lead candidate into clinical development, including a phase I/II trial scheduled for later this year. Last year, Heartseed also licensed its treatment to Novo Nordisk in Denmark to co-develop the treatment outside of Japan.

Founded: 2018

Headquarters: Tokyo

LUCA Science hit the headlines in the last week for raising an impressive $30.3 million (3.86 billion yen) in a Series B round. The company is developing an unusual approach for treating a wide range of diseases: delivering a therapy based on mitochondria, the energy production plants in human cells.

One example where the technology could work well is in strokes and heart attacks, where blood flow is blocked to critical tissue in the brain and heart respectively. The reperfusion of blood to these tissues after the blockage can kill the tissue by damaging its mitochondria. Delivering healthy mitochondria could keep the tissue working properly and protect it from harm.

LUCA Science plans to use its recent Series B winnings to accelerate the preclinical development of its mitochondrial therapies and establish its manufacturing process. In May 2022, the firm also inked a collaboration deal with compatriot pharmaceutical company Kyowa Kirin Co., Ltd. to co-develop a mitochondrial therapy for rare genetic diseases.

Founded: 2016

Headquarters: Boston, U.S., and Tokyo

Modulus Discovery is a preclinical-stage drug discovery specialist. The company focuses on developing small molecule treatments for conditions such as cancer, inflammatory disorders and rare genetic conditions.

The firm uses a mixture of strategies to speed up the drug discovery process. These include simulating target proteins using a supercomputer; structural protein biology; forming collaborations such as with the peptide drug expert PeptiDream; and tapping into global networks for biological expertise. Modulus most advanced drug program is in late-stage preclinical testing for the treatment of chronic inflammatory diseases.

In March 2022, Modulus bagged $20.4 million (2.34 billion yen) in a Series C round. The cash is earmarked to advance the companys R&D programs by expanding its infrastructure, collaborations and headcount.

Founded: 2015

Headquarters: Tokyo

The name Noile-Immune is derived from blending together the phrases no illness and no immunity, no life. This company is developing CAR-T cell therapies for the treatment of cancer, which traditionally consist of extracting the patients immune T cells, engineering them in the lab to hunt down cancer cells, and reinfusing them into the patient.

Unlike approved CAR-T cell therapies, which are limited to treating forms of blood cancer, Noile-Immune aims its therapies at treating solid tumors. The company does this by engineering immune T cells to produce proteins that cause immune cells to migrate into the tumor site.

Noile-Immune is testing its lead candidate in a phase I in patients with solid tumors. The firm is also co-developing therapies with partners including Takeda and the European cell therapy specialists Adaptimmune and Autolus. Additionally, Noile-Immune has an allogeneic version of its cell therapy in the pipeline where immune T cells are sourced from healthy donors rather than the patient.

To finance the clinical development of its lead candidate, Noile-Immune raised $21.8 million (2.38 billion yen) in a Series C round in early 2021. The company hit a setback in January 2022 when a collaboration deal fell through with the U.S. player Legend Biotech. Nonetheless, other external companies remain interested in Noile-Immunes offering, including Japan-based Daiichi Sankyo Company Ltd., which opted to assess Noile-Immunes technology in late 2021.

Cover image via Elena Resko.

Thanks to feedback from Shiohara Azusa, VC Investor at The University of Tokyo Edge Capital, and Hironoshin Nomura, Chief Financial Officer, Sosei Group Corporation.

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The last decade of immunotherapy progress was based on decades of prior research, including other forms of immunotherapy.

Until recent years, cancer treatment revolved around surgery, chemotherapy, and radiation. But the FDA approval of ipilimumab (Yervoy) in 2011 led to a fourth leg of that treatment stool: immunotherapy. This enabled new treatment paradigms, sometimes with shocking levels of success.

The types of immunotherapy treatments available are proliferating, with approved immune checkpoint inhibitors (ICIs) and cellular therapies like chimeric antigen receptor (CAR) T cells as well as other modalities in the research and discovery phases. Some even include more established approaches like vaccines that are being revisited with new information and iterations.

The last decade of immunotherapy progress was based on decades of prior research, including other forms of immunotherapy. The Bacillus Calmette-Gurin vaccine, used to prevent tuberculosis for a century, has also been used as an immunotherapy to treat nonmuscle invasive bladder cancer since 1990.1 And rituximab (Rituxan), a monoclonal antibody therapy approved in 1997 for B-cell malignancies, is seen by some as an early immunotherapy as well.2

What many clinicians think of in terms of immunotherapy, however, are treatments targeting CTLA-4 and PD-1/PD-L1 pathways, brought from the bench by James P. Allison, PhD, and Tasuku Honjo, PhD, respectively, leading to a Nobel Prize awarded jointly to them in 2018.3

Immune responses are tightly controlled by T cells, and these T cells have on/off switches that help control their responses, according to Padmanee Sharma, MD, PhD, a professor in the Department of Genitourinary Medical Oncology in the Division of Cancer Medicine and the scientific director of the James P. Allison Institute at The University of Texas MD Anderson Cancer Center in Houston. Previously, she said, clinicians were not aware of the off switches. Sharma showed that CTLA-4 was an inhibitory pathway and that by blocking it, the T cells could stay longer to eradicate the tumors.

With 8 ICIs approved for immunotherapy in hematological and solid tumors,4 researchers are not only investigating newer forms of therapy, but also combining them to fi nd more effective and durable treatments and introducing them into earlier lines of treatment (TIMELINE). Current research is also attempting to predict who will respond to which therapy based on current and emerging biomarkers.

Ipilimumab, which kicked off the current era of cancer immunotherapy treatment with FDA approval in 2011, targets CTLA-4 for newly diagnosed or previously treated unresectable or metastatic melanoma.5 Ipilimumab blocks CTLA-4, removing its inhibitory signals. This allows the T cells to activate and launch an immune response to the tumors antigens.

CTLA-4 is basically the fi rst inhibitory pathway that comes up on the T cells, Sharma said. CTLA-4 is a member of an immunoglobulin-related receptor family responsible for some immune regulation aspects of T cells.6 It is thought to regulate T-cell proliferation mostly in lymph nodes, early in an immune response, by having an inhibitory role.7

What ipilimumab really did and what the immune checkpoint inhibitors really did is they opened up this whole different way to approach the immune system, Elizabeth Buchbinder, MD, a medical oncologist at Dana-Farber Cancer Institute and an assistant professor of medicine at Harvard Medical School in Boston, Massachusetts, said. Ipilimumab provided amazing durable responses in patients with melanoma with widely metastatic disease, some of whom were alive 10 years later, she said.

The PD-1 and PD-L1 blockades build on ipilimumabs success. Like CTLA-4, PD-1 is a negative regulator of T-cell immune function, inhibiting the target to increase immune system activation. PD-1 suppresses T cells mostly in the peripheral tissues.7 As of November 2021, 8 ICIs have been approved that target CTLA-4, PD-1, and PD-L1 pathways and treat 18 types of cancer.3

AntiPD-1 inhibitors

The percentage of people who benefi tted from ipilimumab was on the low side, Buchbinder said, with only an 11% response rate and 20% of people doing well long term in clinical trials. With PD-1 inhibition, however, there was approximately a 40% response rate and many more patients doing well long term, as demonstrated in clinical trials. So [PD-1 inhibition is] both far more effective and also less toxic, Buchbinder said.

When choosing an agent in the PD-1 class, we dont need to differentiate them. Theyre all antiPD-1, Sharma explained. There arent any data to indicate that patients will respond any differently to pembrolizumab [Keytruda] vs nivolumab [Opdivo]. The mechanism of action for both drugs [is] exactly the same.

Instead, clinicians should consider the FDA approvals for each drugs indications and combinations. But from a scientific standpoint, theres no distinguishing between [them], Sharma said.

AntiPD-L1 inhibitors

PD-1 and PD-L1 targeting drugs were found to work beyond melanoma and kidney cancer, the early indications for treatments targeting the CTLA-4 pathway, Buchbinder said. That was a huge opening up of this fi eld to all of these other cancers, like lung cancer, head and neck cancer, GI [gastrointestinal] cancer, breast [cancer], and beyond, she said.

Before receiving these immunotherapies, patients may need to show PD-1 or PD-L1 expression, although this may not identify all patients who can benefi t from the treatments. Researchers continue to try to identify additional and better biomarkers to indicate which patients may respond.13

In March, the FDA approved the newest ICI, nivolumab and relatlimab-rmbw (Opdualag), for adult and pediatric patients (12 years and older) with unresectable or metastatic melanoma. 3 Nivolumab is a PD-1 inhibitor, and relatlimab blocks LAG3 proteins on immune cells. It is being tested in a lot of other tumors, Buchbinder noted.

Another target in the discovery phase is T cell immunoglobulin and mucin domain 3, which is a checkpoint receptor expressed by many immune cells and leukemic stem cells.14 It is activated by several ligands and is being tested in different cancer types.

Also in clinical trials are tumor-infiltrating lymphocytes (TIL) that recognize cancer cells as abnormal, entering the tumor to kill the cells. TILs already recognize the targets because they originate from the tumor itself.15 Although they need to be expanded, they are not the same as CAR T cells, which must be engineered to recognize the targets.

In addition, older therapies are experiencing a resurgence, with research underway to make interleukin 2 (IL-2) help cytokines function better. That work is trying to optimize what those cytokines do in the body and the immune system, Buchbinder said. There are so many areas where the goal of the therapy is activation of the immune system.

One of these areas includes a return to vaccines. In earlier vaccine therapy, We had no idea that while we were giving therapy to turn on the cells, we were also rapidly turning off the cells because an on switch will automatically drive an off switch for the immune system, Sharma said. The yin and the yang of the immune response is very important to understand because when the immune response is driven in one direction, it will always try to control itself. With that in mind, newer vaccines might work better if given in combination with an antiCTLA-4, for example, to block the inhibitory pathways, she said.

Vaccines are taking many forms, including the mRNA vaccine used for COVID-19, peptide vaccines that include a tiny bit of protein that is expected to be expressed on the tumor surface, and vaccines constructed from dendritic cells, which stimulate T cells, Buchbinder said.

There are also viral therapies injected directly into tumor vaccines, such as talimogene laherparepvec (Imlygic) approved in 2015 for the treatment of some patients with metastatic melanoma that cannot be surgically removed.16 It is a is a modifi ed herpes virus directly injected into the tumor to bring about a local immune response, Buchbinder said.

According to Sharma, approximately 60 targets are currently being evaluated for immunotherapy development.

The FDA has approved 2 CAR T-cell therapies, both in 2017: tisagenlecleucel (Kymriah) for patients 25 years and younger with relapsed B-cell precursor acute lymphoblastic leukemia17 and axicabtagene ciloleucel (Yescarta) for the treatment of adult patients with large B-cell lymphoma that is refractory to fi rst-line chemoimmunotherapy or that relapses within 12 months of fi rst-line chemoimmunotherapy.18 These treatments involve collecting T cells from the patient and engineering them to express CARs that recognize the patients cancer cells. The cells are then enlarged and infused back into the patient, where they can target the antigen- expressing cancer cells. CARs have been shown to greatly improve clinical response and disease remission in some patients.19

I think CAR T cells are clearly building on the concept that T cells are the soldiers of immune response. They are basically engineering the cell to have an antibody that recognizes a specifi c antigen, Sharma said, adding that its important to ensure the targeted antigen is part of the cancer.

CAR T cells have had limited effectiveness in treating solid tumors, given the low T-cell infiltration and immunosuppressive environment that challenges the immune system from successfully reaching and killing solid tumor cancer cells.20

Natural killer (NK) cells are another cell type being researched to attempt tumor eradication, and this therapy is in the early stages, according to Sharma. CAR NK cells can be generated from allogenic donors, making them more attractive as off the shelf treatments compared with CAR T cells, which are collected from the patient. As of early 2021, more than 500 CAR T-cell trials and 17 CAR T-cell/NK-cell trials were in the works globally.21

A major consideration when choosing any treatment, including immunotherapies, is the adverse event (AE) profile. Immunotherapy drugs have different AEs than oncology treatments like chemotherapy or radiation. [With immunotherapy,] what we see is infl ammation because youre turning on the immune system in such a powerful way, Sharma said. Inflammatory reactions include a skin rash or dermatitis, infl ammation in the colon (colitis and diarrhea), and/or infl ammation in the lung with pneumonitis. Clinicians are now aware of these AEs and can monitor them closely, stopping therapy if needed to control them before they become severe, Sharma said.

Toxicities with ipilimumab can be severe, and patients requiring hospital admission might need high-dose steroids, Buchbinder noted. Common AEs for the CTLA-4 inhibitor are typically GI related, including diarrhea, colitis, and hepatitis. Some patients may experience fatigue or a small rash, but most generally make it through treatment with minimal AEs.

The stronger AEs with ipilimumab can be seen from a trial comparing ipilimumab plus nivolumab to nivolumab and relatlimab. Almost 60% of patients experienced AEs with the ipilimumab combination vs 20% in the latter group.17

PD-1 and PD-L1 inhibition typically involve AEs that cause lung issues rather than GI. The types of organ systems affected by immunotherapy AEs can vary based upon which checkpoint inhibitor you use but in some ways, the mechanism by which these occur is very similar, Buchbinder said. Its all an overactivation of the immune system leading to infl ammation in an organ, and there are very few organs that we have not seen toxicity from immunotherapy.

Buchbinder noted that cellular therapies can cause more severe AEs, such as cytokine release syndrome (CRS). Patients can get very sick very quickly, she said, because the therapies given with the cellsincluding the chemotherapy given before and the IL-2 given aftercause most of the AEs. With a lot of the injection therapies, the AEs are related to delivery method, like injection-site issues, but there are also potential systemic AEs like fever, chills, and reactions someone would get to a virus. Its really a huge range in terms of the different [adverse] effects, Buchbinder said.

CRS is the most common AE of CAR T-cell therapy, and it is caused by large numbers of T cells activating, which releases inflammatory cytokines. Although this demonstrates that the therapy is working, it can cause worrisome symptoms. The CRS and the related neurotoxicity can be treated with tocilizumab (Actemra).

One question in the immunotherapy world is whether the development of immune-related AEs predicts a positive or negative response to treatment. With melanoma, we think the data have been very tricky, Buchbinder said. Early trials appeared to show a higher response rate for patients who developed severe symptoms, but as trials developed, that signal was not always there. I think the overall impression is that yes, severe AEs are associated with a better response, she said. A cosmetic AE that clinicians who treat melanoma are excited to see, she said, is vitiligo. It suggests that the immune system is attacking normal melanocytes and that it is attacking cancer cells as well. Those patients generally do far better than patients who dont get vitiligo.

A meta-analysis of 30 studies on the topic, including 4971 individuals, showed that patients who developed immune-related AEs experienced an overall survival benefi t and a progression-free survival benefi t using ICI therapy compared with those who did not. The authors stated that more studies are needed and that the results are controversial.22

Melanoma has been the proving ground for ICIs, Buchbinder said, But now the bar is higher in terms of immunotherapy.

ICIs are now being tested in more immuneresistant tumors. Although there are huge hurdles in terms of some cancers where its going to be hard for immune therapy to do muchlike pancreatic cancer or prostate cancerthere are still diseases where theres opportunity and a possibility that the correct approach or combination might get to some great therapy for those diseases, Buchbinder said

Immunotherapies are being combined with conventional therapies to better integrate treatment. We dont see cancer as a death sentence anymore, Sharma said. We really do see a lot of hope, [and patients with cancer] should be encouraged to discuss immunotherapy with their physician either in a clinical trial or an FDA-approved agent. If you do have a response, its a pretty phenomenal response.

REFERENCES:

1. Lobo N, Brooks NA, Zlotta AR, et al. 100 years of Bacillus Calmette- Gurin immunotherapy: from cattle to COVID-19. Nat Rev Urol. 2021;18(10):611-622. doi:10.1038/s41585-021-00481-1

2. Pierpont TM, Limper CB, Richards KL. Past, present, and future of rituximab-the worlds fi rst oncology monoclonal antibody therapy. Front Oncol. 2018;8:163. doi:10.3389/fonc.2018.00163

3. Kruger S, Ilmer M, Kobold S, et al. Advances in cancer immunotherapy 2019 - latest trends. J Exp Clin Cancer Res. 2019;38(1):268. doi:10.1186/s13046-019-1266-0

4. Lee JB, Kim HR, Ha SJ. Immune checkpoint inhibitors in 10 years: contribution of basic research and clinical application in cancer immunotherapy. Immune Netw. 2022;22(1):e2. doi:10.4110/in.2022.22.e2

5. FDA approves Yervoy (ipilimumab) for the treatment of patients with newly diagnosed or previously-treated unresectable or metastatic melanoma, the deadliest form of skin cancer. News release. Bristol Myers Squibb. March 25, 2011. Accessed May 11, 2022. https://bit.ly/3PFp7q2

6. Rowshanravan B, Halliday N, Sansom DM. CTLA-4: a moving target in immunotherapy. Blood. 2018;131(1):58-67. doi:10.1182/ blood-2017-06-741033

7. Buchbinder EI, Desai A. CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am J Clin Oncol. 2016;39(1):98-106. doi:10.1097/COC.0000000000000239

8. Keown A. Keytruda approvals: a timeline. BioSpace. Aug 13, 2019. Accessed May 11, 2022. https://bit.ly/3yHvfrL

9. Stewart J. Opdivo FDA approval history. Drugs.com. Updated March 15, 2022. Accessed May 20, 2022. https://bit.ly/3lnmtar

10. Markham A, Duggan S. Cemiplimab: fi rst global approval. Drugs. 2018;78(17):1841-1846. doi:10.1007/s40265-018-1012-5

11. FDA grants accelerated approval to dostarlimab-gxly for dMMr endometrial cancer. FDA. Updated April 22, 2021. Accessed May 20, 2022. https://bit.ly/38BSJns

12. Pierpont TM, Limper CB, Richards KL. Past, present, and future of rituximab-the worlds first oncology monoclonal antibody therapy. Front Oncol. 2018;8:163. doi:10.3389/fonc.2018.00163

13. Opdualag becomes fi rst FDA-approved immunotherapy to target LAG-3. National Cancer Institute. April 6, 2022. Accessed May 11, 2022. https://bit.ly/3FZWaAp

14. Acharya N, Sabatos-Peyton C, Anderson AC. TIM-3 finds its place in the cancer immunotherapy landscape. J Immunother Cancer. 2020;8(1):e000911. doi:10.1136/jitc-2020-000911

15. Boldt C. TIL Therapy: 6 things to know. MD Anderson Cancer Center. April 15, 2021. Accessed May 11, 2022. https://bit.ly/3wmguJb

16. FDA approves talimogene laherparepvec to treat metastatic melanoma. National Cancer Institute. November 25, 2015. Accessed May 20, 2022. https://bit.ly/3woTDwA

17. OLeary MC, Lu X, Huang Y, et al. FDA approval summary: tisagenlecleucel for treatment of patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia. Clin Cancer Res. 2019;25(4):1142-1146. doi:10.1158/1078-0432.CCR-18-2035

18. FDA approves CAR-T cell therapy to treat adults with certain types of large B-cell lymphoma. News release. FDA. Oct. 18, 2017. Accessed May 11, 2022. https://bit.ly/3wpECL1

19. FDA approves fi rst CAR T-cell therapy the evolution of CAR T-cell therapy. Cell Culture Dish. October 24, 2017. Accessed May 10, 2022. https:// bit.ly/3LlDD2B

20. Albinger N, Hartmann J, Ullrich E. Current status and perspective of CAR-T and CAR-NK cell therapy trials in Germany. Gene Ther. 2021;28:513-527. doi:10.1038/s41434-021-00246-w

21. Ahmad A, Uddin S, Steinhoff M. CAR-T cell therapies: an overview of clinical studies supporting their approved use against acute lymphoblastic leukemia and large B-cell lymphomas. Int J Mol Sci. 2020;21(11):3906. doi:10.3390/ijms21113906

22. Zhou X, Yao Z, Yang H, Liang N, Zhang X, Zhang F. Are immune-related adverse events associated with the efficacy of immune checkpoint inhibitors in patients with cancer? a systematic review and meta-analysis. BMC Med. 2020;18(1):87. doi:10.1186/s12916-020-01549-2

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10 Years of Immunotherapy: Advances, Innovations, and Better Patient Outcomes - Targeted Oncology

Skin Stem Cells Comments Off on 10 Years of Immunotherapy: Advances, Innovations, and Better Patient Outcomes – Targeted Oncology | June 20th, 2022

An estimated 1,240,000 blood cancer cases emerge annually worldwide, accounting for approximately 6 per cent of all the cancer cases. Meanwhile 720,000 people die of blood cancer every year, accounting for 7 per cent of the cancer deaths.

These statistics were shared by Dr Munira Borhany, haematologist and associate professor at the National Institute of Blood Diseases & Bone Marrow Transplant (NIBD) at a public awareness seminar held recently in collaboration with the Neurospinal & Cancer Care Postgraduate Institute.

The event was titled Rising Burden of Blood Cancers in Pakistan.

"Cancers of blood, bone marrow and lymphatic system are collectively referred to as blood cancers ranging from slow-growing to very aggressive. When the body's red blood cells, white blood cells or platelet production is unusual or abnormal, blood cancer develops. It normally begins in the bone marrow, which is responsible for the production of blood. The normal functioning, growth and development of blood cells that fight infection and make healthy blood cells are disrupted by this type of cancer. There are 137 types of blood cancers and related disorders, she explained, adding that blood cancer was among the most common form of cancers to affect children and adolescents.

The haematologist said that the symptoms of blood cancer could be quite variable depending upon its type. The common symptoms included unexplained fatigue, fever, weakness, and tiredness which could be fast develop in conditions such as acute leukaemia. There may be bleeding manifestations, bone pains, occurrence of swellings in the entire body, loss of appetite, weight loss and abdominal pain, she added.

She said that in general, the symptoms could be quite non-specific such as flu-like symptoms to more dramatic ones such as bleeding manifestations and severe infection. Highlighting the efficacy of bone marrow transplant (BMT) for such patients, she said the BMT was a highly effective therapy and often the only hope for a cure or a longer life for patients with blood cancers.

Dr Munira explained BMT was a procedure to replace disordered bone marrow with healthy bone marrow stem cells. Transplant physicians use this procedure to eliminate cancer or defective stem cells and restore a patient's blood and immune systems.

She added that not all patients with blood cancer required BMT. The need for a bone marrow transplant is evaluated case-wise based on the individual patientss underlying diagnosis, treatment response and disease genetic profile. She informed the event that patients' response to treatment in cases of acute leukemia had improved, due to the cutting-edge genetic profiling technologies combined with innovative medication.

Highlighting the benefits of BMT, Dr Munira said the procedure had two major advantages over other forms of transplants firstly, the donors did not lose any vital part of their body for life and secondly, the recipients had to take the immunosuppressive drug only for nine months.

The bone marrow transplant unit at the NIBD has successfully performed 750 BMT, including 690 allogeneic and 60 autologous blood stem cell transplants with the success rate of more than 80 per cent despite the pressure placed on the healthcare system due to Covid-19 pandemic as well as national economic crisis and escalation of the dollar value against the rupee, she said.

The expert said a bone marrow transplant surgery cost more than Rs4 million in Pakistan but the entire procedure was performed at the NIBD free of charge. She requested the industrial sector, philanthropists and NGOs to support the NIBD for this noble cause.

Blood cancer treatment success rates are improving drastically, and patients are living longer than ever before. There are now various effective and targeted therapeutic agents that have been effective such as chemotherapy, radiotherapy, targeted therapy, bone marrow transplantation and immunotherapy in beating cancer. There is a better chance of a complete cure with early diagnosis, she maintained.

Earlier, NIBD Chief Executive Officer Usama Sultan Shamsi told the seminar that there was a need for increasing awareness among the public as well as medical fraternity to help realise that blood cancer and related disorders were just another forms of disease with a potential for high cure rates provided that they were investigated properly and specific treatment instituted.

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Success rate of blood cancer treatment drastically improving, seminar told - The News International

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First prospective controlled trial in the world on treating chronic back pain with stem cells shows 70% of participants helped by the treatment

Dr. Sairam Atluri has successfully treated more than 400 patients at his StemCures clinic in Cincinnati over the past five years

Proper use of bone marrow mesenchymal stem cells, or BM-MSCs, for chronic pain treatment follows FDA protocols

CINCINNATI, June 15, 2022 /PRNewswire/ --Local Cincinnati pain physician Dr. Sairam Atluri led the first prospective controlled clinical trial on using bone marrow mesenchymal stem cells (BM-MSCs) for chronic pain. 70% of study participants gained significant pain relief and improved physical and mental function. The first of its kind in the world, the study was completed last month in Ohio.

"Evaluation of the Effectiveness of Autologous Bone Marrow Mesenchymal Stem Cells in the Treatment of Chronic Low Back Pain Due to Severe Lumbar Spinal Degeneration: A 12-Month, Open-Label, Prospective Controlled Trial"was published in the official publication of the American Society of Interventional Pain Physicians, Pain Physician Journal. It is the only scientifically accepted controlled study in the world. 15 other physicians participated in the study.

"When I saw the results my patients were getting at my StemCures health facility, I and my colleagues decided the only way to get physicians to accept this treatment as a mainstream therapeutic for chronic pain was to get a study published in a respected journal," said Dr. Atluri. "About 90 percent of physicians have little to no knowledge of this treatment. They, and their patients, need to know."

40 patients were in the BM-MSC treatment group for the study, and 40 were in a control group, receiving traditional pain modalities such as injections, physical therapy, nerve ablations, and pain medications. The research group then followed their progress for one year:

Almost 70% of those receiving BM-MSCs had significant pain relief and improved physical and mental function. All had cut down or eliminated their pain medication.

Only 8% in the controlled group (not receiving BM-MSCs) had any improved functioning.

Story continues

BM-MSC treatment is a constructive pain therapeutic, as the patient's own cells, that are proven to be safe and effective, are extracted and then injected back into the area that needs repair and healing. The painless procedure takes about 90 minutes and is typically performed just one time for each area affected by chronic pain.

According to Dr. Atluri, it's important the public knows what BM-MSCs are, and what they aren't.

Mesenchymal stem cells are designed to repair and heal. They are present in every tissue, ready to spring into action if you cut your finger, or suffer an acute muscle injury.

BM-MSC treatment, done properly, follows allowed FDA protocols.

BM-MSCs are not embryonic or fetal stem cells. There are almost no cell therapies currently performed with these cell types.

These are not amniotic stem cells. This is important because there are many "pseudo clinics" advertising stem cell procedures that use "off-the-shelf" amniotic stem cells. Most are not performed by qualified physicians, are violating FDA protocols, and are a waste of money. They may also adversely affect your health.

BM-MSCs are not hematopoietic stem cells derived from blood platelets for treatments such as leukemia.

Dr. Atluri, who has successfully treated over 400 patients over the last five years at his clinic, also pointed out that by making the treatment more accessible to chronic pain sufferers, more patients can wean themselves off prescription painkillers. The consequences of that could significantly impact this country's opioid addiction problem.

"These results of this treatment are astonishing and now, irrefutable," said Dr. Atluri. "I travel around the world educating and teaching other physicians about BM-MSCs and now I can do it with scientific proof in hand. Every physician treating chronic pain patients should be identifying their BM-MSC candidates, which are those who suffer from arthritis or joint degeneration for more than six months and don't have contraindications such as cancer.

"It's changing people's lives and in many cases, giving them a future to look forward to for the first time in years."

For more information about the study and bone marrow mesenchymal stem cells treatment, contact Dr. Atluri at hisStemCures clinic at 513-624-7525. The clinic address is 7655 Five Mile Rd., Ste. 117, Cincinnati.

Cision

View original content:https://www.prnewswire.com/news-releases/cincinnati-pain-management-physician-leads-first-successful-stem-cell-controlled-trial-with-70-of-participants-seeing-positive-results-301568002.html

SOURCE Dr. Sairam Atluri

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Cincinnati Pain Management Physician Leads First Successful Stem Cell Controlled Trial with 70% of Participants Seeing Positive Results - Yahoo...

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-- First Site Will Enroll First Patient in the Clinical Study--

MELVILLE, NY., June 13, 2022 (GLOBE NEWSWIRE) -- BioRestorative Therapies, Inc. (the Company or BioRestorative) (NASDAQ: BRTX), a clinical stage company focused on stem cell-based therapies, today announced site initiation for its Phase 2 clinical trial targeting chronic lumbar disc disease (cLDD). The Denver Spine and Pain Institute is the first clinical site to be initiated. Additional selected sites are expected to be initiated in 2022.

BioRestoratives Phase 2 trial is a double-blind controlled, randomized study to evaluate the safety and preliminary efficacy of a single dose intradiscal injection of the Companys autologous investigational stem cell-based therapeutic, BRTX-100. A total of up to 99 eligible patients will be randomized at up to 15 centers in the United States to receive either the investigational drug (BRTX-100) or control in a 2:1 fashion.

Currently there are no approved, cell-based therapies for cLDD. While there is encouraging data that suggests that patients with cLDD could benefit from autologous stem cell transplants, the low oxygen micro-environment of the disc makes cell-based therapies challenging. BRTX-100 is manufactured under low oxygen conditions and engineered to survive this environment, said Scott Bainbridge, M.D., Principal Investigator for the BRTX-100 trial at The Denver Spine and Pain Institute. Positive proof-of-concept data in this trial could be disruptive and support the potential applicability of BRTX-100 to other spine and musculoskeletal disorders where low oxygen micro-environments are found.

We are pleased to initiate the first of several sites across the United States that will be enrolling for the trial, said Lance Alstodt, Chief Executive Officer of BioRestorative Therapies. Our sites have been carefully reviewed and selected and have clinical expertise in treating patients who could potentially benefit from BRTX-100. We look forward to working with the principal investigators and their clinical trial teams.

About BioRestorative Therapies, Inc.

BioRestorative Therapies, Inc. (www.biorestorative.com) develops therapeutic products using cell and tissue protocols, primarily involving adult stem cells. Our two core programs, as described below, relate to the treatment of disc/spine disease and metabolic disorders:

Forward-Looking Statements

This press release contains "forward-looking statements" within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, and such forward-looking statements are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. You are cautioned that such statements are subject to a multitude of risks and uncertainties that could cause future circumstances, events or results to differ materially from those projected in the forward-looking statements as a result of various factors and other risks, including, without limitation, those set forth in the Company's latest Form 10-K filed with the Securities and Exchange Commission and other public filings. You should consider these factors in evaluating the forward-looking statements included herein, and not place undue reliance on such statements. The forward-looking statements in this release are made as of the date hereof and the Company undertakes no obligation to update such statements.

CONTACT:Email: ir@biorestorative.com

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BioRestorative Therapies Announces Clinical Site Initiation for the Company's Phase 2 Clinical Trial to Treat Chronic Lumbar Disc Disease (cLDD) -...

Bone Marrow Stem Cells Comments Off on BioRestorative Therapies Announces Clinical Site Initiation for the Company’s Phase 2 Clinical Trial to Treat Chronic Lumbar Disc Disease (cLDD) -… | June 20th, 2022

Symptoms of the disease are usually visible at the age of 5 months and change over time. Some of the common symptoms include pain, anaemia, frequent infections, swelling of hands and feet and vision problem

Sickle-shaped cells and normal blood cells in human blood. Image courtesy: Wikimedia Commons/Dr Graham Beards

World Sickle Cell Day is marked every year on 19 June with an aim to raise awareness about sickle cell disease. Sickle Cell Disease is a group of disorders that impact haemoglobin, the molecule in red blood cells which deliver oxygen to cells throughout the body.

Individuals who live with this disease have haemoglobin S, an atypical haemoglobin molecule which distorts red blood cells into a sickle or a crescent shape. The disease is usually transmitted from parents to children.

What are the symptoms?

Symptoms of the disease are usually visible at the age of 5 months and change over time. Some of the common symptoms include pain, anaemia, frequent infections, swelling of hands and feet and vision problem.

What are the different types of Sickle Cell Disease?

If one of the parents has a problem gene, then the child will not have symptoms but will possess sickle cell trait.

What is the treatment?

The disease can be detected in an infant during the screening process of a newborn. In case, there is a family history of the Sickle Cell disease, it can even be diagnosed at the time of pregnancy.

The only way to cure it is either stem cell or a bone marrow transplant. The symptoms can also be dealt with the use of antibiotics, periodic blood transfusion, pain killers, and vaccinations.

Read all the Latest News, Trending News,Cricket News, Bollywood News,India News and Entertainment News here. Follow us on Facebook, Twitter and Instagram.

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World Sickle Cell Day 2022: Know all about symptoms and treatment of the disease - Firstpost

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MarketQuest.biz has announced the addition of new research titled Global Rheumatoid Arthritis Stem Cell Therapy Market from 2022 to 2028, which encompasses regional and global market data and is predicted to generate attractive valuation.The Rheumatoid Arthritis Stem Cell Therapy research covers market drivers, opportunities, limiting factors, and barriers. It provides a quantitative market study based on annual reports, product literature, industry announcements, and other sources.

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Global Rheumatoid Arthritis Stem Cell Therapy Market 2022 Swot Analysis by Top Key Vendors, Demand And Forecast Research to 2028 Designer Women -...

Bone Marrow Stem Cells Comments Off on Global Rheumatoid Arthritis Stem Cell Therapy Market 2022 Swot Analysis by Top Key Vendors, Demand And Forecast Research to 2028 Designer Women -… | June 20th, 2022

DENVER, June 17, 2022 (GLOBE NEWSWIRE) -- Mydecine Innovations Group (NEO: MYCO) (OTC: MYCOF) (FSE: 0NFA) (“Mydecine” or the “Company”), a biotechnology aiming to transform the treatment of mental health and addiction disorders, today announced that the U.S. Food and Drug Administration (FDA) has cleared MYCO-001 in a recent Investigational New Drug (IND) application, marking the first clearance of the Company’s drug product.

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U.S. FDA Clears MYCO-001 for Multi-Site Government Funded Trial in Smoking Cessation

Global News Feed Comments Off on U.S. FDA Clears MYCO-001 for Multi-Site Government Funded Trial in Smoking Cessation | June 20th, 2022

-Yselty® (linzagolix) is the first and only approved GnRH antagonist to provide flexible dosing options with and without hormonal add-back therapy-

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ObsEva Announces European Commission Marketing Authorization for Yselty® (linzagolix), an Oral GnRH Antagonist, for the Treatment of Uterine Fibroids

Global News Feed Comments Off on ObsEva Announces European Commission Marketing Authorization for Yselty® (linzagolix), an Oral GnRH Antagonist, for the Treatment of Uterine Fibroids | June 20th, 2022

JERSEY, Channel Islands, June 17, 2022 (GLOBE NEWSWIRE) -- Quotient Limited (NASDAQ: QTNT), a commercial-stage diagnostics company, today announced that financial results for its fiscal fourth quarter and full year ended March 31, 2022 will be released before market open on Wednesday, June 22, 2022.

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Quotient Limited to Report Fourth Quarter and Full Year 2022 Financial Results and Host Conference Call on June 22nd

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Presentation to be highlighted in the Best of International Liver Congress Presentation to be highlighted in the Best of International Liver Congress

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Altimmune Announces Oral Presentation of Pemvidutide Clinical Data at Upcoming EASL International Liver Congress™ on June 25, 2022

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Top-line Efficacy Results Expected in Approximately 6 to 8 Weeks Top-line Efficacy Results Expected in Approximately 6 to 8 Weeks

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VYNE Therapeutics Completes Enrollment in Phase 2a Trial of FMX114 for the Treatment of Mild-to-Moderate Atopic Dermatitis

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Collaboration with Merck published in Science magazine

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Codexis Announces the Publication of Research Demonstrating Proof of Concept for Chemoenzymatic Site-Selective Bioconjugation of Native Peptides

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CY6463 alleviated mitochondrial dysfunction and reduced inflammation in preclinical models of mitochondrial complex 1 deficiency

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Cyclerion Therapeutics Announces CY6463 Data Demonstrating Improved Cellular Energetics in Preclinical Models of Mitochondrial Disease

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MONTRÉAL, June 17, 2022 (GLOBE NEWSWIRE) -- ExCellThera Inc. (ExCellThera), an advanced clinical-stage biotechnology company delivering molecules and bioengineering solutions to expand and engineer various cell lines for use in next generation cell and gene therapies, announced today that it has submitted a Type II Drug Master File (DMF) with the U.S. Food and Drug Administration (FDA) for UM171, a proprietary molecule being studied for use in the expansion and rejuvenation of hematopoietic stem cells.

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ExCellThera announces submission of Drug Master File for UM171

Global News Feed Comments Off on ExCellThera announces submission of Drug Master File for UM171 | June 20th, 2022