Stem Cell Clinical Trials Research Articles

Stem Cell Clinical Trials for Spinal Cord Injury: Readiness, Reluctance, Redefinition

A wealth of scientific and clinical research has focused on the use of stem cells as a potential therapy for spinal cord injury (SCI), culminating most recently in the initiation of clinical trials. However, with the urgency that scientists and clinicians have undertaken to move forward with novel therapies for this devastating injury, the perspectives of stakeholders who live with a SCI have been left behind. Translational research in this rapidly growing field therefore overlooks a critically important viewpoint. We address this concern with a qualitative study of the perspectives on experimental stem cell treatments from individuals who have actually suffered a spinal cord injury. Using focus groups and interviews, we engaged individuals with thoracic and cervical SCIs at sub-acute and chronic stages post-injury. We found four major themes that inform the progression of stem cell research to clinical trials: 'readiness', 'the here and now', 'wait and see', and 'informed hope'. Taken together, the data suggest a profound difference related to target timing of stem cell clinical trials and the perspectives about timing from those who are the end-beneficiaries of therapy. To bridge this gap, we conclude with a number of considerations for the timing disparity of trials and recommendations for improving informed consent.

Stem cells therapy for cardiovascular repair in ischemic heart disease: How to predict and secure optimal outcome?

Coronary artery disease is a growing problem worldwide. Early treatment with stabilizing drugs and revascularization by percutaneous coronary intervention or by-pass surgery has reduced the mortality significantly, but it is still the most common cause of death and a major cause of hospital admissions in industrialized countries. Treatment with stem cells with the potential to regenerate the damaged myocardium is a relatively new approach. However, the results from clinical studies on stem cell therapy for cardiac regeneration in patients with acute or chronic ischemic heart disease have been inconsistent. Some of the discrepancy could be due differences in study designs or patient selection. The review will based on conducted clinical stem cell trials try to elucidate how to predict and personalize this new treatment approach.

Adult stem cells in the treatment of acute myocardial infarction

Stem cell therapy has emerged as a novel therapeutic treatment alternative for early and end stage LV dysfunction. The rapid translation into clinical trials has left many questions unanswered. Moreover, results of randomized trials in the setting of acute myocardial infarction are controversial, emphasizing a need for further basic and translational research to improve understanding of cell functionality. This review attempts to summarize some of the functional issues related to cell therapy and also evaluate the current status of stem cell clinical trials. Although results to date have shown modest improvement in left ventricular function, the progress should follow a coordinated, multidisciplinary, and well designed path to address issues of cell homing, cell retention, and also look at outcomes beyond physiological parameters.

Regenerative Medicine in Brazil: Small but Innovative

Although Brazil has received attention for conducting one of the world's largest stem cell clinical trials for heart disease, little has been published regarding Brazil's regenerative medicine (RM) sector. Here we present a comprehensive case study of RM in Brazil, including analysis of the current activity, the main motivations for engaging in RM and the remaining challenges to development in this field. Our case study is primarily based on semi-structured interviews with experts on RM in Brazil, including researchers, policymakers, clinicians, representatives of firms and regulators. Driven by domestic health needs and strategic government support, Brazil is producing innovative RM research, particularly for clinical research in cardiology, orthopedics, diabetes and neurology. We describe the main RM research currently taking place in Brazil, as well as some of the economic, regulatory and policy events that have created a favorable environment for RM development. Brazilian RM researchers need to overcome several formidable challenges to research: research funding is inconsistent, importation of materials is costly and slow, and weak linkages between universities, hospitals and industry impede translational research. Although Brazil's contribution to the RM sector is small, its niche emphasis on clinical applications may become of global importance, particularly if Brazil manages to address the challenges currently impinging on RM innovation.

The Language of Hope: Therapeutic Intent in Stem-Cell Clinical Trials

Electronic registries for clinical trials present an opportunity for miscommunication of benefits and risks to potential subjects. We explored early phase clinical trials registered on the National Library of Medicine's ClinicalTrials.gov for inappropriate language patterns (terms and statements) that could convey therapeutic intent. We sampled early-phase heart disease clinical trial records involving stem cells registered on Clincaltrials.gov between April 24, 2004, and September 18, 2008, and randomly selected heart disease drug trials from the same period for comparison. Trial sponsorship and location were coded. Textual data were extracted from titles, purpose, outcome measures, and detailed description statements and coded for readability and the presence of therapeutic language. Content and multiple correspondence analyses were employed to explore language patterns suggestive of therapeutic intent. We found statistically significant differences in therapeutic language use between stem cell (n = 72, median statement frequency 3.5, IQR 1–7) and drug trial (n = 72 median statement frequency 1, IQR 0–3.5) records; Mann–Whitney U = 1808.5, p = .001. A correspondence plot, accounting for 65% of data variability, suggests correspondences among patterns of therapeutic language, regional location, and type of sponsorship between the two record types. Individual-, institute-, and government-sponsored stem-cell trials showed a tendency toward high frequency use of therapeutic statements. This study, the first to explore the potential for therapeutic miscommunication in electronic registries, suggests the need for greater scrutiny of language used in registered trials. Recommendations are offered to improve the integrity of records submitted to ClinicalTrials.gov.

Resolving Ethical Issues in Stem Cell Clinical Trials: The Example of Parkinson Disease

Clinical trials of stem cell transplantation raise ethical issues that are intertwined with scientific and design issues, including choice of control group and intervention, background interventions, endpoints, and selection of subjects. We recommend that the review and IRB oversight of stem cell clinical trials should be strengthened. Scientific and ethics review should be integrated in order to better assess risks and potential benefits. Informed consent should be enhanced by assuring that participants comprehend key aspects of the trial. For the trial to yield generalizable knowledge, negative findings and serious adverse events must be reported.

Cell Therapy for Alport Syndrome

Cell therapy for the treatment of human disease holds much promise, but few to date are standard of care. For regenerative medicine to be practicable, it is essential to have easily accessible sources of stem cells with high therapeutic potential. Advanced stem cell therapeutics aim to correct tissue or organ defects in a targeted manner by supplying stem cells that differentiate into the required cells in situ or are predifferentiated in vitro before infusion. Furthermore, it is critical that the cell preparation be safe and the method of delivery and patient preparation free of complications. In this issue of JASN , LeBleu et al. 1 report on the use of different cell types for the treatment of Alport syndrome that are safe and efficacious. Historically, many stem cell studies have shown efficacy in animals but used systems that were not conducive to clinical application. For example, introduction of genes into cells using viral vectors to trigger differentiation or to correct a mutation are successful in animal models, but their use in humans remains a source of concern.2 Similarly, for human embryonic stem (ES) cells to be used in patients, hurdles such as tissue matching, sourcing of cells, and the risk for teratomas need to be overcome. Some of these hurdles are circumvented by the production of induced pluripotent stem cells using removable vectors3 and the development of methods to prevent teratoma formation.4 Although many cell therapy studies are not suitable for clinical use, they are important to our understanding of stem cells and their role in treating disease. To date, the only stem cells used therapeutically are hematopoietic stem cells for bone marrow transplantation. Cell-based therapies for the treatment of kidney disease have not been explored extensively. The current treatment for …

FDA green lights stem cell clinical trial for Lou Gehrig's disease

FDA green lights stem cell clinical trial for Lou Gehrig's disease

New perspectives in human stem cell therapeutic research.

Human stem cells are in evaluation in clinical stem cell trials, primarily as autologous bone marrow studies, autologous and allogenic mesenchymal stem cell trials, and some allogenic neural stem cell transplantation projects. Safety and efficacy are being addressed for a number of disease state applications. There is considerable data supporting safety of bone marrow and mesenchymal stem cell transplants but the efficacy data are variable and of mixed benefit. Mechanisms of action of many of these cells are unknown and this raises the concern of unpredictable results in the future. Nevertheless there is considerable optimism that immune suppression and anti-inflammatory properties of mesenchymal stem cells will be of benefit for many conditions such as graft versus host disease, solid organ transplants and pulmonary fibrosis. Where bone marrow and mesenchymal stem cells are being studied for heart disease, stroke and other neurodegenerative disorders, again progress is mixed and mostly without significant benefit. However, correction of multiple sclerosis, at least in the short term is encouraging. Clinical trials on the use of embryonic stem cell derivatives for spinal injury and macular degeneration are beginning and a raft of other clinical trials can be expected soon, for example, the use of neural stem cells for killing inoperable glioma and embryonic stem cells for regenerating β islet cells for diabetes. The change in attitude to embryonic stem cell research with the incoming Obama administration heralds a new co-operative environment for study and evaluation of stem cell therapies. The Californian stem cell initiative (California Institute for Regenerative Medicine) has engendered global collaboration for this new medicine that will now also be supported by the US Federal Government. The active participation of governments, academia, biotechnology, pharmaceutical companies, and private investment is a powerful consortium for advances in health.

Stem cell clinical trials must be closely monitored

Stem cell clinical trials must be closely monitored

In Vivo Cellular Imaging for Translational Medical Research

Personalized treatment using stem, modified or genetically engineered, cells is becoming a reality in the field of medicine, in which allogenic or autologous cells can be used for treatment and possibly for early diagnosis of diseases. Hematopoietic, stromal and organ specific stem cells are under evaluation for cell-based therapies for cardiac, neurological, autoimmune and other disorders. Cytotoxic or genetically altered T-cells are under clinical trial for the treatment of hematopoietic or other malignant diseases. Before using stem cells in clinical trials, translational research in experimental animal models are essential, with a critical emphasis on developing noninvasive methods for tracking the temporal and spatial homing of these cells to target tissues. Moreover, it is necessary to determine the transplanted cell's engraftment efficiency and functional capability. Various in vivo imaging modalities are in use to track the movement and incorporation of administered cells. Tagging cells with reporter genes, fluorescent dyes or different contrast agents transforms them into cellular probes or imaging agents. Recent reports have shown that magnetically labeled cells can be used as cellular magnetic resonance imaging (MRI) probes, demonstrating the cell trafficking to target tissues. In this review, we will discuss the methods to transform cells into probes for in vivo imaging, along with their advantages and disadvantages as well as the future clinical applicability of cellular imaging method and corresponding imaging modality.

Current use of imaging in cardiac stem cell clinical trials

Current use of imaging in cardiac stem cell clinical trials

Manufacturing of human placenta‐derived mesenchymal stem cells for clinical trials

Mesenchymal stem cells (MSC) are being used increasingly in clinical trials for a range of regenerative and inflammatory diseases. Bone marrow is the traditional source but is relatively inaccessible in large volume. MSC have now been derived from tissues other than bone marrow including placenta and adipose tissue. We have used placenta obtained after delivery as a source of MSC and have been unable to detect any marked differences from marrow-derived MSC in terms of cell surface phenotype, chemokine receptor display, mesodermal differentiation capacity or immunosuppressive ability. This report described our manufacturing process for isolating and expanding placenta-derived human MSC and their safe infusion into the first patient in a clinical trial program of human placenta-derived MSC.

Human bone marrow stem cells co-cultured with neonatal rat cardiomyocytes display limited cardiomyogenic plasticity

This study investigated whether neonatal rat cardiomyocytes (NRCM), when co-cultured, can induce transdifferentiation of either human mesenchymal stromal cells (MSC) or hematopoietic stem cells (HSC) into cardiomyocytes. Stem cells were obtained from patients with ischemic heart disease. Ex vivo-expanded MSC or freshly isolated HSC were used to set-up a co-culture system between NRCM and MSC or HSC. 5-azacytidin (5-aza) or dimethylsulfoxide (DMSO) was used as differentiation-inducing factor. Co-cultured stem cells were separated from NRCM by flow sorting, and cardiac gene expression was analyzed by reverse transcriptase-polymerase chain reaction. Cellular morphology was analyzed by immunofluorescence and transmission electron microscopy (TEM). Co-culturing MSC induced expression of troponin T and GATA-4. However, no expression of alpha-actinin, myosin heavy chain or troponin I was detected. In the case of HSC, only expression of troponin T could be induced. Immunofluorescence and TEM confirmed the absence of sarcomeric organization in co-cultured MSC and HSC. Adding 5-aza or DMSO to the co-cultures did not influence differentiation. This in vitro co-culture study obtained no convincing evidence of transdifferentiation of either MSC or HSC into functional cardiomyocytes. Nevertheless, induction of troponin T was observed in MSC and HSC, and GATA-4 in MSC. However, no morphologic changes could be detected by immunofluorescence or by TEM. These data could explain why only limited functional improvement was reported in clinical stem cell trials.

Clinical trials in stem cell transplantation: guidelines for scientific and ethical review

Transplantation of cells derived through the manipulation of pluripotent stem cells may involve great uncertainty and the possibility of serious risks. To develop guidelines for the ethical conduct of clinical trials using such stem cells. Review of literature on clinical trials ethics and clinical applications of stem cells; critical deliberation on potential guidelines. Such transplantation should be allowed in clinical practice only after clinical trials demonstrate efficacy and safety. These clinical trials should follow ethical principles that guide all clinical research. Additional requirements to strengthen trial design, coordinate scientific and ethics review, verify that participants understand key features of the trial, and ensure publication of findings are also warranted because of the highly innovative nature of the intervention, limited experience in humans, and the high hopes of patients who have no alternative effective treatments. These recommendations will need to be modified in light of actual experience with stem cell clinical trials. These recommendations will help guarantee that the efficacy and safety of innovative stem cell interventions will be rigorously established, while also protecting study participants.

Critical Review of Clinical Trials of Bone Marrow Stem Cells in Liver Disease

Morbidity and mortality from cirrhosis is increasing rapidly in the Western world. Currently the only effective treatment is liver transplantation, an increasingly limited and expensive resource. Consequently, there has been great hope that stem cells may offer new therapeutic approaches in the management of liver disease. In this review we critically appraise the 11 published clinical studies of bone marrow stem cells in liver disease, and focus on the unresolved issues regarding their role. We outline the different mechanisms by which stem cells may impact on liver disease, as well as highlight the importance of the type of stem cell chosen. There are multiple different stem cell populations that have, in rodent studies, been shown to have differing effects on liver regeneration and fibrogenesis/degradation. Thus, choice of cell should reflect the desired or expected mechanism of action. The importance, and methods, of studying the fate of stem cells infused in clinical studies is emphasized as we seek to translate observations in rodents into the clinical setting. Finally, we discuss which cohorts of patients with liver disease would benefit from stem cell therapy, as well as establish minimum criteria for future clinical trials of stem cells.

Stem cells in the heart: What's the buzz all about? Part 2: Arrhythmic risks and clinical studies

New approaches for cardiac repair have been enabled by the discovery that the heart contains its own reservoir of stem cells. In Part 1 of this review, we discussed various cardiac stem cell populations, reviewed our own work on cardiosphere-derived cells from human hearts, and outlined large animal preclinical models testing the regenerative potential of cardiac stem cells. Here we continue with a discussion on other adult stem cell sources with clinical potential. We summarize the critical safety issues associated with stem cell therapy and present the possible proarrhythmic and antiarrhythmic effects of stem cell transplantation. We discuss the outcomes of clinical stem cell trials and identify the technical, ethical, and practical issues facing the clinical application of cardiac stem cells.

Stem cells in the heart: What's the buzz all about?—Part 1: Preclinical considerations

New approaches for cardiac repair have been enabled by the discovery that the heart contains its own reservoir of stem cells. These cells are positive for various stem/progenitor cell markers, are self-renewing, and exhibit multilineage differentiation potential. Recently we developed a method for ex vivo expansion of cardiac-derived stem cells from human myocardial biopsies with a view to subsequent autologous transplantation for myocardial regeneration. Here we review the state of the cardiac stem cell field and our own work on cardiosphere-derived stem cells from human hearts. The first of this two-part review outlines emerging preclinical data on the application of cardiac stem cells. Part 2 continues with a discussion of other stem cell sources with clinical potential, a summary of the critical issues surrounding stem cell therapy (with an emphasis on the crucial issue of how cell transplantation may influence arrhythmias), our perception of clinical stem cell trials to date, and the issues facing the clinical application of cardiac stem cells.

Cardioprotective repair through stem cell-based cardiopoiesis

Ischemic heart disease continues to progress at pandemic levels despite current preventive and therapeutic interventions. Recent advances in stem cell biology have provided the impetus for a paradigm shift in treatment options, potentially transforming palliative care into curative therapy. Although delivery of stem cells in clinical trials has resulted in a modest functional improvement of myocardial performance in the setting of infarction, ongoing efforts at the bench and bedside are taking place to increase stem cell propensity for engraftment and homing into diseased myocardium. The newest opportunity has arisen with the delivery of stem cells guided to execute the cardiac program. Here, we examine the recent application of genomic and proteomic technology to decipher the process of cardiopoiesis and to recruit cardiopoietic stem cells for cardioprotection and safe myocardial repair.

Stem cells: moving the biology towards the clinic

Stem cells: moving the biology towards the clinic