Disease Team Planning
This proposal is for the establishment of a group of faculty, staff and industrial partners to develop a proposal for a Diabetes Disease Team. Diabetes is one of the most devastating diseases. Inadequate blood glucose control results on many long term complications including: kidney disease, blindness, amputation and nerve damage. The diabetes epidemic affects almost 10% of California’s population (an estimated 2,500,000+ cases). In fact, diabetes is now the 4th leading cause of death. However, form many individuals, the cure for this disease is at hand. The combination of an insulin-producing islet transplant and effective immunotherapies has resulted in a long-term insulin injection-free existence for some. However, two critical elements had prevented this "cure" from generalized applicability. First, there is a shortage of cadaveric pancreases from which to derive the islet cells. Second, the long term use of immunosuppressive drugs to treat islet rejection has its own health consequences. Therefore, a remarkable opportunity lies ahead for the use of stem cell-derived islets and novel immune therapies as a cure for this disease. The planning effort, supported by this proposal, will be geared towards developing a CIRM Diabetes Disease team that will tackle these problems. Faculty and staff from several California institutions will form the core team. These individuals have combined pre-clinical and clinical studies to demonstrate that stem cell-derived islets and islet transplantation are viable therapeutic opportunities for the treatment of this disease. The Diabetes Disease Team planning grant will provide an opportunity to develop a multi-disciplinary, multi-institutional program that brings the best talent and processes to the problem of developing stem cell-derived islet transplantation for the treatment of diabetes. Investigators with expertise in stem cell and developmental biology, immunology, diabetes and clinical trial process will meet and form subcommittees to contact investigators from around the state and country to identify those that will bring creative ideas and substantive expertise to the Team. We will define the holes in the field and seek out experts to work with the team to fill those holes. In summary, we believe that this Diabetes Disease Team will meet CIRM’s primary goal - namely advancing a stem cell-derived therapy into the clinic while making sure that the therapies are safe and ethically justified.
Statement of Benefit to California:
Diabetes is one of the most devastating diseases. Inadequate blood glucose control results on many long term complications including: kidney disease, blindness, amputation and nerve damage. In fact, diabetes is now the 4th leading cause of death. The diabetes epidemic affects almost 10% of California’s population (an estimated 2,500,000+ cases). The disease affects the underserved and elderly disproportionately and has a particularly destructive affect on the poor. Moreover, Type 1 Diabetes is a disease of children with a sentence to a lifelong requirement for multiple insulin injections each day and compounded clinical complications due to the years of inadequate glucose control. Clinical research efforts to cure this disease would have a tremendous affect on the health and welfare of the citizens of the state of California and financial benefits to a health care system where as much a 1 in every $4 is spent on the consequences of diabetes. By forming a state-wide Diabetes Disease Team, we hope to capture the most advanced technologies and research efforts to create a clinically-effective therapy based on stem cell-derived islet transplantation.
Executive Summary This is a proposal to establish a disease team for developing stem cell-derived islet transplantation therapy for the treatment of diabetes. The team will focus on overcoming two key obstacles to the general applicability of pancreatic islet transplantation: a shortage of islet cells and the immune rejection of transplanted tissue. The planning process will concentrate on formation of a complete team including cell biologists, immunologists, endocrinologists, and experts in clinical trial design. Additional planning activities will focus on processes for proposals and clinical trial development and the generation of a comprehensive plan for translating preclinical findings into islet transplantation therapy. This is an excellent proposal focused on assembling a team of scientists, physicians, and industry partners to develop a stem cell-based therapy for diabetes. Every aspect of the planning process appears well considered, appropriate, and timely. The concept of developing stem cell-derived islet transplantation for the treatment of diabetes is important and mature. It is supported by compelling data on both the success of deceased donor-derived islet transplantation in treating diabetes and the differentiation of human embryonic stem cells (hESCs) into functional pancreatic beta cells. Two key obstacles to the further deployment of this therapy have been identified, and the development of approaches to overcome these impediments will be a major focus of the planning process. The principal investigator (PI) is a key strength of the proposal. He/she has an extensive and distinguished track record in diabetes research, immunotherapy development, and clinical trials. Importantly, the PI has proven experience in assembling and coordinating teams of diverse basic and clinical investigators. Additionally, he/she has worked previously with industry to develop therapies which are currently in clinical trials. The planning process is well designed and clearly outlined. The planning team includes basic and clinical scientists and industry personnel. All members have appropriate expertise and significant experience in areas critical for developing a strong disease team proposal. The team will assess strengths and deficiencies; address scientific, regulatory, and facility requirements; and establish administrative processes to support robust planning and development activities. The proposed team and approach should be highly successful in developing an excellent program to advance stem cell-based therapy for diabetes. All aspects of this proposal are extremely strong. Reviewers were most enthusiastic and felt that this collaborative and well designed plan is highly likely to lead to human clinical trials within the next five years. Reviewer Synopsis This proposal is to establish a Diabetes Disease Team for translating preclinical findings into stem cell-derived islet transplantation. The combination of islet transplant and effective immunotherapies has resulted in long-term insulin independence. However, two obstacles prevent generalized applicability: a shortage of islet cells (now cadaveric), and the need for long-term use of immunosuppression to prevent rejection and recurrent autoimmunity. Both obstacles may now be close to being overcome. UCSF has leadership in the fields of stem cell biology and immunology, an active islet transplant program, an NIH-supported translational research institute and a GMP facility. The Program Director, Jeffrey Bluestone, has extensive experience in leading team-oriented clinical research. The planning process will focus on clinical trial development and execution ranging from clinical trial design, site monitoring and regulatory affairs to bioinformatics, biomarker assay development and clinical and mechanistic assay databasing. Reviewer One Comments Concept: Islet transplantation using cadaveric islets has been shown to work for achieving insulin independence in type 1 diabetics. However, the two main obstacles have been a reliable source of functional tissue and the need for immunomodulation. Bluestone has been a major developer of anti-CD3 therapy (teplizumab) which is in phase II clinical trials for type 1 diabetes as well as preclinical proof of principle for using regulatory T cells as therapy for autoimmune diseases. This proposal is for a team that addresses both issues by combining the success of deriving glucose responsive beta cells from human ES cells by the scientists at Novocell and new tolerance inducing therapies championed by Bluestone with a complement of other excellent scientists who understand transplantation, islet biology and development. This group has unique expertise and approaches for the main issues for beta cell replacement therapy; they could be considered the Dream Team. Their approach offers great hope of success for stem cell based beta cell replacement therapy for diabetes. Principal Investigator: Dr. Bluestone is Clausen Distinguished Professor and Director of the Diabetes Center UCSF as well as being a founder and Director of the Immune Tolerance Network. He is PhD trained immunologist who has been at the forefront of immunomodulation therapy of type 1 diabetes. He has much experience in leading diverse groups of basic and clinical investigators in a JDRF Collaborative Center for Cell Therapy, the Diabetes Center at UCSF and importantly the Immune Tolerance Network which oversees more than 25 clinical trials. He has worked with industry to develop a new generation of tolerogenic drugs, including anti-CD3 currently in phase II trials for type 1 diabetes. Planning Approach: The planning group includes immunologists Bluestone, Abbas, and Lanier, islet biologists Hebrok, German at UCSF, Kim at Stanford and Hayek from UCSD/Whittier, islet transplanters Stock, Santos and Fisher, pediatric diabetologist Gitelman, clinical trial expert Sayre as well as the industry partner Novocell. They propose exploring other essential expertise during the planning phase as the gaps are defined. The current team has a track record of success in team oriented research and the university has resources in the NIH funded Clinical and Translational Research Center to help support the initiation of clinical trials. They should be in good position to put together an excellent proposal for a Disease team for Diabetes. Reviewer Two Comments Concept: This application suggests that scientists from UCSF, Stanford and Novocell will form the core of the proposed application to produce pancreatic beta cells as substitutes for islets for clinical transplantation. The application includes pictures of stem cell derived cells which coexpress insulin and PDX1. They propose to move this technology forward as a team to the clinics. Rationale: Appropriate, sound, in general, but this is not a science application, so no details are provided. Maturity: The group, mainly Novocell (collaborator from San Diego) has generated islet precursors from hES cells. An example of these cells is included as figure 2 of this application. The group includes a company, Novocell, which I think is a strength. The team also includes Dr. Kim at Stanford and Hayek at UCSD, investigators in development and islets. The planning team also includes Dr. Sayre, the director of the clinical trials group at UCSF and Dr. Stock who oversees the only active islet transplant group in CA. The planning team is quite diverse and most appropriate for this task. The team at UCSF has significant experience with clinical trials and is home to the NIH clinical and translational research center (CTSI), has significant infrastructure in place for these trials, is home to the Immune tolerance network (ITN), an extremely well funded, multi centered, multinational clinical/ translational research program committed to research into immune tolerance therapies. Significance. High Principal Investigator: Qualifications, outstanding. The key strength of the application is the PI, Dr. Bluestone. He is highly respected and already directs very substantial NIH funded efforts including the Immune Tolerance Network. His research is cutting edge, and he has demonstrated the ability to conduct translational research. Planning Approach: The team includes basic and clinical scientists and industry personnel. This is a plus from the standpoint of diversity. Importantly, the team will not just try to make islets, but will explore the immune aspect of proposed future transplants. Since the immune system seems to hold the key to sustaining beta cell function, any application that does not include investigation of immune mechanisms is incomplete. Reviewer Three Comments Concept: These investigators propose to create a CIRM Diabetes Disease team comprised of investigators from USCF and Novocell who will develop a multi-disciplinary, multi-institutional program to develop stem cell-derived islet cell therapy for the treatment of diabetes. They will use ES-derived stem cell therapy to overcome the obstacles proposed by cadaveric-derived islet cell transplantation which include donor availability and the need for long term immunosuppressive therapy, both limiting access to and efficacy of this approach. The group has previously demonstrated expertise in developing novel strategies to create immune tolerance and prevent rejection. The target is plausible and likely to lead to human clinical trials within the next 5 years. Principal Investigator: Dr. Bluestone is highly qualified to lead this team and conduct this work. He has a proven track record of productive work with Novocell and other proposed core investigators from Stanford, UCSF and UCSD. He has also lead the NIH-sponsored Immune Tolerance Network, an international clinical trials consortium studying immune tolerance therapies. Planning Approach: The planning process is well designed and targeted to first assess strengths and deficiencies, then to address scientific, regulatory and facility requirements for implementation of human clinical trials. The group has significant expertise and experience in these areas, is collaborative and is highly likely to succeed.