Funding opportunities

Stem Cell Therapy for Muscular Dystrophy

Funding Type: 
Disease Team Planning
Grant Number: 
DT1-00674
Principle Investigator: 
Institution: 
Funds requested: 
$52 650
Funding Recommendations: 
Recommended
Grant approved: 
Yes
Public Abstract: 
The goal of our team is to capitalize on the remarkable advances in stem cell biology to apply those advances to the treatment of human diseases, disorders, and injuries. We are planning to develop and initiate a clinical trial that would use stem cells for the treatment of muscular dystrophies. This application of stem cell therapy has the potential to benefit thousand of individuals, adults and children alike, who have one of the many different types of muscular dystrophy. Moreover, the success of this clinical trial would open the door for the possible use of stem cells in a much wider range of muscle disorders that afflict our population including the treatment of muscle wasting that accompanies prolonged bedrest, many chronic diseases such as AIDS and cancer, and even the muscle loss that accompanies normal aging. Additionally, because we have the advantage of a unique opportunity to study stem cell therapeutics in these well-defined muscular dystrophies, the technological advances that will accompany these studies will likely be applicable to the use of stem cells for the treatment of diverse chronic and degenerative conditions of other solid tissues such as the heart, the liver, and the brain. Among our core team members, there is expertise that includes the basic biology of muscle stem cells and human embryonic stem cells, the use of stem cells in the treatment of muscular dystrophies, and the clinical diagnosis and treatment of humans with muscular dystrophies. We have two main goals of this six-month planning phase. First, we will focus our individual and collaborative efforts on research directions that will be targeted to this specific therapeutic application. This will involve the establishment of specific milestones that we will need to reach in that short time. Second, we will hold regular meetings to consider challenges that we are likely to face in the years ahead, and the solutions will be to expand our team with collaborators and consultants who will be important to the success of our program. These individuals will be included as associate members of the team and will participate in subsequent planning sessions. Additionally, we will form a core Advisory Board consisting of individuals from academia, industry, regulatory agencies, and the general public. This will insure a diverse source of advice and guidance with regard to solutions to problems and anticipation of hurdles that we will need to address. Finally, during this six-month planning phase, we will develop a full proposal that will be ready for submission to CIRM to apply for funding for this major program in stem cell therapeutics. At the conclusion of the six-month planning phase, we will have increased the momentum of our program for this important area of stem cell therapeutics. Our overall goals, specific objectives and proposed program meet the spirit and the letter of CIRM’s mission and that fulfill the promise that CIRM holds for the citizens of California.
Statement of Benefit to California: 
The specific benefit that the success of this planning grant will have for the citizens of the State of California will be realized in the successful planning and execution of the subsequent clinical trial of stem cells in the treatment of muscular dystrophies. Our assembled team has the expertise to capitalize on a unique opportunity at this moment in which advances in stem cell biology, the initiation of numerous clinical trials for muscular dystrophies, and advances in diagnostics methodologies have resulted in a tremendous momentum for translating decades of research into effective clinical treatments for this devastating group of diseases. The success of a stem cell therapeutic approach would represent a true milestone in the treatment of the most common form of muscular dystrophy, Duchenne muscular dystrophy, which is the most common lethal, hereditary disease of childhood. In addition to the historic watershed, the success of such a trial would open the way for the use of stem cells in the treatment of other forms of muscular dystrophy that lead to disability and premature death in adults and children alike. It would also expand the scope of muscle diseases, disorders, and injuries that could potentially be treatable by stem cells. Such conditions would include the profound muscle wasting that accompanies chronic diseases such as AIDS and cancer, as well as the muscle loss that accompanies normal aging. As such, there is great potential for the alleviation of individual suffering and restoration of function for tens of thousands of California citizens and millions of people worldwide. Such success would also carry an enormous economic benefit in terms of elimination of medical costs for the long-term care of individuals, as well as the benefit of increased productivity. Beyond the obvious individual and collective health and economic benefits associated with treatment of any chronic disease, the success of a clinical trial of stem cells in the treatment of muscular dystrophies would have additional benefits in terms of stem cell therapeutics and regenerative medicine. In the process of designing, conducting, and analyzing the results of the clinical trial, we will certainly pave the way for further trials of stem cells for the treatment of diseases and injuries of solid organs such as heart and brain. Many of the technologies we will develop, including optimization of conditions for growth of stem cells, methodologies for delivery of stem cells to tissues, and technologies for imaging the cells within the body once they are there, are certain to be of value for stem cell therapeutics across a wide range of organs and diseases. This will further propel the CIRM mission and lead to further benefits for the citizens of the State of California, on top of which is the potential benefit of the growth an important, new biotechnology industry to partner with academic centers and government programs for the advancement of regenerative medicine.
Review Summary: 
Executive Summary This investigator proposes to assemble a disease team focused on the development of cellular therapies to treat Duchenne Muscular Dystrophy (DMD). DMD is the most common lethal disease of childhood with an incidence of 1/3500 males worldwide. The clinical spectrum includes a rapidly fatal early infantile form of disease and extends to a later onset, more slowly progressive disease causing death from cardiac and respiratory failure in the second or third decades of life. DMD is caused by mutations in the dystrophin gene, leading to progressive degeneration of muscle tissue. Despite significant knowledge about this disease, therapeutic options are palliative at best. This investigator presents a compelling rationale for the development of cellular and stem cell therapeutic approaches that are nearly ready for first in man human clinical trials. The investigator proposes to establish a multidisciplinary team of basic and translational scientists and clinicians to accomplish this work. Reviewers concurred that the proposal addresses an appropriate target for cell therapy, and recognized the clinical significance of the target disease. DMD is a well understood genetic disease affecting large populations of children, and is an ideal candidate for targeted cellular therapies. This investigator presents compelling evidence from pre-clinical studies in various animal models that suggests that the use of stem and or progenitor cells to treat human patients with DMD is valid, feasible and achievable within the next 5 years. One reviewer noted that a clinical trial in humans is already in the planning stages in Italy. The investigator proposes to examine various delivery systems, routes of delivery, and types of cellular therapies, all of which need to be optimized for the clinic. The potential team plans to develop novel imaging techniques to assess engraftment after cell therapies are administered. One reviewer noted that immune rejection was not addressed in the application, and cited this as a weakness of the proposal. Reviewers agreed that the PI is highly qualified to lead a multidisciplinary team and to develop and conduct the proposed studies. The PI is a Harvard trained neurologist who currently is Chief of Neurology at a major health care system. The PI is a recognized expert in the areas of the biology of muscle, muscle stem cells and aging. The PI has demonstrated leadership skills and there are multiple examples of his/her ability to direct multidisciplinary teams conducting translational research. The PI also serves on several advisory committees of a major disease foundation, a biotechnology company, and on the external scientific advisory board for the trial in Italy. The PI has evaluated the various programmatic needs for a program in cell therapy for DMD including regulatory issues and cell production. Reviewers felt the application had a sound planning process. Initially the team will focus on evaluation of the strengths of collaborations between current investigators to determine whether additional expertise will be required. This will be accomplished through monthly meetings of a core team of investigators, the formation of an external advisory board with diverse representation of experts in academia, industry, regulatory affairs and the public. If deficiencies are identified, steps will be taken to recruit individuals to fill the deficits. The group will finally work together to evaluate the need for resources and to formulate plans for implementation of a clinical trial using stem cells to treat DMD. In summary, the target is plausible, and the application and proposed therapeutic concepts are strong and sufficiently mature. The PI is well qualified to lead this multidisciplinary team, and it is highly likely that these investigators will embark on human clinical trials within the next five years. Reviewer Synopsis These investigators propose to assemble a disease team focused on the development of cellular therapies to treat Duchenne Muscular Dystrophy (DMD). DMD is the most common lethal disease of childhood with an incidence of 1/3500 males worldwide. The clinical spectrum includes a rapidly fatal early infantile form of disease and extends to a later onset, more slowly progressive disease causing death from cardiac and respiratory failure in the 2nd or 3rd decades of life. DMD is caused by mutations in the dystrophin gene, leading to progressive degeneration of muscle tissue. Despite significant knowledge about this disease, therapeutic options are palliative at best. These investigators present a compelling rationale for the development of cellular and stem cell therapeutic approaches that are nearly ready for first in man human clinical trials. They propose to establish a multidisciplinary team of basic and translational scientists and clinicians to accomplish this work. Reviewer One Comments Concept: DMD is a well understood genetic disease affecting large populations of children which is in need of novel and innovative therapies. Given the fact that it results from a single gene defect and that it affects a targeted tissue, it is an ideal candidate for targeted cellular therapies. These investigators present compelling evidence of pre-clinical studies in various animal models and most recently in dogs that suggest that the use of stem and or progenitor cells to treat human patients with DMD is valid, feasible and achievable within the next 5 years. They propose to examine various delivery systems, routes of delivery (e.g. intra-arterial, intramuscular), and types of cellular therapies, (e.g. human mesoangioblast cells, myogenic progenitors derived from ES cells, and de-differentiated progenitors from muscle tissue). They plan to develop novel imaging techniques to assess engraftment after cell therapies are administered. Looking broadly ahead, the investigators propose to develop a basic science core, a translational core, and a clinical core that will study cell isolation and propagation, preclinical studies in animals to assess dosing, delivery and toxicity, followed by upscaling and introduction into the human clinical trial setting. The target is plausible, and the application and proposed therapeutic concepts are strong and sufficiently mature. It is highly likely that these investigators will embark on human clinical trials within the next five years. Principal Investigator: The PI, Dr. Thomas Rando, is highly qualified to lead a multidisciplinary team and to develop and conduct the proposed studies. Dr. Rando is a Harvard trained neurologist who currently is Chief of Neurology at the VA Palo Alto Health Care System and the Founding Director of the Muscular Dystrophy Association Clinic at Stanford University Medical Center. He was awarded an NIH Director’s Pioneer Award in 2005 and is a recognized expert in the areas of the biology of muscle, muscle stem cells and aging. He has demonstrated his leadership skills as director of the Geriatric Research, Education and Clinical Center at Stanford since 2000. There are multiple examples of his ability to direct multidisciplinary teams conducting translational research. Dr. Rando has evaluated the various programmatic needs for a program in cell therapy for DMD including regulatory issues and cell production, likely in a GMP facility. Planning Approach: The planning process is well put together, logical and feasible. Initially the team will focus on evaluation of the strengths of collaborations between current investigators to determine whether additional expertise will be required. This will be accomplished through monthly meetings of a core team of investigators, the formation of an external advisory board with diverse representation of experts in academia, industry, regulatory affairs and the public. If deficiencies are identified, steps will be taken to recruit individuals to fill the deficits. The group will finally work together to evaluate the need for resources and to formulate plans for implementation of a clinical trial using stem cells to treat DMD. Reviewer Two Comments Concept: Use stem cell-based therapy to correct the DMD defect, ultimately allowing not only for corrected gene delivery to the syncitial fibers, but also reconstituting the satellite cells allowing for regenerative processes to recover damaged fibers. Initial focus will be on mesoangioblasts, but the team will also test differentiated progenitors from hESC as possible alternative stem cell sources. Strengths of the application include the following: a clinical trial is already in the planning stages in Italy. The team is already assembled, with core competencies in DMD, muscle stem cell biology (Helen Blau), clinical specialists, delivery technologies (intramuscular and intra-arterial delivery), and a consultant for GMP facility and regulatory expertise (Stewart Craig, from Progenitor Cell Therapy). Weaknesses of the application include: the application had no discussion of immune rejection, and there was no discussion of potential immune-mediated responses to “foreign” DMD protein and allogeneic cells. Principal Investigator: PI: Dr. Rando has recognized expertise in biology of muscle, stem cells, and aging. The PI was awarded the NIH Director’s Pioneer Award in 2005. The PI has translational expertise, using non-viral gene therapy, and serves on several advisory committees, including the Muscular Dystrophy Association, a company Asklepios (evaluating gene therapy approaches), and on the external scientific advisory board for the trial in Italy. He is Chief of Neurology at the Palo Alto Veteran’s Administration, and is founding Director of Muscular Dystrophy clinic at Stanford. Planning Approach: The planning approach is to form a disease team with three main cores: basic science, translational research, and a clinical core. The basic science effort will establish the stem and/or progenitor lines, derive optimal culture conditions, optimize transfection (if necessary), and develop the differentiation protocol. Reviewer Three Comments Concept: The proposal presents a focused approach on muscular dystrophy using progenitor cell therapy, either from adult/fetal or embryonic stem cell sources. The concept has a long history and good proof of principle in animal and human studies. Biology of muscle stem cells is mature. Given the devastation of muscular dystrophy, positive clinical results would have major effect on these patients. Principal Investigator: The PI is an accomplished active investigator in the muscle stem cell and aging field. He is the recipient of an NIH Pioneer award (2005) and several grants from the NIH and other sources. He is an appropriate leader for this effort. Planning Approach: The PI has assembled an impressive set of basic, clinical, and translational investigators at Stanford to participate in the disease team. Drs. Blau and Reijo-Pera are basic investgiators, Dr. Gambhir will provide guidance in non-invasive imaging, and Dr. John Cooke is skilled in vascular biology and delivery systems. This is an excellent team and appears to have a sound plan for the next phase of their efforts.
Conflicts: 

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