Trials Of Cell-based Therapies Research Articles

Evaluation of the impact of customized serum-free culture medium on the production of clinical-grade human umbilical cord mesenchymal stem cells: insights for future clinical applications

BackgroundThe selection of suitable culture medium is critical for achieving good clinical outcomes in cell therapy. To support the commercial application of stem cell therapy, customized culture media not only need to promote stem cell proliferation, but also need to save costs and meet industrial requirements for inter-batch consistency, efficacy, and biosafety. In this study, we developed a series of serum-free media (SFM) and elucidated the effects between different SFM, as well as between SFM and serum-containing meida (SCM), on human umbilical cord mesenchymal stem cells (hUC-MSCs) phenotype and function. We analyze and emphasize from the perspectives of clinical and commercial application why research on customized culture media is critical for the success of enterprises developing novel cellular therapeutics.MethodsWe cultured hUC-MSCs with identical cell seeding densities in different formulations of SFM and SCM until passage 10 and examined the changes in cell phenotype and function. We analyzed the results with the commercial application requirments of the cellular therapy industry to assess the potential impact of customized culture media on inter-batch consistency, efficacy, stability, biosafety, and cost-effectiveness of industrial-scale cell production.ResultshUC-MSCs cultured in SCM and SFM exhibit consistent cell morphology and surface molecule expression, but hUC-MSCs cultured in SFM demonstrate higher activity, superior proliferative capacity, and greater stability. Furthermore, hUC-MSCs cultured in different SFM exhibit differences in cell activity, proliferative capacity, senescent rate, and S/M ratio of cell cycle, while maintaining a normal karyotype after long-term in vitro cultivation. Moreover, we found that hUC-MSCs cultured in different media exhibit variations in paracrine capacity and in their support of hematopoietic stem cell (HSC) self-renewal.ConclusionConsidering the substantial funding and time required for cell-based drug development, our results underscore the importances of comprehensively optimizing the composition of medium for the specific disease prior to conducting clinical trials of cell-based therapies. The criteria for selecting culture medium should be based on the requirements of the target disease for cellular function. In addition, we provide a way to formulate different customized SFM, which is beneficial for the development of cell therapy industry.

Moral obligations in conducting stem cell-based therapy trials for autism spectrum disorder

Unregulated patient treatments and approved clinical trials have been conducted with haematopoietic stem cells and mesenchymal stem cells for children with autism spectrum disorder (ASD). While the former direct-to-consumer practice...

Understanding embryonic development for cell-based therapies of intervertebral disc degeneration: Toward an effort to treat disc degeneration subphenotypes.

Chronic low back and neck pain are associated with intervertebral disc degeneration and are major contributors to the global burden of disability. New evidence now suggests that disc degeneration comprises a spectrum of subphenotypes influenced by genetic background, age, and environmental factors, which may be contributing to the mixed outcomes seen in clinical trials of cell-based therapies that aim to treat disc degeneration. This problem is further compounded by the fact that disc degeneration and aging coincide with an exhaustion of endogenous progenitor cells, imposing limitations on the regenerative capacity of the disc. At the bench-side, current work is focused on applying our knowledge of embryonic disc development to direct and refine differentiation of adult and human-induced pluripotent stem cells into notochord-like and nucleus pulposus-like cells for use in novel cell-based therapies. Accordingly, this review presents the salient features of intervertebral disc development, post-natal maintenance, and regeneration, with emphasis on recent advancements. We also discuss how a stratified approach can be undertaken for the development of future cell-based therapies to bring emerging subphenotypes into consideration.

Retinal Dystrophies and the Road to Treatment: Clinical Requirements and Considerations.

Retinal dystrophies (RDs) comprise relatively rare but devastating causes of progressive vision loss. They represent a spectrum of diseases with marked genetic and clinical heterogeneity. Mutations in the same gene may lead to different diagnoses, for example, retinitis pigmentosa or cone dystrophy. Conversely, mutations in different genes may lead to the same phenotype. The age at symptom onset, and the rate and characteristics of peripheral and central vision decline, may vary widely per disease group and even within families. For most RD cases, no effective treatment is currently available. However, preclinical studies and phase I/II/III gene therapy trials are ongoing for several RD subtypes, and recently the first retinal gene therapy has been approved by the US Food and Drug Administration for RPE65-associated RDs: voretigene neparvovec-rzyl (Luxturna). With the rapid advances in gene therapy studies, insight into the phenotypic spectrum and long-term disease course is crucial information for several RD types. The vast clinical heterogeneity presents another important challenge in the evaluation of potential efficacy in future treatment trials, and in establishing treatment candidacy criteria. This perspective describes these challenges, providing detailed clinical descriptions of several forms of RD that are caused by genes of interest for ongoing and future gene or cell-based therapy trials. Several ongoing and future treatment options will be described.

Publication rates and reported results in a cohort of gene- and cell-based therapy trials.

Aim: We investigated publication rates and reported results for gene- and cell-based therapy trials. Materials & methods: In a cohort of Institutional Review Board (IRB)-authorized trials during 2007-2017 in the Netherlands (n=105), we examine publication rates and reported results in scientific papers and conference abstracts as well as associations with the occurrence of trial characteristics. Results: The publication rate for scientific papers was 27% and 17% for conference abstracts (median survival time: 1050days). Academic hospitals published more in scientific papers whereas private sponsors published more in conference abstracts. Manufacturing protocols were underreported compared with clinical outcomes. Most publications reported positive results (78%). Conclusion: Publication rates are currently suboptimal indicating a need for enhanced knowledge sharing to stimulate gene- and cell-based therapy development.

Cell-based therapies for amyotrophic lateral sclerosis/motor neuron disease.

Amyotrophic lateral sclerosis (ALS), which is also known as motor neuron disease (MND), is a fatal disease associated with rapidly progressive disability, for which no definitive treatment exists. Current treatment approaches largely focus on relieving symptoms to improve the quality of life of those affected. The therapeutic potential of cell-based therapies in ALS/MND has not been fully evaluated, given the paucity of high-quality clinical trials. Based on data from preclinical studies, cell-based therapy is a promising treatment for ALS/MND. This review was first published in 2015 when the first clinical trials of cell-based therapies were still in progress. We undertook this update to incorporate evidence now available from randomised controlled trials (RCTs). To assess the effects of cell-based therapy for people with ALS/MND, compared with placebo or no treatment. On 31 July 2019, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, and Embase. We also searched two clinical trials registries for ongoing or unpublished studies. We included RCTs that assigned people with ALS/MND to receive cell-based therapy versus a placebo or no additional treatment. Co-interventions were allowed, provided that they were given to each group equally. We followed standard Cochrane methodology. Two RCTs involving 112 participants were eligible for inclusion in this review. One study compared autologous bone marrow-mesenchymal stem cells (BM-MSC) plus riluzole versus control (riluzole only), while the other study compared combined intramuscular and intrathecal administration of autologous mesenchymal stem cells secreting neurotrophic factors (MSC-NTF) to placebo. The latter study was reported as an abstract and provided no numerical data. Both studies were funded by biotechnology companies. The only study that contributed to the outcome data in the review involved 64 participants, comparing BM-MSC plus riluzole versus control (riluzole only). It reported outcomes after four to six months. It had a low risk of selection bias, detection bias and reporting bias, but a high risk of performance bias and attrition bias. The certainty of evidence was low for all major efficacy outcomes, with imprecision as the main downgrading factor, because the range of plausible estimates, as shown by the 95% confidence intervals (CIs), encompassed a range that would likely result in different clinical decisions. Functional impairment, expressed as the mean change in the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score from baseline to six months after cell injection was slightly reduced (better) in the BM-MSC group compared to the control group (mean difference (MD) 3.38, 95% CI 1.22 to 5.54; 1 RCT, 56 participants; low-certainty evidence). ALSFRS-R has a range from 48 (normal) to 0 (maximally impaired); a change of 4 or more points is considered clinically important. The trial did not report outcomes at 12 months. There was no clear difference between the BM-MSC and the no treatment group in change in respiratory function (per cent predicted forced vital capacity; FVC%; MD -0.53, 95% CI -5.37 to 4.31; 1 RCT, 56 participants; low-certainty evidence); overall survival at six months (risk ratio (RR) 1.07, 95% CI 0.94 to 1.22; 1 RCT, 64 participants; low-certainty evidence); risk of total adverse events (RR 0.86, 95% CI 0.62 to 1.19; 1 RCT, 64 participants; low-certainty evidence) or serious adverse events (RR 0.47, 95% CI 0.13 to 1.72; 1 RCT, 64 participants; low-certainty evidence). The study did not measure muscle strength. Currently, there is a lack of high-certainty evidence to guide practice on the use of cell-based therapy to treat ALS/MND. Uncertainties remain as to whether this mode of therapy is capable of restoring muscle function, slowing disease progression, and improving survival in people with ALS/MND. Although one RCT provided low-certainty evidence that BM-MSC may slightly reduce functional impairment measured on the ALSFRS-R after four to six months, this was a small phase II trial that cannot be used to establish efficacy. We need large, prospective RCTs with long-term follow-up to establish the efficacy and safety of cellular therapy and to determine patient-, disease- and cell treatment-related factors that may influence the outcome of cell-based therapy. The major goals of future research are to determine the appropriate cell source, phenotype, dose and method of delivery, as these will be key elements in designing an optimal cell-based therapy programme for people with ALS/MND. Future research should also explore novel treatment strategies, including combinations of cellular therapy and standard or novel neuroprotective agents, to find the best possible approach to prevent or reverse the neurological deficit in ALS/MND, and to prolong survival in this debilitating and fatal condition.

Imaging characteristics of chronic spinal cord injury identified during screening for a cell transplantation clinical trial.

OBJECTIVEIn cell transplantation trials for spinal cord injury (SCI), quantifiable imaging criteria that serve as inclusion criteria are important in trial design. The authors' institutional experience has demonstrated an overall high rate of screen failures. The authors examined the causes for trial exclusion in a phase I, open-lab clinical trial examining the role of autologous Schwann cell intramedullary transplantation. Specifically, they reviewed the imaging characteristics in people with chronic SCI that excluded applicants from the trial, as this was a common cause of screening failures in their study.METHODSThe authors reviewed MRI records from 152 people with chronic (> 1 year) SCI who volunteered for intralesional Schwann cell transplantation but were deemed ineligible by prospectively defined criteria. Rostral-caudal injury lesion length was measured along the long axis of the spinal cord in the sagittal plane on T2-weighted MRI. Other lesion characteristics, specifically those pertaining to lesion cavity structure resulting in trial exclusion, were recorded.RESULTSImaging records from 152 potential participants with chronic SCI were reviewed, 42 with thoracic-level SCI and 110 with cervical-level SCI. Twenty-three individuals (55%) with thoracic SCI and 70 (64%) with cervical SCI were not enrolled in the trial based on imaging characteristics. For potential participants with thoracic injuries who did not meet the screening criteria for enrollment, the average rostral-caudal sagittal lesion length was 50 mm (SD 41 mm). In applicants with cervical injuries who did not meet the screening criteria for enrollment, the average sagittal lesion length was 34 mm (SD 21 mm).CONCLUSIONSWhile screening people with SCI for participation in a cell transplantation clinical trial, lesion length or volume can exclude potential subjects who appear appropriate candidates based on neurological eligibility criteria. In planning future cell-based therapy trials, the limitations incurred by lesion size should be considered early due to the screening burden and impact on candidate selection.

Acid stimulation-induced semi-pluripotent characteristics in human somatic cells

Background: Clinical trials of cell-based therapies using induced pluripotent stem (iPS) cells have already been started for several neurological diseases.Objective: The purpose of the present study was to explore the characteristics and differentiation of somatic cells in vitro undergoing a low pH treatment, so as to provide new therapeutic strategies for treating sensorineural hearing loss.Methods: Somatic cells were treated with low pH solution to alter their characteristics. In addition, a mouse model of the cochlear lesion was constructed using bilirubin. Subsequently, the characteristics and therapeutic effect of somatic cells undergoing low pH treatment were examined by morphology, alkaline phosphatase (AKP) activity, immunofluorescence assay and q-PCR.Results: The cells in the experimental group grew better than those in the control group. The AKP activity in the experimental group was higher than that in the control group. The expression of Nanog and Oct4 was both positive in the two groups. When the cells were changed to neurobasal medium, the marker of nestin was positive.Conclusion: The human somatic cells undergoing a low pH treatment showed the similar characteristics as those of iPS cells, although the functions and therapeutic effect of these altered human somatic cells need to be further studied.

Bone Marrow-Derived Cellular Therapies in Orthopaedics: Part I: Recommendations for Bone Marrow Aspiration Technique and Safety.

* Bone marrow is a valuable source of cells for cell-based therapies in orthopaedics.* Bone marrow aspiration is most frequently performed from the iliac crest and has been reported to be a safe procedure, with a low complication rate in orthopaedics.* The bone marrow aspiration site, technique, and subsequent processing have a profound effect on the concentration and prevalence of connective tissue progenitors. The iliac crest generally provides the highest yield and prevalence of connective tissue progenitors.* Small aspiration volumes (1 to 2 mL each), using 10-mL syringes, and modifying the aspiration sites by 5 to 10 mm are recommended to optimize the yield of connective tissue progenitors during bone marrow aspiration.* In clinical trials of cell-based therapies derived from bone marrow aspiration, the aspiration technique (site, needle, syringe, aspiration volume, and anticoagulant, if used) should be reported.

Cell-Based Therapies for Tissue Fibrosis.

The development of tissue fibrosis in the context of a wound-healing response to injury is common to many chronic diseases. Unregulated or persistent fibrogenesis may lead to structural and functional changes in organs that increase the risk of significant morbidity and mortality. We will explore the natural history, epidemiology, and pathogenesis of fibrotic disease affecting the lungs, kidneys, and liver as dysfunction of these organs is responsible for a substantial proportion of global mortality. For many patients with end-stage disease, organ transplantation is the only effective therapy to prolong life. However, not all patients are candidates for the major surgical interventions and life-long immunosuppression required for a successful outcome and donor organs may not be available to meet the clinical need. We will provide an overview of the latest treatment strategies for these conditions and will focus on stem or progenitor cell-based therapies for which there is substantial pre-clinical evidence based on animal models as well as early phase clinical trials of cell-based therapy in man.

Abstract 133: Effectiveness of a Stem Cell-derived Therapeutic Factor Concentrate in a Mouse Embolic Stroke Model

Background: Early clinical trials of cell-based therapies in stroke have been very encouraging; however, technical hurdles may prevent widespread adoption. The salutary effects appear to be through release of “trophic” factors and immunomodulators which affect host repair and protection responses. We are developing a novel stroke therapy which is a clinically compliant cell-free, therapeutic factor concentrate (TFC) derived from adipose stem cell conditioned medium (ASC-CM). We will present data from a murine embolic stroke model study to determine the potential for clinical translation of TFC. Methods: Embolic stroke was induced in C57/Bl6 male mice (16 - 18 wks old) by delivering 9 - 10 mm clot into the middle cerebral artery (MCA) territory. Mice were randomly picked up for the intravenous treatments (either vehicle or 20/50/100 uL of TFC; N= 10/group) immediately after stroke. Neurological deficits were evaluated at 48 hrs post stroke, and mice were also tested for the somatosensory functions using adhesive tape removal test (ATT) at 72 hrs before the sacrifice for TTC-stained infarct analysis. Statistical significance was determined at P < 0.05. Results: Our data demonstrate a clear dose dependent response, with the highest dose tested (100 uL; ~4 mg total protein/kg body weight) being the most effective in the embolic stroke model. While the low-dose (20 uL; 0.8 mg/kg) did not show an effect in any outcomes measured, the middle dose (50 uL, ~2 mg/kg) was effective but less so than the highest dose (100 uL). TFC at 100 uL significantly improved neurological outcomes on Bederson scale, and also somatosensory function as determined by ATT. There was also a trend toward improved survival after stroke in 100 uL TFC treated group. Most importantly, while the 50 uL dose reduced the infarction volume by ~20%, the effect was >50% reduction with 100 uL treatment. TFC at any dose did not show any adverse effects such as the hemorrhagic transformation. Conclusion: TFC is a potential therapy to improve post-stroke outcomes. We are repeating these studies with ovariectomized female mice and extending the studies to 1 month. Future studies with this model will test TFC (1) in combination with IV-tPA, (2) with delayed delivery (up to 24 hours post-stroke), (3) and in aged animals.

The quest for a successful cell-based therapeutic approach for heart failure.

This editorial refers to ‘Cardiopoietic cell therapy for advanced ischaemic heart failure: results at 39 weeks of the prospective, ramdomized, double-blind, sham-controlled CHART-1 clinical trial’, by J. Bartunek et al. , doi:10.1093/eurheartj/ehw543. Two-thirds of all heart failure is due to ischaemic heart disease.1 These patients receive lifelong medication, experience significant morbidity and mortality, and often progress to heart transplantation or insertion of a left ventricular assist device,1,2 In terms of population impact, a successful regenerative medicine strategy will have enormous impact upon patients with heart failure, who number in the millions worldwide. The staggering impact upon patients and healthcare systems provides extraordinary impetus for the development of a regenerative approach to treat these patients.2,3 Indeed, the notion of affecting an improvement in left ventricular structure as a substrate for enhancing patients’ quality of life and functional capacity (ultimately leading to reducing morbidity and mortality) is extraordinarily attractive.2 This quest has spawned several clinical investigative efforts to devise an effective and efficient way to deliver cell-based therapy to this large patient population with major unmet needs.4,5 This resulted in the testing of a vast array of cells ( Table 1 ).2 Currently, there are few decisive successes in the field. However, all of the current efforts are small, with no published studies exceeding 200 patients, and very importantly lack standardization. For reference, an early important study in the development of biventricular pacing enrolled 453 patients.6 View this table: Table 1 Cell types under investigation in cell-based therapy trials for heart failure In 2010, Behfar and colleagues demonstrated that mesenchymal stem cells (MSCs) could be guided to become cardiac progenitor cells in mice.7 Furthermore, this study demonstrated that there are individuals that harbour stem cells with unique reparative capabilities, which are characterized …

Advanced imaging of transplant survival, fate, differentiation, and integration.

Stem cell-based therapy trials for the treatment of neurodegenerative diseases such as Parkinson's and Huntington's disease are being actively prepared both at the preclinical and clinical level. Preclinical validation of these stem cell transplantations necessitates to implement a translational continuum to take one pluripotent stem cell through the point of "first-in-man" clinical trial. Main steps along this translational continuum include stem cell GMP production, in vitro optimization of differentiation protocols necessary to direct stem cells to the desired neuronal phenotype, and evaluation of functional efficacy in animal models including large animal models. Whereas the first two steps only require in vitro techniques and can be expedited smoothly, the last step is generally time consuming as functional assessment requires transplantation of the animal models with sufficient time for cells to develop, reconnect, and exert their therapeutic effect (around 40 weeks for human cells in the rodent brain). In such a context, brain imaging techniques that allow noninvasive longitudinal evaluation/characterization of the grafted cells in the living animals have the potential to speed-up the evaluation of candidate cell lines. This chapter describes an assemblage of imaging methods that over the years proved useful in preclinical and clinical applications for cell therapy, providing in a noninvasive way unique insights on graft cellular composition, phenotypic differentiation, as well as signs of hyperproliferation and/or immunological rejection and inflammation.

Development of a Functional Biomarker for Use in Cell-Based Therapy Studies in Seropositive Rheumatoid Arthritis.

Cell-based therapy has potential therapeutic value in autoimmune diseases such as rheumatoid arthritis (RA). In RA, reduction of disease activity has been associated with improvement in the function of regulatory T cells (Treg) and attenuated responses of proinflammatory effector T cells (Teff). Mesenchymal stem cells (MSCs) and related multipotent adult progenitor cells (MAPC) have strong anti-inflammatory and immunomodulatory properties and may be able to "reset" the immune system to a pre-RA state. MAPC are MSC-like cells that are slightly earlier in lineage, have greater expansion capacity, and can be used as "off-the-shelf" therapy. Assessment of cell-based therapy to treat arthritis and related diseases is limited by the lack of available biological correlates that can be measured early on and indicate treatment response. We set out to develop a functional measure that could be used ex vivo as a biomarker of response. We were able to demonstrate that MAPC products could inhibit Teff responses from patients with active RA and that Treg from RA patients suppressed Teff. This assay used ex vivo can be used with MAPC or Treg alone or in combination and reflects the overall level of Teff suppression. Use of a novel functional biomarker as an exploratory endpoint in trials of cell-based therapy should be of value to detect biological outcomes at a point prior to the time that clinical response might be observed. Therapy with mesenchymal stem cells and related multipotent adult progenitor cells is immune modifying in a variety of diseases. There is interest in using cell-based therapy in rheumatoid arthritis (RA) to induce tolerance and "reset" the immune system to its pre-RA state. In a clinical trial, it should be known as soon as possible if there is a chance of response. A biomarker has been developed that permits measurement of the effects of cell-based therapy on effector T cell function.

Concise Review: Review and Perspective of Cell Dosage and Routes of Administration From Preclinical and Clinical Studies of Stem Cell Therapy for Heart Disease.

An important stage in the development of any new therapeutic agent is establishment of the optimal dosage and route of administration. This can be particularly challenging when the treatment is a biologic agent that might exert its therapeutic effects via complex or poorly understood mechanisms. Multiple preclinical and clinical studies have shown paradoxical results, with inconsistent findings regarding the relationship between the cell dose and clinical benefit. Such phenomena can, at least in part, be attributed to variations in cell dosing or concentration and the route of administration (ROA). Although clinical trials of cell-based therapy for cardiovascular disease began more than a decade ago, specification of the optimal dosage and ROA has not been established. The present review summarizes what has been learned regarding the optimal cell dosage and ROA from preclinical and clinical studies of stem cell therapy for heart disease and offers a perspective on future directions. Significance: Preclinical and clinical studies on cell-based therapy for cardiovascular disease have shown inconsistent results, in part because of variations in study-specific dosages and/or routes of administration (ROA). Future preclinical studies and smaller clinical trials implementing cell-dose and ROA comparisons are warranted before proceeding to pivotal trials.

Density-gradient centrifugation enables the purification of cultured corneal endothelial cells for cell therapy by eliminating senescent cells.

The corneal endothelium is essential for maintaining corneal transparency; therefore, corneal endothelial dysfunction causes serious vision loss. Tissue engineering-based therapy is potentially a less invasive and more effective therapeutic modality. We recently started a first-in-man clinical trial of cell-based therapy for treating corneal endothelial dysfunction in Japan. However, the senescence of corneal endothelial cells (CECs) during the serial passage culture needed to obtain massive quantities of cells for clinical use is a serious technical obstacle preventing the push of this regenerative therapy to clinical settings. Here, we show evidence from an animal model confirming that senescent cells are less effective in cell therapy. In addition, we propose that density-gradient centrifugation can eliminate the senescent cells and purify high potency CECs for clinical use. This simple technique might be applicable for other types of cells in the settings of regenerative medicine.

Design and implementation of the START (STem cells for ARDS Treatment) trial, a phase 1/2 trial of human mesenchymal stem/stromal cells for the treatment of moderate-severe acute respiratory distress syndrome

BackgroundDespite advances in supportive care, moderate-severe acute respiratory distress syndrome (ARDS) is associated with high mortality rates, and novel therapies to treat this condition are needed. Compelling pre-clinical data from mouse, rat, sheep and ex vivo perfused human lung models support the use of human mesenchymal stem (stromal) cells (MSCs) as a novel intravenous therapy for the early treatment of ARDS.MethodsThis article describes the study design and challenges encountered during the implementation and phase 1 component of the START (STem cells for ARDS Treatment) trial, a phase 1/2 trial of bone marrow-derived human MSCs for moderate-severe ARDS. A trial enrolling 69 subjects is planned (9 subjects in phase 1, 60 subjects in phase 2 treated with MSCs or placebo in a 2:1 ratio).ResultsThis report describes study design features that are unique to a phase 1 trial in critically ill subjects and the specific challenges of implementation of a cell-based therapy trial in the ICU.ConclusionsExperience gained during the design and implementation of the START study will be useful to investigators planning future phase 1 clinical trials based in the ICU, as well as trials of cell-based therapy for other acute illnesses.Trial registrationClinical Trials Registration: NCT01775774 and NCT02097641.

Current clinical trials of cell-based therapies in cardiac repair: too many variables spoil the stem cell broth

This editorial refers to ‘Impact of intracoronary bone marrow cell therapy on left ventricular function in the setting of ST-segment elevation myocardial infarction: a collaborative meta-analysis’, by R. Delewi et al. doi:10.1093/eurheartj/eht372 Even the staunchest advocate of the use of cell-based therapies in cardiac repair would be forced to admit that progress has thus far been slow. Both use of therapeutic stem cells and gene-based approaches have met with significant hurdles in their clinical development. However, significant progress does continue to be made towards the ultimate goal of a safe and efficacious cell-based therapy for routine clinical use in cardiac repair. In the area of stem cells, a number of approaches have been proposed, tested pre-clinically, and then clinically evaluated, albeit in relatively small studies thus far.1 These include use of skeletal muscle myoblasts (SKMs), bone marrow-derived mononuclear cells (BMCs), mesenchymal stem cells (MSCs, both bone marrow and adipose tissue derived), and cardiac stem cells. Amongst these, the most rigorously evaluated thus far have undoubtedly been the BMCs. Bone marrow-derived mononuclear cells used therapeutically may be unselected or selected according to characteristic cell surface markers, e.g. CD34+, CD133+, and/or CXCR4+, amongst many other identifiers.2 Putative mechanisms of benefit of BMCs in the post-myocardial infarction (MI) cardiac repair setting have been variously ascribed to both direct transdifferentiation into cardiomyocytes (likely to play only a minimal, if any, role), indirect actions such as vasculogenesis and angiogenesis, antiapoptotic and antinecrotic effects, and favourable paracrine effects on the extracellular matrix.3 Intravascular delivery methods invariably result in only minimal local accumulation and retention of cells within the heart in general and the peri-infarct region specifically post-MI.4 In addition, the cardiac microenvironment in the early post-infarct setting is relatively hostile …

1．脳梗塞患者に対する再生医療の現状とその未来

Cerebral infarction causes permanent neurological damage. Recently, the intravenous administration of bone marrow-derived mononuclear cells has been shown to improve functional recovery through enhanced angiogenesis in an experimental stroke model. Based on these observations, we have started a phase 1/2a clinical trial of cell-based therapy for patients with cardiogenic cerebral embolism. The major inclusion criterion was patients in whom severe cerebral embolism was diagnosed (more than 9 in the NIHSS score on day 7 after the onset of stroke) at age 75 or younger. The patients received 25 ml (low-dose group, n=6) or 50 ml (high-dose group, n=6) of bone marrow aspirate on days 7-10 after the onset of stroke. Autologous bone marrow-derived mononuclear cells were purified by the density gradient method and administered intravenously on the day of cell aspiration. The primary endpoint was safety and improvement of the NIHSS score compared with our historical control. We treated 6 patients in the low-dose group and 4 patients in the high-dose group. No adverse effects were observed and most of the patients showed a significant improvement in neurological function at 6 months after cell transplantation. No enrolled patients showed worsening of the NIHSS score at 30 days after the treatment compared with the NIHSS score before the treatment. Autologous bone marrow mononuclear cell transplantation is apparently safe and feasible, and it improves functional recovery.

Cell-Based Therapy to Promote Angiogenesis in the Brain Following Ischemic Damage

Cell-based therapies are a novel approach for regeneration of microvasculature. We have shown that administration of CD34-positive cells, the rich cell fraction of endothelial progenitor cells, after stroke induces angiogenesis that results in enhanced endogenous neurogenesis and functional recovery in a murine model. Moreover, injury-induced neurogenesis occurs in the human brain following a stroke during the acute to sub-acute period. Based on these observations, clinical trials of cell therapies that aim to regenerate micro-circulation in the brain following a stroke are ongoing worldwide. This review summarizes the current basic research findings about the link between angiogenesis and neurogenesis in the post-stroke brain and introduces the ongoing clinical trials of cell-based therapies for patients that have suffered a stroke.