Disease Team Research I
Diabetes exacts a tremendous toll on patients, their families, and society in general. Autoimmune Type 1 diabetes, often called juvenile-onset diabetes, is caused by a person’s own immune system mistakenly destroying their insulin-producing cells in the pancreas, known as beta cells. When those beta cells are lost, the ability to produce insulin in response to food intake is lost, and blood sugar can increase to toxic levels. Although not due to autoimmunity, Type 2 diabetics often lose their ability to produce insulin as well. While pharmaceutical insulin is commonly used to control both types of diabetes, it does not sufficiently replace beta cells, and the adverse short- and long-term effects of diabetes remain, including dangerous episodes of low blood sugar, nerve damage, blindness, kidney damage, foot ulcers leading to amputations, and cardiovascular disease. Ideally, one would like to replace lost beta cells, and attempts to do so have included the use of pancreatic transplants, beta cell (islet) transplants, and transplants of animal cells or tissues. Unfortunately, those approaches are hindered by 1) the limited amount of donor tissue available, and 2) issues regarding immunological complications between donors and recipients. To solve the first problem, the Diabetes Disease Team applying for this CIRM award has developed methods to make replacement beta cells from human embryonic stem cells (hESC), which can be reliably grown in large-scale batches. The hESC-derived beta cells have been shown to cure experimental diabetes in mice and rats. Regarding the issue of donor-recipient compatibility, the Team has had initial success with several strategies, including administering the cells inside a simple device, implantable under the skin, as well as next-generation pharmaceuticals that enable transplantation between unmatched individuals without major side effects. With the critical proof-of-concept milestones behind us, the Team now needs to perform all of the manufacturing and laboratory testing required to assure reliable production of a safe and effective product, thereby generating the data needed to seek FDA approval to test the product in humans. The project engages over 30 scientists and physicians, as well as numerous associates and technicians, whose expertise covers all of the critical areas from process development and manufacturing to clinical testing of novel biomedical products. The proposal includes active project management, and regulatory and ethical oversight. The Team has well defined time lines and milestones to advance the candidate product to an FDA submission. If successful, testing in diabetic patients could begin as early as 3 years from the project initiation.
Statement of Benefit to California:
Diabetes mellitus currently afflicts more than 250 million people worldwide, with projections of 380 million by the year 2030 (source: International Diabetes Federation). In 2007, there were an estimated 2.7 million Californians with diabetes (source: California Diabetes Program, California Department of Public Health). Further, the disease disproportionately affects certain minority groups and the elderly. Despite the use of insulin and advances in its delivery, the human cost of diabetes is underscored by the financial costs to society: tens of billions of dollars each year in California alone. The primary cause of Type 1 diabetes, and contributing significantly to Type 2 diabetes as well, is the loss of insulin-producing pancreatic beta cells. The proposed Disease Team will develop a beta cell replacement therapy for diabetes. If successful, the therapy will go beyond insulin function, and will perform the full array of normal beta cell functions, including responding in a more physiological manner than manual or mechanized insulin administration. Because they will be more physiological, the replacement cells should also reduce the long-term effects of diabetes. Moreover, the cell therapy will alleviate patients of the constant monitoring of blood glucose and painful insulin injections. For these reasons, it is possible that the product could transform the diabetes treatment landscape and replace pharmaceutical insulin in the market. This product will be available in California first, through clinical trials, and if approved by the FDA for commercial production, could eventually help hundreds of thousands of diabetic Californians. The product will substantially increase quality of life for diabetics and significantly reduce the health care burden in the state. The Team will employ various Californian physicians and scientists, and success of the Team will generate positive recognition for the state. Lastly, once commercially marketed, the product will yield additional jobs in manufacturing, sales, and related industries, and generate revenue for California. Given the market need and the clear feasibility, the product could become the most significant stem cell-based medical treatment of the coming decade, and that would be a great achievement for California, its taxpayers, and CIRM.
Type I, and to some extent type II diabetics, suffer from a loss of pancreatic islet beta cells that results in poor blood sugar control. This application proposes development of a combination encapsulation device/pancreatic islet progenitor cell therapy for the treatment of diabetes. The investigators have developed a method to produce islet progenitor cells from human embryonic stem cells (hESC) that differentiate into glucose responsive islet beta cells after transplantation in vivo. These hESC-derived islet progenitor cells, hESC-IP, will be encapsulated in a durable, retrievable device and implanted subcutaneously. Limited immunosuppression or immunomodulation may be required. The proposal consists of three main parts: device development, therapeutic cell development and the preclinical development plan. The device work entails transitioning from research grade to FDA Quality System Regulation (QSR) grade device production and testing. The islet progenitor cell work consists of process development and scale up, assay development and quality control and stability studies. Preclinical development will include an assessment of immunomodulatory strategies, device integrity and biocompatibility testing, as well as combination product dose ranging and IND enabling safety studies using the cells in the QSR device. The diabetes disease team is organized into functional groups that will address the various aspects of the plan. Overall, this application addresses a large unmet medical need, contains strong preliminary data and applies a sound and well planned approach. All the elements necessary for a successful IND filing have been adequately addressed, and the team is extraordinarily well equipped to successfully perform the proposed studies. These elements make a successful IND filing to treat diabetes likely and led to a strong recommendation for funding. Diabetes is a common disease that negatively impacts both the lifespan and quality of life of millions of Americans. Insulin injection cannot replicate the level of feedback control afforded by intact beta cells. Recently, transplantation of deceased donor-derived pancreas and islets has produced a major breakthrough in the treatment of diabetes. These treatments cannot meet the clinical demand, however, due to limitations in the donor organ supply. In addition, transplant recipients must take lifelong immunosuppressive therapy which increases their risk of developing infections and cancers. Finally, despite the use of immunosuppression to promote graft survival, islet grafts are ultimately attacked by the host immune system. Reviewers noted that this application addresses each of these limitations. By using hESC-IP, the investigators tap a potentially limitless source of islet like cells. Encapsulation in the device should protect the grafts from immune attack and rejection by acting as a barrier to host immune cells. Proposed immunomodulatory strategies to prevent activation of T and B cells by the graft could further improve graft survival. Furthermore, device encapsulation of the graft mitigates the risk of teratoma formation from any potential, residual undifferentiated cells by retaining the cells and allowing easy retrieval. Reviewers emphasized that a readily available source of safe islet like-cells for transplantation that improves glucose stability would provide a clinical benefit to many patients. If there was the further benefit of a reduced need for immunosuppression to maintain the graft, this therapeutic candidate could have a huge impact on the diabetes field. Reviewers expressed unanimous enthusiasm for this proposal. It is well written, practical and addresses all the steps necessary to achieve a successful IND filing in four years. They cited the solid preliminary data which provided excellent proof of concept. For example, rescue of chemically-induced diabetes was demonstrated with the encapsulated hESC-IP in vivo for at least several months, and the device successfully prevented infiltration of the recipient’s cells. Concern was expressed regarding the potential for graft cell antigens to escape the device and activate the immune system ultimately resulting in graft rejection. However, encouraging preliminary data suggested that a two-week application of the selected immuno-modulatory strategy promoted xenograft persistence in immunocompetent hosts for several months. The selected immuno-isolation device protected allogeneic grafts for up to one year in clinical use. While their overall enthusiasm was high, the reviewers expressed some uncertainties regarding the usage and performance of the device for the treatment of diabetes. For example, they questioned the number of devices and the resulting skin surface area coverage that would be required to support efficacy in a human patient, but acknowledged that clinical testing would ultimately be required to resolve these questions. Reviewers, however, also noted that these concerns were mitigated by the ability to monitor glucose levels that could alert patients to problems with transplanted beta cell function, as well as the ability to remove and replace the device. The reviewers generally found of the project plan to be very practical and complete reflecting the relatively advanced state of development of the project. They were impressed by the plan to generate GMP hESC-IP at scale and found all elements including scale up, assay development, and quality control were well considered. Milestones and timelines were well delineated and comprehensive. Reviewers generally felt the three-year timeline was optimistic, but that a successful IND filing in four years was likely. Two areas of concern contributed to this sentiment. First, while the applicant institution is currently generating research grade encapsulation devices, the generation of QSR grade devices imposes an additional regulatory burden and may require more infrastructure development and time than anticipated. Since much of the preclinical plan depends upon these devices, this could impact progress. Reviewers thought the timelines for the immunology plan were overly optimistic and that this too could impact the timeline for IND filing. They also would have the liked the immunology plan to be more developed. In particular, the immunomodulatory studies in the relevant preclinical model are inadequately described and inadequate time is allowed for the effort likely to be required to extrapolate immunomodulation protocols from immunodeficient rodent models to a more relevant, immunocompetent model as well as to conduct the necessary studies. Further, the large list of immunomodulatory strategies to be tested is not adequately justified given very recent transplantation studies with some of these agents in the immunocompetent model. One reviewer commented that the developmental biology studies appeared tangential to achieving an IND filing and wondered why they were funded throughout the period of the award. Despite these surmountable issues, reviewers agreed that these investigators describe an excellent near term approach to achieve a reliable source of functional beta cells for human therapy. Reviewers lauded the applicant for assembling a well-established leadership plan and a “dream team” with all the necessary skills to accomplish the goals of the program. The principal investigator (PI) has experience in encapsulation and has led the efforts that resulted in recent publications in top tier journals. The world-renowned immunology collaborator is well published, has experience in translational immunology and clinical trial design, and will lead a group of established immunologists at the collaborating institution. The applicant institutions are committed to the program and the investigators have access to all the necessary facilities and equipment to perform the proposed studies. Reviewers commented that the budget was well developed and well justified although there were questions on some of the proposed immune studies and on the rationale for funding developmental biology studies throughout the term of the award. Overall, this application’s extremely strong team, compelling preliminary data and rational, well planned approach rendered it likely to result in a successful IND filing and resulted in its enthusiastic recommendation for funding.
- Joy Cavagnaro