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Archive for the ‘Stem Cell Therapy’ Category

Stem Cell Therapy for Cancer: Hope on the Horizon? – Corporate Wellness Magazine

Tuesday, February 27th, 2024

Stem Cell Therapy for Cancer: Hope on the Horizon?  Corporate Wellness Magazine

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Ethical considerations in Stem Cell therapy for ALS – Cyprus Mail

Tuesday, February 27th, 2024

Ethical considerations in Stem Cell therapy for ALS  Cyprus Mail

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AI Biotech Secures Funding to Speed Up Stem Cell Therapy Development – BioPharm International

Wednesday, January 17th, 2024

AI Biotech Secures Funding to Speed Up Stem Cell Therapy Development  BioPharm International

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Therapeutic Solutions International Launches Adult Stem Cell Therapy Company Focused on Curing Epilepsy – Yahoo Finance

Wednesday, January 17th, 2024

Therapeutic Solutions International Launches Adult Stem Cell Therapy Company Focused on Curing Epilepsy  Yahoo Finance

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Eggs from men, sperm from women: Stem cell therapy may just turn reproduction upside down! – The Economic Times

Wednesday, January 17th, 2024

Eggs from men, sperm from women: Stem cell therapy may just turn reproduction upside down!  The Economic Times

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Stem Cell Therapy Market is Expected to Reach $615 Million | MarketsandMarkets. – Yahoo Finance

Wednesday, January 17th, 2024

Stem Cell Therapy Market is Expected to Reach $615 Million | MarketsandMarkets.  Yahoo Finance

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James Shapiro, MD: Insulin Production In T1D Patients After Stem Cell Therapy – MD Magazine

Tuesday, January 9th, 2024

James Shapiro, MD: Insulin Production In T1D Patients After Stem Cell Therapy  MD Magazine

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Global Stem Cell Therapy Market to Reach Value of USD 26.15 Billion by 2030 | Skyquest Technology – GlobeNewswire

Tuesday, January 9th, 2024

Global Stem Cell Therapy Market to Reach Value of USD 26.15 Billion by 2030 | Skyquest Technology  GlobeNewswire

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Stem Cell Therapy: From Idea to Clinical Practice – PMC

Wednesday, December 13th, 2023

Int J Mol Sci. 2022 Mar; 23(5): 2850.

Akiko Maeda, Academic Editor and Ali Gorji, Academic Editor

Received 2022 Jan 25; Accepted 2022 Mar 3.

Regenerative medicine is a new and promising mode of therapy for patients who have limited or no other options for the treatment of their illness. Due to their pleotropic therapeutic potential through the inhibition of inflammation or apoptosis, cell recruitment, stimulation of angiogenesis, and differentiation, stem cells present a novel and effective approach to several challenging human diseases. In recent years, encouraging findings in preclinical studies have paved the way for many clinical trials using stem cells for the treatment of various diseases. The translation of these new therapeutic products from the laboratory to the market is conducted under highly defined regulations and directives provided by competent regulatory authorities. This review seeks to familiarize the reader with the process of translation from an idea to clinical practice, in the context of stem cell products. We address some required guidelines for clinical trial approval, including regulations and directives presented by the Food and Drug Administration (FDA) of the United States, as well as those of the European Medicine Agency (EMA). Moreover, we review, summarize, and discuss regenerative medicine clinical trial studies registered on the Clinicaltrials.gov website.

Keywords: regenerative medicine, stem cell therapy, mesenchymal stem cell, clinical trial

Despite the progress in medical science, there still exist various diseases in the world for which there is no suitable treatment. People affected by incurable disorders typically use treatment methods intended to decrease the somatic and psychological symptoms and, in these situations, the physician offers treatment methods only to manage the disease, not treat it. Therefore, researchers are attempting to develop new treatment methods to not only control the symptoms of, but also to treat those diseases for which no cure is available at present.

Regenerative medicine is considered a promising new source of treatment for untreatable diseases in modern science [1]. Regenerative medicine is a multidisciplinary field including cell biology, genetic, biomechanics, material science, and computer science [2,3], the ultimate target of which is returning normal function to defective cells and tissues [4]. Since the discovery of stem cells and the spread of awareness regarding their unique properties, they have been defined as therapeutic agents for organ and tissue repair, and so are widely considered good candidates for regenerative medicine, due to their many potential applications [5]. Regenerative medicine is now regarded as an alternative to traditional drug-based treatments by researchers who study its potential applications in various diseases, including degenerative diseases, among others [6,7,8,9,10]. The main concept of regenerative medicine is implied tissue/organ regeneration using cells and, to reach this target, different kinds of cells have been used. However, various studies have indicated that cell therapy is restricted by a few limitations. In recent years, different alternatives have been introduced for cell therapy in order to resolve these limitations, including the improved application of stem cells for the restoration of tissue, such as the combination of cells with scaffolds, cell cultures with suitable biochemical properties, gene editing, and the immunomodulation of stem cells, as well as the use of stem cell derivatives [11,12,13,14,15]; however, the use of these alternatives clinically may be postponed, as more preclinical studies are required due to their status as newer technologies [16].

Stem cells are a group of immature cells that have the potential to build and recover every tissue/organ in the body due to their unique proliferative, differentiation, and self-renewal abilities [17]. Stem cells provide therapeutic effects which improve physical development by regenerating damaged cells to assist in organ recovery. Relying on the natural abilities of stem cells, researchers have used their biological mechanisms for stem-cell-based therapy. The mechanisms of action through which stem cells can promote the regeneration of tissue are diverse, including (1) inhibition of inflammation cascades [18,19], (2) reduction of apoptosis [20,21], (3) cell recruitment [22,23], (4) stimulation of angiogenesis [24,25], and (5) differentiation [26]. The cause of a disease is a vital consideration in selecting the proper stem cell mechanism and in the regeneration of tissue/organs using stem cells. Many examinations must be carried out to determine the main mechanisms involved in treatment when these cells are to be used in clinical practice, and the convergence of stem cell therapeutic mechanisms and disease mechanisms is expected to increase the chance of developing cures through stem cell applications.

From 1971 to 2021, 40,183 research papers were published regarding stem-cell-based therapies. All of these studies were conducted around discoveries and for the goal of Stem Cell Therapy based on the therapeutic efficacy of stem cells [27]. As basic stem cell research has soared over the past few years, translation research, a relatively new field of research, has recently greatly developed, making use of basic research results to develop new treatments. Although many articles on stem-cell-based therapies are published annually and their number increases every year, the number of clinical trial studies has not increased rapidly. Furthermore, among these studies, only a small portion of them can receive full regulatory approval for verification as treatment methods. Although one reason for this difference is due to the need for various prerequisite preclinical studies before carrying out a clinical trial study, the main reason is due to the sharply defined guidelines which prevent the translation of many preclinical studies to clinical trials.

In this review, we provide a general overview regarding the translation of stem cell therapies from idea to clinical service. Understanding the step-by-step knowledge underlying the translation of ideas to medical services is the first step in introducing a new treatment method. In this review, we divide this pathway into four levels, including idea evaluation, preclinical studies, clinical trial studies, and clinical practice. We focus not only on understanding each levels requirements, but also discuss how an idea is assessed during the transition from one level to the next and, finally, move on to marketing.

If a researcher has an idea regarding regenerative medicine using stem cells that inspires their use in a study, it must first be evaluated. During the evaluation step, it is important to select the target disease and make sure that the mechanism causing the disease is understood. Disease-related mechanisms refer to the cellular and molecular processes by which a particular disorder is caused [28,29], and stem-cell-based therapies are considered a treatment method intended to compensate for the disruption caused by such mechanisms in order to finally restore the defective tissue. Multiple mechanisms cause diseases [30,31,32]; however, stem cells, with their tremendous differentiation, self-renewal, angiogenesis, anti-inflammation, anti-apoptotic, and immunomodulatory potentials, as well as their capacity for induction of growth factor secretion and cell signaling, can affect these mechanisms [33,34,35,36,37].

After subject evaluation, preclinical studies should be carried out to determine whether the idea has any potential to treat the disease, and the safety of the final product should be assessed in an animal model of the target disease [38,39,40]. Preclinical studies are composed of in vitro and in vivo studies. In vitro experiments are performed with biological molecules and cells based on various hypotheses and, during the in vitro evaluation, a new treatment method is assayed in this controlled environment [39]. In contrast, during in vivo studies, as controlling all biological entities is impossible, the new product may be affected by various factors and thus present different effects. The general purpose of a preclinical study is to present scientific evidence supporting the performance of a clinical study, and the following are required for a decision to move forward to clinical study: (i) the feasibility and establishment of the rationale (e.g., validation, separation of active ingredients in vitro, and determination of its mechanism in vivo), (ii) establishment of a pharmacologically effective capacity (e.g., secure initial dose verification), (iii) optimization of administration route and usage (e.g., safe administration method, repeated administration, and interval verification), (iv) identification and verification of the potential activity and toxicity (e.g., toxicity analysis according to single and repetitive testing), (v) identification of the potential for special toxicity (e.g., genetic, carcinogenic, immunological, and neurotoxic analyses), and (vi) determination of whether to continue or discontinue development of the treatment [41,42].

In principle, any idea regarding stem cell therapy should be assessed using comprehensive studies (i.e., in vitro and in vivo) before a clinical trial is considered, and the results of these studies should be proved by competent authorities. It can be easy during an in vitro study to create manipulative biological environments such as through the use of genetic mutation, drug testing, and pharmaceuticals, and it is easy to observe changes through the application of manipulated variables through living cells [43,44,45]. However, given the many associated variables, such as molecular transport through circulating blood and organ interactions, it is hard to say whether such a study can completely mimic the in vivo environment [43,44,45]. Before application in patients, in vivo experiments are conducted after in vitro experiments in order to overcome these weaknesses.

Many researchers use rodents for in vivo studies, due to their anatomical, physiological, and genetic similarities to humans, as well as their other unique advantages including small size, ease of maintenance, short life cycle, and abundant genetic resources [46]. The strength of in vivo studies is that they can supplement the limitations of in vitro studies, and the outcomes of their applications can be inferred in humans through the use of human-like biological environments. To establish in vivo experiments for stem cell therapies, the most correlated animal model should be selected depending on the specific safety aspects to be evaluated. Where possible, cell-derived drugs made for humans should be used for proof-of-concept and safety studies [47]. Homogeneous animal models can also be utilized as the most correlated systems in proof-of-concept studies [48].

Furthermore, in vivo studies require ethical responsibilities and obligations to be upheld according to experimental animal ethics. In other words, unnecessary and unethical experiments must be avoided. Summing up the above, we can see that both in vitro and in vivo approaches are used in preclinical studies, which should be carried out before clinical trial applications based on various interests.

Several factors must be considered in different in vitro and in vivo studies, including cell type determination, cell dose specification, route of administration, and safety and efficiency.

As expectations rise for regenerative treatment through the application of stem cell therapies, the number of applications of various types and stem cell sources has increased, and stem cell therapies have diversified from autologous to allogenic to iPSCs. These stem cell treatments can vary in risk, depending on the cell manufacturing process [49], among other factors, and in clinical experience, such that all types of stem cell treatments must be evaluated on the same basis [50]. Therefore, the strengths and weaknesses of each type of stem cell should be identified in order to determine the maximum therapeutic effect of stem cells in various diseases. This will enable us to build disease-targeted stem cells by applying the appropriate stem cells to the appropriate diseases. Below, we briefly discuss the characteristics of various stem cells.

MSCs are lineage-committed cells that divide into mesenchymal systems, primarily fatty cells, chondrocytes, and osteocytes [51]. It is well known that MSCs can be differentiated into dry cells, nerve cells, glioma cells, and skeletal muscle cells under proper in vitro culture conditions [52,53,54,55,56,57]. MSCs are primarily derived from myeloid and adipose tissues [58,59]. At present, MSCs are also isolated from many other tissues, such as the retina, liver, gastric mucosa, tendon, cartilage, placenta, cord blood, and blood [60,61,62,63]. The biggest characteristics of MSCs are their immunosuppressive functions, which prevent the proliferation of activated T cells through immunosuppressive cytokine secretion and suppression of programmed cell death signaling [64,65]. Due to this role, they have been spotlighted as a potential treatment for immune-related inflammation and disease. The initial clinical application of MSCs was in a case of patients with severe graft versus host disease (GVHD), and these cells have since been well applied in clinical practice, as evidenced through various studies [66,67,68].

MSCs have a variety of characteristics according to their organ of origin [69]. BM-MSCs, which are isolated from bone marrow, are useable in both autologous and allogenic contexts, and can perform stromal functions. However, the process of cell isolation from bone marrow is not only accompanied by the risk of pain and infection, but also has a lower efficiency of collection than other MSC sources. Furthermore, these cells have a longer doubling time (DT) in comparison to MSCs derived from other sources (approximately 60 h) [70]. Compared to BM-MSCs, AD-MSCs are not only easy to collect, but are also 100 to 500 times more efficient to harvest and have a shorter DT (approximately 20 h) [71]. However, these are adipose-derived stem cells that have a strong characteristic of adipogenic differentiation, such that they can be suggested as a valid alternative to BM-MSCs, but their nature must be considered regarding proper culture and body environment. Furthermore, there are concerns that these factors may affect the efficacy of treatment, as the amount of cytokines secreted is significantly lower when compared to BM-MSCs [72]. MSCs extracted from the umbilical cord (UC-MSCs) have come into the spotlight to compensate for these issues: UC-MSCs not only have the advantage of being easily collected compared to other stem cells, but also avoid ethical or donor age issues. They have superior proliferation and differentiation capabilities compared to BM-MSCs and AD-MSCs, and their DT has been reported as 24 h [69,73]. UC-MSCs are currently a subject of concern, as although they are easy to store frozen for a long time (e.g., in a cord blood bank), the cell survival rate and success rate during extraction are not high, due to exposure to cryogenic protectors during cryogenic storage [73]. Furthermore, as the cells are isolated from other organs, they have limited self-renewal capacity, and their senescence is faster than in other stem cells in long-term cultivation [66,74].

HSCs can be differentiated into cells from all hematopoietic systems present in the bone marrow and chest glands, namely myeloid cells and lymphocytes. HSCs can be obtained at good levels from adult bone marrow, the placenta, and cord blood. They can cause immunological problems such as transplant rejection. Nevertheless, they have been shown to be an effective treatment method in various diseases, including leukemia, malignant lymphoma, and regenerative anemia, as well as congenital metabolism, congenital immunodeficiency, nonresponsive autoimmune disease, and solid cancer to date. Furthermore, HSCs are the only stem cell type approved for stem cell treatment by the Food and Drug Administration (FDA) [75,76].

ESCs have established cell lines that can be maintained through in vitro culture. They are pluripotent cells that can be differentiated into almost any type of cell present in the body, and can be differentiated in vitro by adding external factors to the culture medium or by genetic modification. However, they may form teratomas, which are composed of various forms of cells derived from the endoderm, mesoderm, and exoderm, when transplanted into an acceptable host [77].

iPSCs are artificially created stem cells. These cells are made by reprogramming adult somatic cells such as fibroblast cells. They share many of the characteristics of ESCs, including self-renewability, pluripotent differentiation, and malformed species performance. Unfortunately, these cells have little scientific evidence regarding changes in cell-specific regulatory pathways, gene expression, and epigenetic regulation. These characteristics pose a risk of tissue chimerism or cell dysfunction [78].

In summary, although the FDA-approved stem cell type is HSCs from healthy donors, a variety of issues have been raised, including a lack of donors and immune rejection. Therefore, we need to understand the characteristics of stem cells in order to handle them accordingly and overcome their disadvantages while maximizing their advantages. As stem cells derived from various sources have different characteristics, capabilities, potential, and efficiency, selecting the right source of stem cells that is appropriate for the target can be effective in assuring treatment efficiency.

The effective range of administration (i.e., dosage) of stem cells or stem-cell-derived products used in treatment should be determined through in vivo and in vitro studies. The safe and effective treatment capacity must be identified and, where possible, the minimum effective capacity must also be determined. When administered to vulnerable areas such as the central nervous system and myocardium, it has been reported that conducting normal dosage determination tests is unlikely. Thus, if the results of nonclinical studies can safety demonstrate treatment validity, it may be appropriate to conduct early human clinical trials with doses that may indicate therapeutic effects [79].

Will a high cell dose have better effects, considering only the effectiveness of stem cells? We answer this question below. An increasing dose of CD34+ cells (0.5 105 per mouse) has been shown to have positive effects, stimulating multilineage hematopoiesis at early stages and increasing the magnitude of reconstitution at post-transplant stages. Furthermore, improved T-cell reconstitution was correlated with higher cell doses of stem cells, compared to lower cell doses [80]. However, a few studies related to acute myeloblastic leukemia (AML) have reported that high doses of HSCs were correlated with restored function and rapid hematological and immunological recovery, but these results were not unconditional. In this study, a higher dose of HSCs (7 106/kg) resulted in poorer outcomes and a higher relapse rate than the lower dose of HSCs (<1 106/kg) [81]. In preclinical studies on heart disease, Golpanian et al. have demonstrated, through comparison of some preclinical studies for optimized cell dose, the therapeutic effects of stem cell types (i.e., allogenic and autologous MSCs), as well as the proper cell dose of stem cells and route of administration (direct epicardial and intravenous) in heart disease. Their results showed that the total number of cells used was different, but were inconsistent with the hypothesis that a higher number of cells would have higher therapeutic efficacy [82]. Therefore, these conclusions suggest that the currently reported data do not provide a decisive answer, such that sufficient and detailed early-stage studies may be needed before proceeding with clinical trials.

Stem cells have been extensively studied under various disease conditions, depending on their type and characteristics. At this time, the route of administration should not be overlooked in favor of the number of stem cells transplanted. Several reports have shown that engraftment ability typically has a lower rate of reaching target organs relative to the number of transplanted cells, and does not have a temporary longer duration [83,84].

The methods of stem cell administration can largely be divided into local and systemic transmission. Local transmission involves specific injections through various manipulations and direct intra-organ injections, such as intraperitoneal (IP), intramuscular, and intracardiac injections. Systemic transmission uses vascular pathways, such as intravenous (IV) and intra-arterial (IA) methods. According to the publications in the literature, IV is the most common method, followed by intrasplenic and IP [85,86,87]. In a liver disease model, IV was shown to be not only suitable for targeting the liver, but also showed better liver regeneration effects than other routes of administration [85,88]. Intracardial injection showed better cell retention in heart disease, while intradermal injection showed better treatment in skin diseases [89,90]. Hence, we can determine that, in the context of these various diseases, the routes of administration should be different depending on the target organ. Many researchers have suggested that intravascular injection is a minimally invasive procedure, but it also poses a risk of clogged blood vessels, such that direct intravascular injection increases the risk of requiring open-air operations [91]. Clinical trials have reported that the number of cells and treatment efficacy under the same conditions, as in preclinical studies, are not significant, but also differ in significance depending on the route of administration [92,93]. Therefore, researchers should continue to study which cells are appropriate for a given route of administrationeven within the same diseasebased on many precedents [82]. In addition, researchers should explore the appropriate routes of administration for safer and more effective therapeutic effects.

All medical treatments have benefits and risks. It is not particularly safe to apply these unproven stem cell treatments to patients. As expectations for regenerative treatment through stem cell therapies increase, the application of various administration pathways, including through the spinal cord, subcutaneous, and intramuscular, as well as the stem cell therapies themselves, have been diversifying, from autologous to homogenous to iPS. These stem cell treatments can vary in risk, depending on the cell type manufacturing process among other factors, and they differ in clinical experience, such that all types of stem cell treatments must be evaluate on the same basis. Furthermore, it should only be in limited and justified contexts that stem cells which can proliferate and have all-purpose differentiation remain in a final product.

Unfortunately, the only safe stem cells that have been employed in regenerative medicine so far are omnipotent stem cells, such as HSCs and MSCs, which are isolated from their self-origin [94]. Unfortunately, potential clinical applications using iPSCs and ESCs face many hurdles, as they present higher risk, including the possibility of rejection, teratoma formation, and genomic instability [95]. Hence, many researchers have attempted to overcome stem cell tracking for safety assessment. To check the engraftment and the remaining amount of stem cells, they have been labeled using BrdU, CM-Dil, and iron oxide nanoparticles, and visualized using Magnetic resonance imaging (MRI) [84,96,97].

A close analysis of the distribution patterns of administrative sites and target organs is required, as well as whether a distribution across the body is expected, and the organ that the cells are predicted to be distributed through should undergo a full-term analysis, including evaluation at administrative sites. To date, studies have reported assessments in the brain, lungs, heart, spleen, testicles, ovaries, kidneys, pancreas, bone marrow, blood, and lymph nodes, including areas of administration [98].

Some researchers have carried out the detection of transplanted UC-MSCs delivered by IV injection in the lung, heart, spleen, kidney, and liver. According to their results, the transplanted cells were not detected in other organs, except the lung and liver, for 7 days. In the lung and liver, the detected cells persisted at least 7 days after the transplant [99]. Furthermore, in a study comparing BM-MSCs and UC-MSCs in terms of cell tracking, they reported on the persistence of stem cells according to the route of administration used. In the results of the comparison of intracardiac and intravenous routes, the transplanted stem cells were detected in the lung for 10 days, but the signal disappeared after 21 days [100]. In other research, the stem cells were transplanted with using a biomaterial scaffold. The AD-MSCs were transplanted with hyaluronic acid/alginate hydrogel through intradermal injection, and could be detected by CM-Dil staining for 30 days [101]. These studies may show that the transplanted cells localized to the damaged organs through their homing ability, but the results of these previous studies seem to indicate that the residual volume and the residual date vary significantly depending on the target disease, organs, and type of stem cells. The cell residual means the survival of the cell, which represents the risk of formation of tumors. To overcome the problem of teratoma formation, the following results have been reported: According to one study, ESCs showed the following rates of teratoma formation: 100% under the kidney capsule, 60% intratesticular, 25100% subcutaneous, and 12.5% intramuscular. To overcome this problem, the investigators performed a co-injection with Matrigel into an animal model. According to their results, subcutaneous implantation of ESCs in the presence of Matrigel appeared to be the most efficient, reproducible, and easiest approach for preventing teratoma formation, other than only using ESCs [102]. Moreover, cellular products derived from iPSCs have higher potential as potential cell sources in personalized medicine [103]. Their applicability is currently limited due to concerns regarding the potential risk of serious transplant-related side effects, such as tumor formation due to residual pluripotent cells [104]. Hence, a recent study reported the establishment of an optimized tool for therapeutic intervention that allows for controlled specific and selective ablation of iPSCs through the use of LVCAGstransgenic iPSCs [104].

Unlike MSCs, which are generally considered immune-tolerant as an immunomodulator, transplantation of ESCs and HSCs requires close examination of the matching of histocompatibility antigen (HLA) between the donor and beneficiary [105,106]. Although homogeneous mesenchymal stem cells are known to have immunogenicity in immune-active rodent models and are quickly removed from the peripheral blood, studies have shown that a few MSCs remain for weeks to months. Therefore, it is recommended to conduct a study to assess the persistence of MSCs in the cell preparations administered, in order to assess the risk of stem cell removal. Therefore, for stem cell therapies that have undergone extensive in vitro manipulation such as long-term cell cultureincluding those derived from ESCs and iPSCsboth oncogenicity and genetic stability must be evaluated before clinical research begins. Furthermore, we must constantly review and study the latest research on safety, as well as the effects of regeneration using stem cells, and discuss and study the potential of regenerative medicine [107,108,109,110,111].

As discussed earlier, in vitro and in vivo preclinical studies are the direction of current research, and encompass the tasks that need to be completed. If we reinforce the current strengths and weaknesses based on the preceding content, we are already a step closer to developing stem cell treatments.

Before a treatment is applied in humans (i.e., patients), preclinical study must involve checking whether the effect of treatment will be positive or negative and, if there are any negative effects, the researcher must check the safety possibilities at every step. Due to concerns relating to treatment using stem-cell-based products, deciding whether preclinical studies are sufficient for translating to clinical trials raises several issues that must be assessed by competent authorities. An application for a clinical trial should be submitted to the Food and Drug Administration (FDA), the European Medicine Agency (EMA), or another organization, based on the country [112].

The FDA is responsible for certifying clinical trial studies for stem-cell-based products in the United States [113]. If a new drug is introduced to a clinical investigator which has not been approved by the FDA, an Investigational New Drug (IND) application may need to be submitted [114]. The IND application includes data from animal pharmacology and toxicology studies, clinical protocols, and investigator information [115]. A lack of preclinical support (e.g., in vitro and in vivo studies) can lead to required modification or disapproval. If the FDA has announced that an IND requires modifications (meaning that the application is intended to secure approval but has not yet been approved), the results of the preclinical studies were deemed insufficient or inadequate for translation to clinical trial study, such that further study must be completed, after which an amended IND should be submitted.

The FDA has published guidelines for the submission of an IND in the Code of Federal Regulations (CFR). These regulations are presented in 21 CFR part 210, 211 (Current Good Manufacturing Practice (cGMP)), 21 CFR part 312 (Investigational New Drug Application), 21 CFR 610 (General Biological Product Standards), and 21 CFR 1271 (Human Cells, Tissues, and Cellular and Tissue-Based Products) [116,117,118]. These guidelines have been issued for the development of stem cell products with the highest standards of safety and potential effective translation to clinical trial studies.

The FDA issued 21 CFR parts 210 and 211to ensure the quality of the final products [119]. The 21 CFR part 210 contains the minimum current good manufacturing practice (cGMP) considered at the stages of manufacturing, processing, packing, or holding of a drug, while the 21 CFR part 211 contains the cGMP for producing final products. The 21 CFR 211 includes FDA guidelines for personnel, buildings and facilities, equipment, and control of components, process, packaging, labeling, holding, and so on, all of which are critical for pharmaceutical production [116,117,118,119,120,121]. The requirements for IND submission and conducting clinical trial studies, reviewed by the FDA in the 21 CFR part 312 (Investigational New Drug Applications), includes exemptions that are described in detail in 312.2 (general provisions). Such exemptions do not require an IND to be submitted, but other studies must present an IND based on 21 CFR part 312. The section, 21 CFR part 312, provides different information, including the requirements for an IND, its content and format, protocols, general principles of IND submission, and so on. In addition, the FDA describes the administrative actions of IND submission, the responsibilities of sponsors and investigators, and so on, in this section [116,117,122]. The 21 CFR part 610 contains general biological product standards for final product characterization. The master cell bank (MCB) or working cell bank (WCB) used as a source for stem-cell-based final products must be tested before the release or use of the product in humans. The MCB and WCB should be tested for sterility, mycoplasma, purity, identity, and potency, among other tests based on the final products (e.g., viability, stability, phenotypes), before use at the clinical level. The FDA provides all required information regarding general biological product standards in this section, including release requirements, testing requirements, labeling standards, and so on [116,117,123,124]. The 21 CFR part 1271 focuses on introducing the regulations for human cells, tissues, and cellular and tissue-based products (HCT/Ps), in order to ensure adequate control for preventing the transmission of communicable disease from cell/tissue products. Current Good Tissue Practice (GTP) is a part of 21 CFR part 1271, where the purpose of GTP is to present regulations for the establishment and maintenance of quality control for prevention of introduction, transmission, or spread of communicable diseases, including regulations for personnel, procedures, facilities, environmental control, equipment, and so on [125,126,127,128].

The EMA is an agency in the European Union (EU) which is responsible for evaluating any investigational medical products (IMPs) in order to make sure that the final product is safe and efficient for public use. When planning to introduce a new drug for a clinical trial in Europe, one may be required to submit clinical trial applications to the EMA for IMPs. Clinical trial applications for IMPs include summaries of chemical, pharmacological, and biological preclinical data (e.g., from in vivo and in vitro studies) [129]. The EMA has presented different regulations to support the development of safe and efficient products for public usage, including Regulation (EC) No. 1394/2007, Directive 2004/23/EC, Directive 2006/17/EC, Directive 2006/86/EC, Directive 2001/83/EC, Directive 2001/20/EC, and Directive 2003/94/EC.

Regulation (EC) No. 1394/2007 defines the criteria for regulation regarding ATMPs. Advanced therapy products (ATMPs) are focused on gene therapy medicinal products (GTMP), somatic cell therapy medicinal products (sCTMP), tissue-engineered products (TEP), and combined ATMPs, which refers to a combination of two different medical technologies. Regulation (EC) No. 1394/2007 includes the requirements to be used in development, manufacturing, or administration of ATMPS [130,131,132]. Directive 2004/23/EC, Directive 2006/17/EC, and Directive 2006/86/EC define standards for safety and quality, as well as technical requirements for donation, procurement, testing, preservation, storage, and distribution of tissue and cells intended for human applications [133,134,135]. Directive 2001/83/EC applies to medicinal products for human use [136]. Directive 2001/20/EC presents the regulations for the implantation of products in clinical trials in the EU [137]; however, this directive will be replaced by regulation (EU) No. 536/2014. Regulation (EU) No. 536/2014 was adapted by the European Parliament in 2014, and provides regulation for clinical trials on medical products intended for human use. The new EU regulation comes into effect on 31 January 2022 and aims to coordinate all clinical trials performed throughout the EU, using clinical trials submitted into CTIS (Clinical Trials Information System). The definition of regulation (EU) No. 536/2014 as a homogeneous regulation serves an important role in the EU, as all member states of the EU can be involved in multicenter clinical trials using international coordination, thus allowing larger patient populations [138]. Directive 2003/94/EC provides Good Manufacturing Practice (GMP) Guidelines in relation to medicinal products or IMPs intended for human use [139]. All process and application requirements for the IMP application are present in the regulations and directives of the EMA. After presenting an IND/IMP to the regulatory authority responsible for clinical trial oversight (FDA or EMA), the application will be reviewed in accordance with the FDA/EMA criteria and, if assured of the protection of humans enrolled in the clinical study, the application will be approved by the investigational review boards (IRBs) in the United States or Ethics Committees (ECs) in the European Union. Clinical trial studies are composed of different steps where, at each step, products are assessed using different quality and quantity measurements by the responsible agency. An efficient clinical trial study should address the safety and efficiency of new stem cell products in each of the different steps, and it is important to complete each step based on defined instructions and regulations, as the results of previous steps are needed to move forward.

Almost all clinical trial studies that have been approved for testing in humans have been registered online (https://www.clinicaltrials.gov/ accessed 12 December 2021). Our search on this website revealed more than 6500 records for interventional studies registered using Stem Cells up to December 2021. The recorded clinical trials can be analyzed from different aspects.

Recruiting status: The recruiting status of these studies indicated that 18% of these studies were ongoing (recruitment) and 42% were completed (). Although completed, suspended, terminated, and withdrawn studies are all terms used for studies that have ended, each is used to describe a different status. Completed studies are those that have ended normally and the participants were completely enrolled in the study. Suspended, terminated, and withdrawn studies are studies that stopped early; however, the participant enrolment status differs between them. A suspended study may start again, but nobody can continue to participate in terminated or withdrawn studies [140,141].

Status of clinical trials using stem cells.

Type of disease: Stem-cell-based therapy is a new approach for the treatment of various diseases in different clinical trial studies. Blood and lymph diseases are the most common diseases that have benefited from this new approach (). Blood and lymph diseases refer to any type of disorder related to blood and lymph deficiency or abnormality, such as anemia, blood protein disorder, bone marrow disease, leukemia, hemophilia, thalassemia, thrombophilia, lymphatic disease, lymphoproliferative disease, thymoma, and so on. In addition, various clinical trial studies have been performed using stem cells to treat immune system disease; neoplasm, heart, and blood disease; and gland- and hormone-related disease (). However, this does not mean that all of these studies had great results, nor does it mean that all of these studies introduced a new treatment method; some of these clinical trial studies were only intended to increase treatment efficiency, compare different types of treatment methods, or analyze various parameters after the administration of stem cells into the body.

Diseases considered in clinical trials using stem cells.

Autologous vs. Allogenic: Stem-cell-based products for use in clinical trial studies can be divided into two categories: autologous and allogeneic stem cells. In autologous stem cell therapy, the stem cells are collected from the patients own body. Culture-expanded autologous stem cells are autologous stem cells that are expanded before transplantation, and can be divided into two groups: modified and unmodified expanded autologous stem cells. If autologous stem cells were transplanted to the donor immediately after collection, this is a nonexpanded autologous stem cell treatment. The use of these cells usually has fewer restrictions for receiving clinical trial authorization. The classification of allogenic stem cells is similar to that of autologous stem cells, except that allogeneic stem cells are collected from a healthy donor. The use of these cells requires more prerequisite tests, in order to check the donors health. Allogenic stem cells have been used more than autologous stem cells in the clinical trial studies (46.34% vs. 44.51%), as shown in .

Applied stem cell types in clinical trials using stem cells.

Phase: Clinical trial studies are conducted in different phases. In each phase, the purpose of study, the number of participants, and the follow-up duration may differ. A new phase of clinical trials should not be started unless the results of the completed phase(s) have been reviewed by competent authorities, in order to that certify the results of the completed phase(s) are valid for authorization of the start a new phase of the clinical trial. For this purpose, at the end of each phase of a clinical trial study, competent authorities evaluate whether the new drug is safe, efficient, and effective for the treatment of the target disease ().

Status of clinical phase within clinical trials using stem cells.

Early Phase I emphasizes the effects of the drug on the human body and how the drug is processed in the body.

Phase I of a clinical trial is carried out to ensure that a new treatment is safe and to determine how the new medicine works in humans. The FDA has estimated that about 70% of the studies pass this phase.

In Phase II, the accurate dose is determined and initial data on the efficiency and possible side effects are collected. The FDA has estimated that roughly 33% of the studies move to the next phase.

Phase III evaluates the safety and effectiveness of products. The result of this phase is submitted to the FDA/EMA for new product approval, which allows manufacturing and marketing of the drug. The FDA has estimated that 25%30% of the drugs pass at this phase.

Phase IV take place after the approval of new products and is carried out to determine the public safety of the new product [142,143,144].

The number of participants and the duration: A new stem cell product is eligible for marketing after completing successful clinical trial phases. As the new product has been used on volunteers and the effects/side effects of the drug have also been followed for a long time throughout the different phases, it is now possible to make a decision regarding its introduction to the market for public use. The number of participants and the duration of long-term follow-up in each study and each phase differ ( and ). The number of volunteers that participate in each phase of a clinical trial study varies, as each phase has a different target. The FDA has recommended 2080, 100300, and several hundred to thousands of volunteers for Phase I, Phase II, and Phase III, respectively [144,145]. Although the FDA has defined a range for enrolments per phase, the number of participants can vary depending on the type of disease. The number of participants for clinical studies in rare diseases will be lower than when studying common diseases. Searching for stem cells in clinicaltrial.gov, studies can be found with only one participant (e.g., {"type":"clinical-trial","attrs":{"text":"NCT02235844","term_id":"NCT02235844"}}NCT02235844, {"type":"clinical-trial","attrs":{"text":"NCT02383654","term_id":"NCT02383654"}}NCT02383654, {"type":"clinical-trial","attrs":{"text":"NCT03979898","term_id":"NCT03979898"}}NCT03979898, and {"type":"clinical-trial","attrs":{"text":"NCT01142856","term_id":"NCT01142856"}}NCT01142856). The sponsor/investigator must provide the FDA with strong documentation regarding the selection of such a number of volunteers. The volunteers for each clinical trial study, before attending, should be informed about the enrolment criteria of each study, possible side effects, and the advantages of the study.

Enrolment of clinical trials using stem cells.

The duration of each clinical trial study using stem cells.

Age of participants: Roughly 190,000 people participated in all the completed clinical trial studies using stem cells that had been registered. Each clinical study was performed in different age groups, which differed among the various studies depending on the type of drug, type of disease, and sponsor decision, as shown in .

The age of patients participating in clinical trials using stem cells.

Number of clinical trial studies: The number of clinical trial studies increased gradually from 2000 to 2014, although it fluctuated after 2014 but did not change significantly (). The reason for this increase in 2014 is not clear, but it may have been related to the introduction of the first advanced medicinal therapy product containing stem cells (Holoclar) by the EMA in 20142015 [146].

The proportion of clinical trials using stem cells by year: (A) the proportion of new clinical trial studies using stem cells by year (green bar) and the proportion of registration results accordingly (orange color line); (B) the proportion of completed registered clinical trial studies using stem cells by year (blue bar) and the updated results of completed clinical trial studies using stem cells by year (orange line).

Place of study: According to economic website reports, the cell therapy market has grown significantly in recent years, and it is expected to grow more in the coming years; therefore, many countries have begun research in this field. Our data from clinicaltrial.gov showed that the United States has conducted the most clinical trials using stem cells (). Government agencies, industry, individuals, universities, and private organizations have all invested in stem-cell-based therapy. The number of stem-cell-based companies has rapidly increased in recent years, and a brief overview of the submitted clinical trial studies indicated that the studies were mostly aimed at introducing therapeutic products for clinical applications. Therefore, we can expect the introduction of stem-cell-based products to the market.

The registered and completed clinical trial studies using stem cells according to participating countries: (A) top 10 participating countries with registered clinical trials using stem cells; and (B) top 10 countries based on the completion of registered clinical trials using stem cells.

As indicated above, translational research from the laboratory to clinical services has many layers which must be passed through, each with its own requirements and measurements. Therefore, the only way to introduce a new stem-cell-based product onto the market is for competent authorities to make sure that the discovery is safe and effective for its intended human use, and that the product has successfully passed all of the clinical trial stages.

One of the most important issues regarding the introduction of a new product for use in humans through a clinical trial is evaluation of its safety. Although many clinical trials have been performed using stem cells for the treatment of various diseases, as stem-cell-based therapies are one of the newest groups of therapeutic products in medicine, it is very hard to introduce new products based on stem cells onto the market, as many different parameters must be evaluated. There are several concerns regarding stem-cell-based therapies, including genetic instability after long-term expansion, stem cell migration to inappropriate regions of the body, immunological reaction, and so on. However, all challenges depend on the type of stem cell (e.g., embryonic stem cell, adult stem cell, iPS), type of disease, route of administration, and many other factors. Almost all researchers in the field of stem cell therapy believe that despite stem cells having great potential to treat disease through their intrinsic potential, unproven stem-cell-based therapies that have not been shown to be safe or effective may be accompanied by very serious health risks. In order to receive clinical trial approval from a competent regulatory authority, different tests must be performed for each study phase, and the results of one study should not be generalized to another study. The FDA and EMA have defined different regulations to ensure that stem-cell-based products are consistently controlled through the use of different preclinical studies (in vitro and in vivo). Based on these preclinical data, the FDA and EMA have the authority to approve a clinical trial study, as discussed in this review.

Another challenge that researchers and companies face is the duration of a clinical trial study before a stem-cell-based product can be introduced onto the market. At present, hematopoietic progenitor cells are the only FDA-approved product for use in patients with defects in blood production, while other stem-cell-based products used in clinical trials have not yet been introduced to the market.

In the past few years, several clinical trials have been conducted using stem cells, most of which have indicated the safety and high efficiency of stem-cell-based therapies. An attractive future option for regenerative medicine is the use of cell derivatives, including exosomes, amniotic fluid, Whartons jelly, and so on, for the treatment of diseases. Recently, the safety and efficiency of these products have been evaluated and optimized in preclinical studies. In addition, regenerative medicine using modified stem cells and combinations of stem cells with scaffolds and chemicals to overcome stem cell therapy challenges and increase the associated efficiency are two important future directions of research. However, establishing a safe method for stem cell modification and moving this technology toward clinical trial studies requires many preclinical studies.

The regenerative medicine market is developing and, due to encouraging findings in preclinical studies and predictable economic benefits, competition has increased between companies focused on the development of cell products. Therefore, government agencies, industries, individuals, universities, and private organizations have invested heavily into the development of the regenerative medicine market in recent years, such that we can be more hopeful about the future of stem-cell-based therapies.

In recent years, regenerative medicine has become a promising treatment option for various diseases. Due to their therapeutic potential, including the inhibition of inflammation or apoptosis, cell recruitment, stimulation of angiogenesis, and differentiation, stem cells can been seen as good candidates for regenerative medicine. In the last 50 years, more than 40,000 research papers have focused on stem-cell-based therapies. In this review study, we present a general overview of the translation of stem cell therapy from scientific ideas to clinical applications. Multiple mechanisms causing disease could be reversed by stem cells, due to their tremendous therapeutic potential. However, preclinical studies including in vitro and in vivo experiments are necessary to evaluate the potential of stem-cell-based treatments. Through preclinical research, it is possible to present scientific evidence and optimal treatment options for subsequent clinical studies. Before starting a clinical trial based on preclinical data, the application must be approved by a relevant regulatory administration, such as the FDA, EMA, or another organization. If the application is for the use of a new drug (including stem cells) which has never been tested before, the submission of an IND is required for FDA approval. Approximately 50% of clinical trials using stem cells take 2 to 5 years to complete. To minimize possible side effects, every new stem cell product should be approved for clinical marketing only after completing Phase IIV clinical trials successfully. Interestingly, the number of stem-cell-based companies aimed at introducing clinical applications has rapidly increased in recent years. Therefore, it may be possible to find stem-cell-based products on the clinical market in the near future. As described in this paper, there are several steps that should be carried out on the path from the laboratory to the clinical setting. To develop new stem-cell-based medicine for the clinical market, researchers should follow the guidelines suggested by the relevant authorities. Through these well-controlled development processes, researchers can achieve safe and effective stem-cell-based therapies, thus brings their research ideas into the clinical field.

All authors have read and agreed to the published version of the manuscript.

This review funded by National Institutes of Health grant: R01HD087417-01A1, R01HD094378-01, R01HD094380-01, R01HD100367-01, R01HD100563, R01HD100563.

The author has no conflicts of interest to declare.

Publishers Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Stem Cell Investig. 2020; 7: 8.

1Department of Basic Dental Science, National Research Centre, Cairo, Egypt;

2Stem Cell Laboratory, Center of Excellence for Advanced Sciences, National Research Centre, Cairo, Egypt

1Department of Basic Dental Science, National Research Centre, Cairo, Egypt;

2Stem Cell Laboratory, Center of Excellence for Advanced Sciences, National Research Centre, Cairo, Egypt

Received 2020 Jan 3; Accepted 2020 Apr 30.

Recent research reporting successful translation of stem cell therapies to patients have enriched the hope that such regenerative strategies may one day become a treatment for a wide range of vexing diseases. In fact, the past few years witnessed, a rather exponential advancement in clinical trials revolving around stem cell-based therapies. Some of these trials resulted in remarkable impact on various diseases. In this review, the advances and challenges for the development of stem-cell-based therapies are described, with focus on the use of stem cells in dentistry in addition to the advances reached in regenerative treatment modalities in several diseases. The limitations of these treatments and ongoing challenges in the field are also discussed while shedding light on the ethical and regulatory challenges in translating autologous stem cell-based interventions, into safe and effective therapies.

Keywords: Stem cells, therapies, clinical trials, translation

Cell-based therapy as a modality of regenerative medicine is considered one of the most promising disciplines in the fields of modern science & medicine. Such an advanced technology offers endless possibilities for transformative and potentially curative treatments for some of humanities most life threatening diseases. Regenerative medicine is rapidly becoming the next big thing in health care with the particular aim of repairing and possibly replacing diseased cells, tissues or organs and eventually retrieving normal function. Fortunately, the prospect of regenerative medicine as an alternative to conventional drug-based therapies is becoming a tangible reality by the day owing to the vigorous commitment of the research communities in studying the potential applications across a wide range of diseases like neurodegenerative diseases and diabetes, among many others (1).

Recent research reporting successful translation of stem cell therapies to patients have enriched the hope that such regenerative strategies may one day become a treatment for a wide range of vexing diseases (2). In fact, the past few years witnessed, a rather exponential advancement in clinical trials revolving around stem cell-based therapies. Some of these trials resulted in remarkable impact on various diseases (3). For example, a case of Epidermolysis Bullosa manifested signs of skin recovery after treatment with keratinocyte cultures of epidermal stem cells (4). Also, a major improvement in eyesight of patients suffering from macular degeneration was reported after transplantation of patient-derived induced pluripotent stem cells (iPSCs) that were induced to differentiate into pigment epithelial cells of the retina (5).

However, in spite of the increased amount of publications reporting successful cases of stem cell-based therapies, a major number of clinical trials have not yet acquired full regulatory approvals for validation as stem cell therapies. To date, the most established stem cell treatment is bone marrow transplants to treat blood and immune system disorders (1,6,7).

In this review, the advances and challenges for the development of stem-cell-based therapies are described, with focus on the use of stem cells in dentistry in addition to the advances reached in regenerative treatment modalities in several diseases. The limitations of these treatments and ongoing challenges in the field are also discussed while shedding light on the ethical and regulatory challenges in translating autologous stem cell-based interventions, into safe and effective therapies.

Stem cell-based therapies are defined as any treatment for a disease or a medical condition that fundamentally involves the use of any type of viable human stem cells including embryonic stem cells (ESCs), iPSCs and adult stem cells for autologous and allogeneic therapies (8). Stem cells offer the perfect solution when there is a need for tissue and organ transplantation through their ability to differentiate into the specific cell types that are required for repair of diseased tissues.

However, the complexity of stem cell-based therapies often leads researchers to search for stable, safe and easily accessible stem cells source that has the potential to differentiate into several lineages. Thus, it is of utmost importance to carefully select the type of stem cells that is suitable for clinical application (7,9).

There are mainly three types of stem cells. All three of them share the significant property of self-renewal in addition to a unique ability to differentiate. However, it should be noted that stem cells are not homogeneous, but rather exist in a developmental hierarchy (10). The most basic and undeveloped of stem cells are the totipotent stem cells. These cells are capable of developing into a complete embryo while forming the extra-embryonic tissue at the same time. This unique property is brief and starts with the fertilization of the ovum and ends when the embryo reaches the four to eight cells stage. Following that cells undergo subsequent divisions until reaching the blastocyst stage where they lose their totipotency property and assume a pluripotent identity where cells are only capable of differentiating into every embryonic germ layer (ectoderm, mesoderm and endoderm). Cells of this stage are termed embryonic stem cells and are obtained by isolation from the inner cell mass of the blastocyst in a process that involves the destruction of the forming embryo. After consecutive divisions, the property of pluripotency is lost and the differentiation capability becomes more lineage restricted where the cells become multipotent meaning that they can only differentiate into limited types of cells related to the tissue of origin. This is the property of adult stem cells, which helps create a state of homeostasis throughout the lifetime of the organism. Adult stem cells are present in a metabolically quiescent state in almost all specialized tissues of the body, which includes bone marrow and oral and dental tissues among many others (11).

Many authors consider adult stem cells the gold standard in stem cell-based therapies (12,13). Adult stem cells demonstrated signs of clinical success especially in hematopoietic transplants (14,15). In contrast to ESCs, adult stem cells are not subjected to controversial views regarding their origin. The fact that ESCs derivation involves destruction of human embryos renders them unacceptable for a significant proportion of the population for ethical and religious convictions (16-18).

It was in 2006 when Shinya Yamanka achieved a scientific breakthrough in stem cell research by succeeding in generating cells that have the same properties and genetic profile of ESCs. This was achieved via the transient over-expression of a cocktail of four transcription factors; OCT4, SOX2, KLF4 and MYC in, fully differentiated somatic cells, namely fibroblasts (19,20). These cells were called iPSCs and has transformed the field of stem cell research ever since (21). The most important feature of these cells is their ability to differentiate into any of the germ layers just like ESCs precluding the ethical debate surrounding their use. The development of iPSCs technology has created an innovative way to both identify and treat diseases. Since they can be generated from the patients own cells, iPSCs thus present a promising potential for the production of pluripotent derived patient-matched cells that could be used for autologous transplantation. True these cells symbolize a paradigm shift since they enable researchers to directly observe and treat relevant patient cells; nevertheless, a number of challenges still need to be addressed before iPSCs-derived cells can be applied in cell therapies. Such challenges include; the detection and removal of incompletely differentiated cells, addressing the genomic and epigenetic alterations in the generated cells and overcoming the tumorigenicity of these cells that could arise on transplantation (22).

With the rapid increase witnessed in stem cell basic research over the past years, the relatively new research discipline Translational Research has evolved significantly building up on the outcomes of basic research in order to develop new therapies. The clinical translation pathway starts after acquiring the suitable regulatory approvals. The importance of translational research lies in its a role as a filter to ensure that only safe and effective therapies reach the clinic (23). It bridges the gap from bench to bed. Currently, some stem cell-based therapies utilizing adult stem cells are clinically available and mainly include bone marrow transplants of hematopoietic stem cells and skin grafts for severe burns (23). To date, there are more than 3,000 trials involving the use of adult stem cells registered in WHO International Clinical Trials Registry. Additionally, initial trials involving the new and appealing iPSCs based therapies are also registered. In fact, the first clinical attempt employing iPSCs reported successful results in treating macular degeneration (24). Given the relative immaturity in the field of cellular therapy, the outcomes of such trials shall facilitate the understanding of the timeframes needed to achieve successful therapies and help in better understanding of the diseases. However, it is noteworthy that evaluation of stem cell-based therapies is not an easy task since transplantation of cells is ectopic and may result in tumor formation and other complications. This accounts for the variations in the results reported from previous reports. The following section discusses the published data of some of the most important clinical trials involving the use of different types of stem cells both in medicine and in dentistry.

The successful generation of neural cells from stem cells in vitro paved the way for the current stem cell-based clinical trials targeting neurodegenerative diseases (25,26). These therapies do not just target detaining the progression of irrecoverable neuro-degenerative diseases like Parkinsons, Alzheimers, amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), but are also focused on completely treating such disorders.

PD is characterized by a rapid loss of midbrain dopaminergic neurons. The first attempt for using human ESC cells to treat PD was via the generation of dopaminergic-like neurons, later human iPSCs was proposed as an alternative to overcome ESCs controversies (27). Both cells presented hope for obtaining an endless source of dopaminergic neurons instead of the previously used fetal brain tissues. Subsequently, protocols that mimicked the development of dopaminergic neurons succeeded in generating dopaminergic neurons similar to that of the midbrain which were able to survive, integrate and functionally mature in animal models of PD preclinically (28). Based on the research presented by different groups; the Parkinsons Global Force was formed which aimed at guiding researchers to optimize their cell characterization and help promote the clinical progress toward successful therapy. Recently, In August 2018, Shinya Yamanka initiated the first approved clinical trial to treat PD using iPSCs. Seven patients suffering from moderate PD were recruited (29). Donor matched allogeneic cells were used to avoid any genetic influence of the disease. The strategy behind the trial involved the generation of dopaminergic progenitors followed by surgical transplantation into the brains of patients by a special device. In addition, immunosuppressant medications were given to avoid any adverse reaction. Preliminary results so far revealed the safety of the treatment.

MS is an inflammatory and neurodegenerative autoimmune disease of the central nervous system. Stem cell-based therapies are now exploring the possibility of halting the disease progression and reverse the neural damage. A registered phase 1 clinical trial was conducted by the company CelgeneTM in 2014 using placental-derived mesenchymal stem cells (MSCs) infusion to treat patients suffering from MS (30). This trial was performed at 6 centers in the United States and 2 centers in Canada and included 16 patients. Results demonstrated that cellular infusions were safe with no signs of paradoxical aggravation. However, clinical responses from patients indicated that the cellular treatment did not improve the MS condition (31). For the last decade immunoablative therapy demonstrated accumulative evidence of inducing long-term remission and improvement of disability caused by MS. This approach involves the replacement of the diseased immune system through administration of high-dose immunosuppressive therapy followed by hematopoietic stem cells infusion (32). However, immunoablation strategies demonstrated several complications such as infertility and neurological disabilities. A number of randomized controlled trials are planned to address these concerns (32). Currently, new and innovative stem cell-based therapies for MS are only in the initial stages, and are based on different mechanisms exploring the possibility of replacing damaged neuronal tissue with neural cells derived from iPSCs however, the therapeutic potential of iPSCs is still under research (33).

ALS is a neurodegenerative disease that causes degeneration of the motor neurons which results in disturbance in muscle performance. The first attempt to treat ALS was through the transplantation of MSCs in a mouse model. The outcomes of this experiment were promising and resulted in a decrease of the disease manifestations and thus providing proof of principal (34). Based on these results, several planned/ongoing clinical trials are on the way. These trials mainly assess the safety of the proposed concept and have not proved clinical success to date. Notably, while pre-clinical studies have reported that cells derived from un-diseased individuals are superior to cells from ALS patients; most of the clinical trials attempted have employed autologous transplantation. This information may account for the absence of therapeutic improvement reported (35).

Other neurologic indications for the use of stem cells are spinal cord injuries. Though the transplantation of different forms of neural stem cells and oligo-dendrocyte progenitors has led to growth in the axons in addition to neural connectivity which presents a possibility for repair (36), proof of recovered function has yet to be established in stringent clinical trials. Nevertheless, Japan has recently given approval to stem-cell treatment for spinal-cord injuries. This approval was based on clinical trials that are yet to be published and involves 13 patients, who are suffering from recent spinal-cord injury. The Japanese team discovered that injection of stem cells isolated from the patients bone marrow aided in regaining some lost sensation and mobility. This is the first stem cell-based therapy targeting spinal-cord injuries to gain governmental approval to offer to patients (37).

A huge number of the currently registered clinical trials for stem cell-based therapies target ocular diseases. This is mainly due to the fact that the eye is an immune privileged site. Most of these trials span various countries including Japan, China, Israel, Korea, UK, and USA and implement allogeneic ESC lines (35,36). Notably, the first clinical trial to implement the use autologous iPSCs-derived retinal cells was in Japan which followed the new regulatory laws issued in 2014 by Japans government to regulate regenerative medicine applications. Two patients were recruited in this trial, the first one received treatment for macular degeneration using iPSCs-generated retinal cell sheet (37). After 1 year of follow-up, there were no signs of serious complications including abnormal proliferation and systemic malignancy. Moreover, there were no signs of rejection of the transplanted retinal epithelial sheet in the second year follow-up. Most importantly, the signs of corrected visual acuity of the treated eye were reported. These results were enough to conclude that iPSCs-based autologous transplantation was safe and feasible (38). It is worthy to mention that the second patient was withdrawn from the study due to detectable genetic variations the patients iPSCs lines which was not originally present in the patients original fibroblasts. Such alterations may jeopardize the overall safety of the treatment. The fact that this decision was taken, even though the performed safety assays did not demonstrate tumorgenicity in the iPSCs-derived retinal pigment epithelium (RPE) cells, indicates that researchers in the field of iPSCs have full awareness of the importance of safety issues (39).

Pancreatic beta cells are destructed in type 1 diabetes mellitus, because of disorders in the immune system while in type 2 insulin insufficiency is caused by failure of the beta-cell to normally produce insulin. In both cases the affected cell is the beta cell, and since the pancreas does not efficiently regenerate islets from endogenous adult stem cells, other cell sources were tested (38). Pluripotent stem cells (PSCs) are considered the cells of choice for beta cell replacement strategies (39). Currently, there are a few industry-sponsored clinical trials that are registered targeting beta cell replacement using ESCs. These trials revolve around the engraftment of insulin-producing beta cells in an encapsulating device subcutaneously to protect the cells from autoimmunity in patients with type 1 diabetes (40). The company ViaCyteTM in California recently initiated a phase I/II trial ({"type":"clinical-trial","attrs":{"text":"NCT02239354","term_id":"NCT02239354"}}NCT02239354) in 2014 in collaboration with Harvard University. This trial involves 40 patients and employs two subcutaneous capsules of insulin producing beta cells generated from ESCs. The results shall be interesting due to the ease of monitoring and recovery of the transplanted cells. The preclinical studies preceding this trial demonstrated successful glycemic correction and the devices were successfully retrieved after 174 days and contained viable insulin-producing cells (41).

Stem cells have been successfully isolated from human teeth and were studied to test their ability to regenerate dental structures and periodontal tissues. MSCs were reported to be successfully isolated from dental tissues like dental pulp of permanent and deciduous teeth, periodontal ligament, apical papilla and dental follicle (42-44). These cells were described as an excellent cell source owing to their ease of accessibility, their ability to differentiate into osteoblasts and odontoblasts and lack of ethical controversies (45). Moreover, dental stem cells demonstrated superior abilities in immunomodulation properties either through cell to cell interaction or via a paracrine effect (46). Stem cells of non-dental origin were also suggested for dental tissue and bone regeneration. Different approaches were investigated for achieving dental and periodontal regeneration (47); however, assessments of stem cells after transplantation still require extensive studying. Clinical trials have only recently begun and their results are yet to be fully evaluated. However, by carefully applying the knowledge acquired from the extensive basic research in dental and periodontal regeneration, stem cell-based dental and periodontal regeneration may soon be a readily available treatment. To date, there are more than 6,000 clinical trials involving the use of with stem cells, however only a total of 44 registered clinical trials address oral diseases worldwide (48). Stem cell-based clinical trials with reported results targeting the treatment of oral disease are discussed below.

The first human clinical study using autologous dental pulp stem cells (DPSCs) for complete pulp regeneration was reported by Nakashima et al. in 2017 (49). This pilot study was based on extensive preclinical studies conducted by the same group (50). Patients with irreversible pulpitis were recruited and followed up for 6 months following DPSCs transplantation. Granulocyte colony-stimulating factor was administered to induce stem cell mobilization to enrich the stem cell populations. The research team reported that the use of DPSCs seeded on collagen scaffold in molars and premolars undergoing pulpectomy was safe. No adverse events or toxicity were demonstrated in the clinical and laboratory evaluations. Positive electric pulp testing was obtained after cell transplantation in all patients. Moreover, magnetic resonance imaging of the de-novo tissues formed in the root canal demonstrated similar results to normal pulp, which indicated successful pulp regeneration. A different group conducted a clinical trial that recruited patients diagnosed with necrotic pulp. Autologous stem cells from deciduous teeth were employed to induce pulp regeneration (51). Follow-up of the cases after a year from the intervention reported evidence of pulp regeneration with vascular supply and innervation. In addition, no signs of adverse effects were observed in patients receiving DPSCs transplantation. Both trials are proceeding with the next phases, however the results obtained are promising.

Aimetti et al. performed a study which included eleven patients suffering from chronic periodontitis and have one deep intra bony defect in addition to the presence of one vital tooth that needs extraction (52). Pulp tissue was passed through 50-m filters in presence of collagen sponge scaffold and was followed by transplantation in the bony defects caused by periodontal disease. Both clinical and radiographic evaluations confirmed the efficacy of this therapeutic intervention. Periodontal examination, attachment level, and probe depth showed improved results in addition to significant stability of the gingival margin. Moreover, radiographic analysis demonstrated bone regeneration.

The first clinical study using DPSCs for oro-maxillo-facial bone regeneration was conducted in 2009 (53). Patients in this study suffered from extreme bone loss following extraction of third molars. A bio-complex composed of DPSCs cultured on collagen sponge scaffolds was applied to the affected sites. Vertical repair of the damaged area with complete restoration of the periodontal tissue was demonstrated six months after the treatment. Three years later, the same group published a report evaluating the stability and quality of the regenerated bone after DPSCs transplantation (54). Histological and advanced holotomography demonstrated that newly formed bone was uniformly vascularized. However, it was of compact type, rather than a cancellous type which is usually the type of bone in this region.

Sjgrens syndrome (SS) is a systemic autoimmune disease marked by dry mouth and eyes. A novel therapeutic approach for SS. utilizing the infusion of MSCs in 24 patients was reported by Xu et al. in 2012 (55). The strategy behind this treatment was based on the immunologic regulatory functions of MSCs. Infused MSCs migrated toward the inflammatory sites in a stromal cell-derived factor-1-dependent manner. Results reported from this clinical trial demonstrated suppressed autoimmunity with subsequent restoration of salivary gland secretion in SS patients.

The ability to bank autologous stem cells at their most potent state for later use is an essential adjuvant to stem cell-based therapies. In order to be considered valid, any novel stem cell-based therapy should be as effective as the routine treatment. Thus, when appraising a type of stem cells for application in cellular therapies, issues like immune rejection must be avoided and at the same time large numbers of stem cells must be readily available before clinical implementation. iPSCs theoretically possess the ability to proliferate unlimitedly which pose them as an attractive source for use in cell-based therapies. Unlike, adult stem cells iPSCs ability to propagate does not decrease with time (22). Recently, California Institute for Regenerative Medicine (CIRM) has inaugurated an iPSCs repository to provide researchers with versatile iPSCs cell lines in order to accelerate stem cell treatments through studying genetic variation and disease modeling. Another important source for stem cells banking is the umbilical cord. Umbilical cord is immediately cryopreserved after birth; which permits stem cells to be successfully stored and ready for use in cell-based therapies for incurable diseases of a given individuals. However, stem cells of human exfoliated deciduous teeth (SHEDs) are more attractive as a source for stem cell banking. These cells have the capacity to differentiate into further cell types than the rest of the adult stem cells (56). Moreover, procedures involving the isolation and cryopreservation of these cells are un-complicated and not aggressive. The most important advantage of banking SHEDs is the insured autologous transplant which avoids the possibility of immune rejection (57). Contrary to cord blood stem cells, SHEDs have the ability to differentiate into connective tissues, neural and dental tissues (58) Finally, the ultimate goal of stem cell banking, is to establish a repository of high-quality stem cell lines derived from many individuals for future use in therapy.

With the increased number of clinical trials employing stem cells as therapeutic approaches, the need for developing regulatory guidelines and standards to ensure patients safety is becoming more and more essential. However, the fact that stem cell therapy is rather a new domain makes it subject to scientific, ethical and legal controversies that are yet to be regulated. Leading countries in the field have devised guidelines serving that purpose. Recently, the Food and Drug Administration (FDA) has released regulatory guidelines to ensure that these treatments are safe and effective (59). These guidelines state that; treatments involving stem cells that have been minimally manipulated and are intended for homogeneous use do not require premarket approval to come into action and shall only be subjected to regulatory guidelines against disease transmission. In 2014, a radical regulatory reform in Japan occurred with the passing of two new laws that permitted conditional approval of cell-based treatments following early phase clinical trials on the condition that clinical safety data are provided from at least ten patients. These laws allow skipping most of the traditional criteria of clinical trials in what was described as fast track approvals and treatments were classified according to risk (60). To date, the treatments that acquired conditional approval include those targeting; spinal-cord injury, cardiac disease and limb ischemia (61). Finally, regulatory authorities are now demanding application of standardization and safety regulations protocols for cellular products, which include the use of Xeno-free culture media, recombinant growth factors in addition to Good Manufacturing Practice (GMP) culture supplies.

Stem cell-based therapies face many obstacles that need to be urgently addressed. The most persistent concern is the ethical conflict regarding the use of ESCs. As previously mentioned, ESCs are far superior regarding their potency; however, their derivation requires destruction human embryos. True, the discovery of iPSCs overcame this concern; nevertheless, iPSCs themselves currently face another ethical controversy of their own which addresses their unlimited capacity of differentiation with concerns that these cells could one day be applied in human cloning. The use of iPSCs in therapy is still considered a high-risk treatment modality, since transplantation of these cells could induce tumor formation. Such challenge is currently addressed through developing optimized protocols to ensure their safety in addition to developing global clinical-grade iPSCs cell lines before these cells are available for clinical use (61). As for MSCs, these cells have been universally considered safe, however continuous monitoring and prolonged follow-up should be the focus of future research to avoid the possibility of tumor formation after treatments (62). Finally, it could be postulated that one of the most challenging ethical issues faced in the field of stem cell-based therapies at the moment, is the increasing number of clinics offering unproven stem cell-based treatments. Researchers are thus morally obligated to ensure that ethical considerations are not undermined in pursuit of progress in clinical translation.

Stem cell therapy is becoming a tangible reality by the day, thanks to the mounting research conducted over the past decade. With every research conducted the possibilities of stem cells applications increased in spite of the many challenges faced. Currently, progress in the field of stem cells is very promising with reports of clinical success in treating various diseases like; neurodegenerative diseases and macular degeneration progressing rapidly. iPSCs are conquering the field of stem cells research with endless possibilities of treating diseases using patients own cells. Regeneration of dental and periodontal tissues using MSCs has made its way to the clinic and soon enough will become a valid treatment. Although, challenges might seem daunting, stem cell research is advancing rapidly and cellular therapeutics is soon to be applicable. Fortunately, there are currently tremendous efforts exerted globally towards setting up regulatory guidelines and standards to ensure patients safety. In the near future, stem cell-based therapies shall significantly impact human health.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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Current state of stem cell-based therapies: an overview - PMC

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Stem Cell Therapy Is It Right for You? Cleveland Clinic

Tuesday, January 31st, 2023

Few of us know what they are or exactly how they work. But many of us have heard about the healing powers of stem cells, as well as the controversy surrounding them. Stem cells are well-debated and highly complex with promises ranging from fixing damaged knees to regenerating receding hairlines.

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But what are stem cells? And, whats all the fuss all about?

Director of the Center for Regenerative Medicine and Surgery, Amy Lightner, MD, shares the differences between stem cell types, how stem cells can be used and when to be cautious of claims that might be too good to be true.

When most of us think of stem cells, we probably recall images of Dolly the cloned sheep. While its true that Dolly was born of stem cells, her place in science history is just one of many advancements in the field.

In fact, there are many different types of stem cells, each of which has different responsibilities and abilities. What unifies them is their ability to regenerate into new cells.

Regenerative medicine is an emerging field that uses innovative treatments to help regenerate or heal cell function thats lost due to aging, disease or injury, Dr. Lightner explains. The way we achieve this is by using stem cells in large quantities, targeted to a certain area, that the body uses to promote healing.

Adult stem cells are the only type of stem cells that are currently approved for medical use in the United States by the U.S. Food and Drug Administration (FDA). The term adult stem cells is a little confusing because theyre actually found in infants, children and adults. These cells live in a variety of tissue in our bodies including bone marrow, muscles, your brain, your intestines and more.

Think of adult stem cells as a little army of cells that can regenerate themselves into new cells to maintain and repair the tissue or muscle where theyre found. The catch with adult stem cells is that they cant become different types of cells (for example, blood stem cells can only become new blood cells, not skin or brain cells).

Unlike adult stem cells, embryonic stem cells have many more possibilities. Harvested during an embryos blastocyst stage (about five or six days after an embryo has been fertilized in a lab), embryonic stem cells have the potential to become any type of cell (called pluripotent cells). For these reasons, embryonic stem cells are the type of stem cells that generate the controversy most people associate with the topic.

Stem cell therapy has been around since the 1970s, when the first adult bone marrow cells were used to treat blood disease. A bone marrow transplant allows a recipient whose bone marrow cells have been damaged by chemotherapy or disease to receive healthy bone marrow stem cells from a donor.

Those stem cells have the potential to mature within the blood system into different immune cells that recognize and fight off different types of blood cancer. And they also have the ability to heal, says Betty Hamilton, MD, Department of Hematology and Medical Oncology.

Bone marrow transplants are currently used to treat diseases including:

While you may have heard about the use of stem cell therapy for knees, back pain, arthritis, hair loss, diabetes and more, no other types of stem cell therapy beyond bone marrow transplants have yet been approved by the FDA. But thousands of clinical trials are available ranging from treatments for Crohns disease to multiple sclerosis and more. The common link between all these trials is the ability of the stem cells to reduce inflammation and repair damage to your body.

Dr. Hamilton and Dr. Lightner agree that were only just beginning to scratch the surface of stem cell therapy. In recent years, during the height of the COVID-19 pandemic, many clinical trials were underway to explore whether stem cells could be used to help treat the damaged lungs in people severely affected by the disease.

I think potential is the perfect word to describe stem cells, says Dr. Hamilton. We know they have these anti-inflammatory and regenerative properties where they can provide a significant improvement to someone dealing with a certain disease. There are so many diseases where inflammation happens, and something needs to be repaired, and so any help the immune system can get provides a lot of potential.

Scientists are also researching whether adult stem cells can turn into pluripotent stem cells, which would allow the cells to change into any cell type without involving the use of embryonic stem cells.

While the potential for stem cell therapy is great, doctors caution that were not quite there yet.

I always tell patients that ask about stem cell therapy clinics or traveling overseas for stem cell therapy treatment that if its not something that is a clinical trial with FDA oversight, then they have no real way of knowing whats being given to them, advises Dr. Lightner.

This means more harm can come than good if you dont know exactly whats being given to you. Or, in some cases, youre just spending thousands of dollars for what ends up being saline, Dr. Lightner says.

The best way to know that youre receiving sound medical treatment is to make sure the one youre considering is approved by the FDA on its Clinical Trials database.

Dr. Lightner cautions against treatments that sound too good to be true. While stem cell therapy has helped improve and save millions of lives, its best to know what exactly youre signing up for by seeking out a qualified medical provider offering an FDA-approved clinical trial.

Excerpt from:
Stem Cell Therapy Is It Right for You? Cleveland Clinic

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Stem Cell Therapy | Mellon Center Approach | Cleveland Clinic

Tuesday, January 31st, 2023

Q: What are the types of stem cell therapy?

A: Stem cells are primitive cells that are capable of self-renewal (i.e., to divide to replenish their population); are pluripotent (i.e., able to differentiate into different mature cells); and are able to create, maintain, or repair tissues. There are several general categories of stem cells, including:

Two general stem-cell-based therapeutic strategies have been considered in MS:1

This document addresses AHSCT and MSC transplantation separately.

A: AHSCT is a multi-step procedure, which includes:

Mobilization typically is performed as an outpatient. Conditioning, PBHSC infusion, and initial recovery usually are performed during an approximately 1-month hospitalization in a specialized transplant unit.

A: A sizable number of case series, uncontrolled phase 2 clinical trials, and randomized clinical trials have demonstrated, in aggregate, potent efficacy of AHSCT in patients with active relapsing MS, including marked reduction in relapses, MRI lesion activity, and brain volume loss (after initial acceleration).1-3 In two analyses, the rate of no evidence of disease activity at 2 years was 70-90% in AHSCT case series and trials compared to 15-50% in clinical trials of MS disease modifying therapies (DMTs).4,5 A sizable proportion of patients treated with AHSCT demonstrate improvement in disability, for example, 64% at 4 years in a recent case series.6 Disease control often is durable, lasting up to 15 years or more without the need for ongoing disease modifying therapy (DMT) in many patients.7 Nonetheless, some patients require resumption of standard DMTs at some point after AHSCT, particularly with lower intensity non-myeloablative conditioning regimens.

The potent efficacy is attributed to immunoablative conditioning that depletes pathogenic immune cells; the durability of benefit is attributed more normal regulatory function and T-cell and B-cell repertoires following immune reconstitution.4

A: Early toxicity is common in patients undergoing AHSCT and potentially includes MS relapse during mobilization and conditioning, complications of leukapheresis, side effects of cytotoxic agents comprising the conditioning regimen (e.g., nausea or infertility), complications of myelosupression (e.g., infection or bleeding complications), and engraftment syndrome after re-infusion of PBHSCs (fever, rash, pulmonary edema, liver or renal impairment, and encephalopathy). Patients typically are hospitalized for approximately 1 month when undergoing conditioning and transplantation, and for initial recovery. Previous estimates of overall transplant-related mortality in MS were 2% or more. The current estimate is 0.2-0.3% for AHSCT performed after 2012.4 The improved safety is due to increased experience with the procedure, refinement of the protocol, and better selection of patients with lower risk of complications.

After recovery, adverse effects are rare and include infection (principally related to herpes zoster) and secondary autoimmune disorders. One potential advantage is that after AHSCT patients typically do not need ongoing MS DMT, with the associated cumulative risk of adverse effects.

A: The estimated cost for uncomplicated AHSCT is approximately $150,000. One potential advantage is that after recovery patients typically do not need ongoing MS DMT, with the associated cumulative cost. Nevertheless, most health insurance plans do not cover AHSCT, so obtaining coverage often is difficult.

A: Patients most likely to benefit from AHSCT are young (approximately 55 years or less), with relatively recent disease onset (approximately 10 years or less), still ambulatory, with highly active MS with recent clinical relapses or MRI lesion activity, and continued disease activity despite treatment with approved DMTs especially high-efficacy DMTs. Both the American Society for Blood and Marrow Transplantation 2 and National MS Society3 have published policy statements that AHSCT is a reasonable option in such patients, who are at high risk for disability.

A: Because of the complexity of the AHSCT procedure and the need for appropriate patient selection and follow-up, AHSCT for MS should be performed by centers with expertise and experience in transplant and that are affiliated with centers with experience and expertise in management of MS.1-3We advise patient not to undergo AHSCT in free-standing transplant clinics, especially in the absence of a detailed plan for follow-up and management of medical and neurologic issues post-transplant.

A: Because of the uncertain efficacy and safety of AHSCT compared to approved DMTs for MS, the Mellen Center is participating in the ongoing Best Available Therapy Versus Autologous Hematopoietic Stem Cell Transplant for Multiple Sclerosis (BEAT-MS) clinical trial sponsored by the National Institute of Allergy and Infectious Diseases and the Immune Tolerance Network (ClinicalTrials.gov Identifier: NCT04047628). This multicenter, randomized, rater-blinded trial compares the efficacy, safety, cost-effectiveness, and immunologic effects of AHSCT versus high-efficacy DMTs in participants with highly active, treatment-refractory, relapsing MS.

Because of unanswered questions regarding the efficacy of AHSCT in MS and substantial associated risk, our priority is to enroll patients for whom AHSCT is being considered into the BEAT-MS trial. We will consider AHSCT outside of the BEAT-MS trial for selected patients for whom AHSCT appears indicated but who are not eligible to participate in the study.

A: Typically, transplant physicians monitor and manage transplant-related adverse effects for the first 6 months following uncomplicated AHSCT (longer if there are complications). After 6 months following uncomplicated AHSCT, transplant-related adverse effects are rare. Patients need to be monitored primarily for symptoms or other findings suggesting infection or secondary autoimmune disorders. Long-term MS disease monitoring is similar to typical MS, with clinical visits and periodic MRIs.

A: Several analyses demonstrated that AHSCT has modest or no efficacy in preventing or reversing progressive disability worsening in the absence of recent relapses or MRI lesion activity. Conversely, the risk of adverse effects and transplant-related mortality are increased in progressive MS due to greater neurologic disability, older age, and increased likelihood of comorbidities. Many of the transplant-related deaths in recent series were patients with progressive MS.4 As a result, AHSCT generally is not advised for patients with non-active progressive MS and/or severe disability.

A: A recent publication reported potent efficacy of non-myeloablative AHSCT in preventing relapses, improving disability, and improving quality of life in 11 patients with aquaporin-4-positive neuromyelitis optica spectrum disorders (NMOSD).8 There now are 3 medications with regulatory approval to treat NMOSD plus several other medications used off-label. The findings from this small uncontrolled case series suggests AHSCT might be an option for patients with NMOSD who do not achieve adequate disease control from the available medication options. Rigorous formal clinical trials are needed to more definitively assess the efficacy and safety of AHSCT in NMOSD. We have not performed AHSCT for NMOSD at Cleveland Clinic.

A: Studies of various stem cell approaches to directly replace myelin-forming cells have been proposed (e.g., transplantation of oligodendrocyte progenitor cells or induced pluripotent stem cells), but none has been completed.1 To date, the most experience is with transplantation of mesenchymal stem cells (MSCs), pluripotent stromal cells present in a perivascular niche in a variety of tissues. In addition to their ability to differentiate into mesodermal lineage derivatives (e.g., bone, cartilage, connective tissue, and adipose tissue), MSCs appear to function to limit inflammatory tissue damage and promote tissue repair, including in the central nervous system, through elaboration of a large number of soluble immunomodulatory and trophic factors. These properties have led to a large number of studies investigating the potential benefit of MSC transplantation to treat a wide variety of inflammatory and tissue injury conditions.1 There also are a large number of commercial stem cell clinics offering MSC transplantation for a wide range of conditions.

A: A sizable number of preliminary trials of MSC transplantation in MS have been reported,1 including one conducted at the Mellen Center.9 These studies had different study populations, cell products, routes of administration, and study protocols, making it difficult to generalize the results. In aggregate, the studies reported good safety and tolerability, and some provided preliminary evidence of benefit. A recent study utilizing cell production procedures intended to augment production of neurotrophic factors by the MSCs and multiple intrathecal administrations, reported more prominent efficacy.10

Despite the sizable number of studies of MSC transplantation, there are a many unanswered technical questions, including the best tissue source (e.g., bone marrow, adipose tissue, or placenta/umbilical cord), whether the cells should be autologous (i.e., from the patient) or allogeneic (i.e., from someone without MS), the optimal cell culture methods to maximize yield and stimulate characteristics that increase therapeutic potency, whether the cells can be cryopreserved (frozen and stored) or need to be harvested directly from culture, dose (i.e., how many MSCs are administered), dosing schedule (i.e., for how long the therapeutic benefit lasts and how often the MSCs need to be administered), and optimal route of administration (i.e., intravenous, intrathecal, or both), among other issues. Because of these unanswered technical questions, MSC transplantation currently is an experimental treatment and should not be performed outside of rigorous formal clinical trials

A: There are a large number of commercial stem cell clinics in the U.S. and other countries offering treatments marketed as stem cells and presumed to be predominantly MSCs, on a fee-for service basis. However, because of the lack of quality control, lack of regulatory oversight, and lack of any validation of their efficacy or safety, we strongly advise patients not to pursue stem cell treatments at commercial stem cell clinics, outside of rigorous formal clinical trials. Many of these operations are potentially fraudulent.

Although MSC transplantation generally has been well-tolerated and safe in formal clinical trials, complications have been reported when administered in commercial stem cell clinics, including among other reports severe loss of vision following intravitreal injection11 and malignant spinal cord neoplasm following intrathecal injection.12

In addition, a number of concerns regarding commercial stem cell clinics have been raised: 13,14

A: Patient who undergo MSC transplantation should be monitored for symptoms or other findings indicating potential complications, including local or systemic infection, ectopic tissue formation, neoplasia, and arachnoiditis (following intrathecal administration). Long-term MS disease monitoring is similar to typical MS, with clinical visits and periodic MRIs.

Last Updated: 10 DEC 2020

Approach last updated: February 14, 2021

Link:
Stem Cell Therapy | Mellon Center Approach | Cleveland Clinic

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Stem Cell Therapy for Parkinson’s: Current Developments – Healthline

Saturday, December 3rd, 2022

Parkinsons disease is a neurological disorder with symptoms that become more severe over time. It affects about 1% of people ages 60 years and older in industrialized nations. The exact cause of the disease isnt known, but experts believe that both genetic and environmental factors play a role.

Parkinsons disease causes neurons to die in certain parts of your brain, leading to a decrease of dopamine. Dopamine is a neurotransmitter. Cells in your brain release dopamine as a way of sending signals to other nearby cells.

When you have Parkinsons, a decrease in dopamine activity can lead to such symptoms as:

Theres no cure for Parkinsons disease. But over the past few decades, researchers have been studying stem cell therapy to provide better treatment options.

Read on to learn more about current and future developments in using stem cell therapy to treat Parkinsons disease.

Stem cells are special because theyre undifferentiated, meaning they have the potential to become many types of specialized cells.

You might think of stem cells as natural resources for your body. When your body needs a specific type of cell from bone cells to brain cells an undifferentiated stem cell can transform to fit the need.

There are three main types of stem cells:

Stem cell therapy is the use of stem cells usually from a donor, but sometimes from your own body to treat a disorder.

Because Parkinsons disease leads to the death of brain cells, researchers are trying to use stem cells to replace brain cells in the affected areas. This could help treat the symptoms of Parkinsons disease.

Researchers are exploring various approaches to use stem cells to treat Parkinsons disease.

The current idea is to introduce stem cells directly into the affected areas of your brain where they can transform into brain cells. These new brain cells could then help regulate dopamine levels, which should improve the symptoms of the disease.

Its important to note that experts believe this would only be a treatment for Parkinsons disease and not a cure.

While stem cell therapy has the potential to replace the brain cells destroyed by Parkinsons disease, the disease would still be present. Parkinsons disease would likely destroy the implanted stem cells eventually.

Its unclear right now whether stem cell therapy could be used multiple times to continue to reduce symptoms of Parkinsons disease or if the effect would be the same after multiple procedures.

Until the discovery of the process of creating iPSCs, the only stem cell therapies for Parkinsons disease required the use of embryonic stem cells. This came with ethical and practical challenges, making research more difficult.

After iPSCs became available, stem cells have been used in clinical trials for many conditions involving neural damage with overall mixed results.

The first clinical trial using iPSCs to treat Parkinsons disease was in 2018 in Japan. It was a very small trial with only seven participants. Other trials have been completed using animal models.

So far, trials have shown improvement to symptoms affecting movement as well as nonmotor symptoms such as bladder control.

Some challenges do arise from the source of the stem cells.

Stem cell therapy can be thought of as being similar to an organ transplant. If the iPSCs are derived from a donor, you may need to use immunosuppressant drugs to prevent your body from rejecting the cells.

If the iPSCs are derived from your own cells, your body might be less likely to reject them. But experts believe that this will delay stem cell therapy while the iPSCs are made in a lab. This will probably be more costly than using an established line of tested iPSCs from a donor.

There are many symptoms of Parkinsons disease. Theyre often rated using the Unified Parkinsons Disease Rating Scale (UPDRS) or the Movement Disorder Societys updated revision of that scale, the MDS-UPDRS.

Clinical trials today are generally looking to significantly improve UPDRS or MDS-UPDRS scores for people with Parkinsons disease.

Some trials are testing new delivery methods, such as intravenous infusion or topical applications. Others are looking to determine the safest number of effective doses. And other trials are measuring overall safety while using new medical devices in stem cell therapy.

This is an active area of research. Future trials will help narrow down the most safe and effective approach to stem cell therapy for Parkinsons disease.

Clinical trials are usually conducted in three phases. Each phase adds more participants, with the first phase usually limited to a few dozen people and several thousand in the third phase. The purpose is to test the treatments safety and effectiveness.

Clinical trials testing stem cell therapy for Parkinsons disease are still in the early phases. If the current trials are successful, it will likely still be 4 to 8 years before this treatment is widely available.

The goal of stem cell therapy for Parkinsons disease is to replace destroyed brain cells with healthy, undifferentiated stem cells. These stem cells can then transform into brain cells and help regulate your dopamine levels. Experts believe this can relieve many of the symptoms of Parkinsons disease.

This therapy is still in the early stages of clinical testing. Many trials are either proposed, currently recruiting, or already active. The results of these trials will determine how soon stem cell therapy might become widely available as a treatment for Parkinsons disease.

At the moment, its not believed that stem cell therapy will cure Parkinsons disease. But it might be an alternative to existing treatments such as drug therapies and deep brain stimulation.

Excerpt from:
Stem Cell Therapy for Parkinson's: Current Developments - Healthline

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Canine Stem Cell Therapy Market Size 2022 with a CAGR of % Market Share, prime companies report covers, world business Trends, Statistics, Definition,…

Thursday, June 16th, 2022

Final Report will add the analysis of the impact of COVID-19 on this Canine Stem Cell Therapy industry.Canine Stem Cell Therapy Market watch out for new highest revenue Study Reports 2022 with Top Countries Data 2022 , with 115 Report Page, Current Trends 2022, Future Estimations and Opportunity Analysis, TableofContent, Top Countries key players in a business ,,Stroypribor,C-Therm Technologies,Xiatech,TA Instruments,Hot Disk,Xiangke Yiqi,Linseis,EKO Instruments,Hukseflux,Ziwei Electromechanical,Netzsch,Kyoto Electronics,Dazhan,Taurus Instruments,,

In 2022, Canine Stem Cell Therapy MarketSize, Status and Development Strategy Pre and Post COVID-19, by Corporate Strategy Analysis, Landscape, Type, Application, and Leading 20 Countries

What is Canine Stem Cell Therapy Industry Insights?

Canine Stem Cell Therapy Market growth and Trend By Type (,Allogeneic Stem Cells,Autologous Stem Cells,,,), By Application ( ,Veterinary Hospitals,Veterinary Clinics,Veterinary Research Institutes,, ) Geography (North America (United States, Canada and Mexico), South America (China, Japan, Korea, India and Southeast Asia), Europe (Germany, France, UK, Russia and Italy), Asia-Pacific (China, Japan, Korea, India and Southeast Asia), Middle East and Africa (Saudi Arabia, Egypt, Nigeria and South Africa)) Industry Trends 2022.

Canine Stem Cell Therapy market identifies the increase in RandD of therapeutic vaccines as one of the prime reasons driving the Canine Stem Cell Therapy market growth during the next few years. Also, increased disease diagnostic modalities, and increasing research on combination therapies will lead to sizable demand in the market.

Canine Stem Cell Therapy refers to the treatment of canine joint-related diseases using stem cells. Adipose-derived stem cells (ASCs) are the most common and most desirable adult stem cells because of their safety, their ability to be harvested and used, and the ability to differentiate into multiple cell lineages. Most early clinical studies have focused on adipose-derived stem cells for the treatment of a variety of chronic diseases such as arthritis, tendinitis, lameness and atopic dermatitis in dogs. A lot of attention in veterinary medicine is the treatment of osteoarthritis in dogs.

The Canine Stem Cell Therapy market revenue was Million USD in 2016, grew to Million USD in 2020, and will reach Million USD in 2026, with a CAGR of during 2020-2026.

Global Canine Stem Cell Therapy Market Development Strategy Pre and Post COVID-19, by Corporate Strategy Analysis, Landscape, Type, Application, and Leading 20 Countries covers and analyzes the potential of the global Canine Stem Cell Therapy industry, providing statistical information about market dynamics, growth factors, major challenges, PEST analysis and market entry strategy Analysis, opportunities and forecasts. The biggest highlight of the report is to provide companies in the industry with a strategic analysis of the impact of COVID-19. At the same time, this report analyzed the market of leading 20 countries and introduce the market potential of these countries.

COVID-19 / Great lockdown has compress the global economy and with it the manufacturing sector, production, disruption, financial.

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Who are some of the key players operating in the Canine Stem Cell Therapy market and how high is the competition 2022?

Company Information: List by Country Top Manufacturers/ Key Players In Canine Stem Cell Therapy Market Insights Report Are:

Get a sample copy of the Canine Stem Cell Therapy market report 2022

It also discussions about the market size of different segments and their growth aspects along with Competitive benchmarking, Historical data and forecasts, Company revenue shares, Regional opportunities, Latest trends and dynamics, growth trends, various stakeholders like investors, CEOs, traders, suppliers, Research and media, Global Manager, Director, President, SWOT analysis i.e. Strength, Weakness, Opportunities and Threat to the organization and others. Revenue forecast, company share, competitive landscape, growth factors and trends

What are the major applications and type, of Canine Stem Cell Therapy?

In on the basis of types, the Thermal Conductivity Measuring Apparatus market from 2015 to 2025 is primarily split into:

In on the basis of applications, the Thermal Conductivity Measuring Apparatus market from 2015 to 2025 covers:

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360 market updates presents a detailed picture of the market by the way of study, and summation of data from multiple sources by an analysis of key parameters. Our antimicrobial therapeutics market covers the following areas: Canine Stem Cell Therapy market sizing Canine Stem Cell Therapy market forecast Canine Stem Cell Therapy market industry analysis

What is our report scope?

This report focuses on the Canine Stem Cell Therapy in Global market, especially in North America, Europe and Asia-Pacific, South America, Middle East and Africa. This report categorizes the market based on manufacturers, regions, type and application. The Canine Stem Cell Therapy market report gives the clear picture of current market scenario which includes historical and projected market size in terms of value and volume, technological advancement, macro economical and governing factors in the market.

What are the major regional markets of Canine Stem Cell Therapy in Global, according to the 360 market updates report?

Canine Stem Cell Therapy Market analysis, by Geography: Major regions covered within the report: Consumption by Region 2022:-

North America,U.S.,Canada,Europe,Germany,France,U.K.,Italy,Russia,Asia-Pacific,China,Japan,SouthKorea,India,Australia,Taiwan,Indonesia,Thailand,Malaysia,Philippines,Vietnam,Latin America,Mexico,Brazil,Argentina,Middle East and Africa,Turkey,Saudi Arabia,U.A.E

The report can help to know the market and strategize for business expansion accordingly. Within the strategy analysis, it gives insights from market positioning and marketing channel to potential growth strategies, providing in-depth analysis for brand fresh entrants or exists competitors within the Canine Stem Cell Therapy industry. Global Canine Stem Cell Therapy Market Report 2022 provides exclusive statistics, data, information, trends and competitive landscape details during this niche sector.

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With tables and figures helping analyze worldwide Global Canine Stem Cell Therapy Market Forecast this research provides key statistics on the state of the industry and should be a valuable source of guidance and direction for companies and individuals interested in the market.

Major Points from Table of Contents:

Table of Content

1 Canine Stem Cell Therapy Market Definition and Overview

1.1 Objectives of the Study

1.2 Overview of Canine Stem Cell Therapy

1.3 Canine Stem Cell Therapy Market Scope and Market Size Estimation

1.4 Market Segmentation

1.4.1 Types of Canine Stem Cell Therapy

1.4.2 Applications of Canine Stem Cell Therapy

1.5 Market Exchange Rate

2 Research Method and Logic

2.1 Methodology

2.2 Research Data Source

3 Market Competition Analysis

3.1 Aratana Therapeutics Market Performance Analysis

3.1.1 Aratana Therapeutics Basic Information

3.1.2 Product and Service Analysis

3.1.3 Strategies for Company to Deal with the Impact of COVID-19

3.1.4 Aratana Therapeutics Sales, Value, Price, Gross Margin 2016-2022

3.2 Stem Cell Vet Market Performance Analysis

3.2.1 Stem Cell Vet Basic Information

3.2.2 Product and Service Analysis

3.2.3 Strategies for Company to Deal with the Impact of COVID-19

3.2.4 Stem Cell Vet Sales, Value, Price, Gross Margin 2016-2022

3.3 Magellan Stem Cells Market Performance Analysis

3.3.1 Magellan Stem Cells Basic Information

3.3.2 Product and Service Analysis

3.3.3 Strategies for Company to Deal with the Impact of COVID-19

3.3.4 Magellan Stem Cells Sales, Value, Price, Gross Margin 2016-2022

3.4 Cell Therapy Sciences Market Performance Analysis

3.4.1 Cell Therapy Sciences Basic Information

3.4.2 Product and Service Analysis

3.4.3 Strategies for Company to Deal with the Impact of COVID-19

3.4.4 Cell Therapy Sciences Sales, Value, Price, Gross Margin 2016-2022

3.5 VetStem Biopharma Market Performance Analysis

3.5.1 VetStem Biopharma Basic Information

3.5.2 Product and Service Analysis

3.5.3 Strategies for Company to Deal with the Impact of COVID-19

3.5.4 VetStem Biopharma Sales, Value, Price, Gross Margin 2016-2022

3.6 Medrego Market Performance Analysis

3.6.1 Medrego Basic Information

3.6.2 Product and Service Analysis

3.6.3 Strategies for Company to Deal with the Impact of COVID-19

3.6.4 Medrego Sales, Value, Price, Gross Margin 2016-2022

3.7 Regeneus Ltd Market Performance Analysis

3.7.1 Regeneus Ltd Basic Information

3.7.2 Product and Service Analysis

3.7.3 Strategies for Company to Deal with the Impact of COVID-19

3.7.4 Regeneus Ltd Sales, Value, Price, Gross Margin 2016-2022

3.8 MediVet Biologic Market Performance Analysis

3.8.1 MediVet Biologic Basic Information

3.8.2 Product and Service Analysis

3.8.3 Strategies for Company to Deal with the Impact of COVID-19

3.8.4 MediVet Biologic Sales, Value, Price, Gross Margin 2016-2022

3.9 Okyanos Market Performance Analysis

3.9.1 Okyanos Basic Information

3.9.2 Product and Service Analysis

3.9.3 Strategies for Company to Deal with the Impact of COVID-19

3.9.4 Okyanos Sales, Value, Price, Gross Margin 2016-2022

4 Market Segment by Type, Historical Data and Market Forecasts

4.1 Global Canine Stem Cell Therapy Production and Value by Type

4.1.1 Global Canine Stem Cell Therapy Production by Type 2016-2022

4.1.2 Global Canine Stem Cell Therapy Market Value by Type 2016-2022

4.2 Global Canine Stem Cell Therapy Market Production, Value and Growth Rate by Type 2016-2022

4.2.1 Allogeneic Stem Cells Market Production, Value and Growth Rate

4.2.2 Autologous Stem Cells Market Production, Value and Growth Rate

4.3 Global Canine Stem Cell Therapy Production and Value Forecast by Type

4.3.1 Global Canine Stem Cell Therapy Production Forecast by Type 2022-2026

4.3.2 Global Canine Stem Cell Therapy Market Value Forecast by Type 2022-2026

4.4 Global Canine Stem Cell Therapy Market Production, Value and Growth Rate by Type Forecast 2022-2026

4.4.1 Allogeneic Stem Cells Market Production, Value and Growth Rate Forecast

4.4.2 Autologous Stem Cells Market Production, Value and Growth Rate Forecast

5 Market Segment by Application, Historical Data and Market Forecasts

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Canine Stem Cell Therapy Market Size 2022 with a CAGR of % Market Share, prime companies report covers, world business Trends, Statistics, Definition,...

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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 -…

Thursday, June 16th, 2022

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.

The report explains the market definition, classifications, applications, engagements, and global Rheumatoid Arthritis Stem Cell Therapy industry trends are.It gives a realistic picture of the current market position incorporating original and predicted market estimates.The report gives a thorough analysis of their product portfolios to investigate the products and applications they focus on while working in the worldwide Rheumatoid Arthritis Stem Cell Therapy market. The report offers valuable suggestions to new just as set up players of the market.

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In order to improve industrial planning, data points such as flow patterns, openings, drivers, limits, and statistics are acquired from trusted sources. The data and numbers in the research report have been provided comprehensively, using graphical and pictorial representations to understand the market better.Further when datais synthesised, statistical analysis takes place. Several processes, including screening, integration, and data extrapolation, must be performed prior to data validation.

The product types covered in the report include:

The application types covered in the report include:

The countries covered in the market report are:

The key and emerging market players in the global market include:

ACCESS FULL REPORT: https://www.marketquest.biz/report/121261/global-rheumatoid-arthritis-stem-cell-therapy-market-2022-by-company-regions-type-and-application-forecast-to-2028

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Contact UsMark StoneHead of Business DevelopmentPhone: 1-201-465-4211Email: sales@marketquest.biz

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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 -...

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Sutton boy pledges to raise money to help his brother with autism go to America for stem cell therapy – Mansfield and Ashfield Chad

Thursday, June 16th, 2022

Max, five, from Sutton, was diagnosed as autistic when he was three-years-old. He is non verbal, but makes repetitive noises such as screeching and screaming sounds to communicate.

His brother, Noah, eight, who also has autism, has pledged to read a different book each evening in the hope of raising funds.

Rebecca Brett, 38, Max and Noahs mum, said: Max runs non stop, climbs, bounces and makes repetitive noises.

"He struggles to fall asleep and frequently wakes at midnight or 1am and will stay awake all night.

"Max eats a very limited diet and consequently suffers with severe constipation. As a result he has been hospitalised several times and needed medical interventions.

"He really struggles to make eye contact and now often removes his cochlear implants leaving him with no access to sound.

"We just want people to see him for the wonderful little boy he is and give him a chance.

"With your help and support we can provide Max with an opportunity to move forward with stem cell therapy which has proven to assist and reduce the severe impact autism has on his life and give him a chance to regain some of the basic qualities of life that he deserves.

"Noah reads a different book each evening and he tries to dress up or add silly voices or get involved with me reading a story and we share the stories on my Facebook site with his charity fundraising page, in the hope of raising funds.

"Noah is raising money to go to America for stem cell therapy for Max. We have had one treatment so far in Vienna, and seen some really promising changes to Max and it has raised our hopes that we can help Max push back his autism and regain more control of his own life.

If you would like to support Max and make a donation towards Noahs reading challenge visit gofund.me/3d02a131.

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Sutton boy pledges to raise money to help his brother with autism go to America for stem cell therapy - Mansfield and Ashfield Chad

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Japan’s five hottest biotech companies in healthcare – Labiotech.eu

Thursday, June 16th, 2022

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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Japan's five hottest biotech companies in healthcare - Labiotech.eu

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Hemostemix Announces the Incorporation of PreCerv Inc. And a Global Field of Use License to NCP-01 – Yahoo Finance

Thursday, June 16th, 2022

Calgary, Alberta--(Newsfile Corp. - June 14, 2022) - Hemostemix Inc. (TSXV: HEM) (OTCQB: HMTXF) ("Hemostemix" or the "Company") is pleased to announce it has incorporated PreCerv Inc. ("PreCerv"), as a wholly owned subsidiary. PreCerv will obtain from Hemostemix a global field of use license to NCP-01 and its autologous stem cell technologies, to treat conditions of the central and peripheral nervous system, including but not limited to the following:

Neuropathic pain syndromes.

Traumatic spinal cord injury, chronic brainstem injury, traumatic brain injury, peripheral nerve injury.

Rare diseases including: syringomyelia, Charcot-Marie tooth disease, and Guillain-Barre syndrome, Amyotrophic lateral sclerosis (ALS), age-related macular degeneration (ARMD), corneal or eye diseases and retinopathies of any cause.

Cerebral stroke

"NCP-01 are autologous neuronal cell precursors which, alone or in combination with ACP-01, have the potential to treat many conditions of the central and peripheral nervous system. I want to thank our medical and science teams for translation of that potential into significant studies, and for introductions to the most talented scientists in this field. By originating a field of use license, PreCerv's new management team will fund its studies to unlock NCP's value for the shareholders of Hemostemix," stated Thomas Smeenk, CEO.

ABOUT HEMOSTEMIX

Hemostemix is a publicly traded autologous stem cell therapy company, founded in 2003. A winner of the World Economic Forum Technology Pioneer Award, the Company developed and has published seven peer reviewed articles about the safety and efficacy of its lead product ACP-01 as a treatment of CLI, PAD, Angina, Ischemic Cardiomyopathy, Dilated Cardiomyopathy and other conditions of ischemia. ACP-01 has been used to treat over 300 patients, and it is the subject of a randomized, placebo-controlled, double blind trial of its safety and efficacy in patients with advanced critical limb ischemia who have exhausted all other options to save their limb from amputation.

Story continues

On October 21, 2019, the Company announced the results from its Phase II CLI trial abstract presentation entitled "Autologous Stem Cell Treatment for CLI Patients with No Revascularization Options: An Update of the Hemostemix ACP-01 Trial With 4.5 Year Follow-up" which noted healing of ulcers and resolution of ischemic rest pain occurred in 83% of patients, with outcomes maintained for up to 4.5 years.

The Company owns 91 patents across five patent families titled: Regulating Stem Cells, In Vitro Techniques for use with Stem Cells, Production from Blood of Cells of Neural Lineage, and Automated Cell Therapy. For more information, please visit http://www.hemostemix.com.

For further information, please contact:

Thomas Smeenk, President, CEO & Co-FounderTSmeenk@Hemostemix.com 905-580-4170

Neither the TSX Venture Exchange nor its Regulation Service Provider (as that term is defined under the policies of the TSX Venture Exchange) accepts responsibility for the adequacy or accuracy of this release.

Forward-Looking Information: This news release contains "forward-looking information" within the meaning of applicable Canadian securities legislation. All statements, other than statements of historical fact, included herein are forward-looking information. In particular, this news release contains forward-looking information in relation to: the incorporation of PreCerv Inc., the completion of studies of NCP-01, or NCP-01 in combination with ACP-01, a financing of PreCerv Inc. There can be no assurance that such forward-looking information will prove to be accurate. Actual results and future events could differ materially from those anticipated in such forward-looking information. This forward-looking information reflects Hemostemix's current beliefs and is based on information currently available to Hemostemix and on assumptions Hemostemix believes are reasonable. These assumptions include, but are not limited to: the underlying value of Hemostemix and its Common Shares; the results of ACP-01 research, trials, studies and analyses, including the analysis being equivalent to or better than previous research, trials or studies as well as management's expectations of anticipated results; Hemostemix's general and administrative costs remaining relatively constant; the receipt of all required regulatory approvals for research, trials or studies; the level of activity, market acceptance and market trends in the healthcare sector; the economy generally; consumer interest in Hemostemix's services and products; competition and Hemostemix's competitive advantages; and Hemostemix obtaining satisfactory financing to fund Hemostemix's operations including any research, trials or studies, and the Litigation. Forward-looking information is subject to known and unknown risks, uncertainties and other factors that may cause the actual results, level of activity, performance or achievements of Hemostemix to be materially different from those expressed or implied by such forward-looking information. Such risks and other factors may include, but are not limited to: the ability of Hemostemix to complete its current CLI clinical trial, complete a satisfactory analyses and the results of such analyses and future clinical trials; litigation and potential litigation that Hemostemix may face; general business, economic, competitive, political and social uncertainties; general capital market conditions and market prices for securities; delay or failure to receive board or regulatory approvals; the actual results of future operations including the actual results of future research, trials or studies; competition; changes in legislation affecting Hemostemix; the timing and availability of external financing on acceptable terms; long-term capital requirements and future developments in Hemostemix's markets and the markets in which it expects to compete; lack of qualified, skilled labour or loss of key individuals; and risks related to the COVID-19 pandemic including various recommendations, orders and measures of governmental authorities to try to limit the pandemic, including travel restrictions, border closures, non-essential business closures, service disruptions, quarantines, self-isolations, shelters-in-place and social distancing, disruptions to markets, disruptions to economic activity and financings, disruptions to supply chains and sales channels, and a deterioration of general economic conditions including a possible national or global recession or depression; the potential impact that the COVID-19 pandemic may have on Hemostemix which may include a decreased demand for the services that Hemostemix offers; and a deterioration of financial markets that could limit Hemostemix's ability to obtain external financing. A description of additional risk factors that may cause actual results to differ materially from forward-looking information can be found in Hemostemix's disclosure documents on the SEDAR website at http://www.sedar.com. Although Hemostemix has attempted to identify important factors that could cause actual results to differ materially from those contained in forward-looking information, there may be other factors that cause results not to be as anticipated, estimated or intended. Readers are cautioned that the foregoing list of factors is not exhaustive. Readers are further cautioned not to place undue reliance on forward-looking information as there can be no assurance that the plans, intentions or expectations upon which they are placed will occur. Forward-looking information contained in this news release is expressly qualified by this cautionary statement. The forward-looking information contained in this news release represents the expectations of Hemostemix as of the date of this news release and, accordingly, it is subject to change after such date. However, Hemostemix expressly disclaims any intention or obligation to update or revise any forward-looking information, whether as a result of new information, future events or otherwise, except as expressly required by applicable securities law.

To view the source version of this press release, please visit https://www.newsfilecorp.com/release/127665

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Hemostemix Announces the Incorporation of PreCerv Inc. And a Global Field of Use License to NCP-01 - Yahoo Finance

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