Early Translational I
More than 25,000,000 people in the USA have diabetes, now the commonest cause of premature death in the nation. Diabetes is due to inadequate secretion of insulin, either because of near complete loss (type 1 diabetes) or partial loss (type 2 diabetes) of the pancreatic beta cells that make and secrete insulin. The discovery of insulin in the 1920’s led to a revolution in diabetes care, permitting injection of this hormone to replace insulin deficiency. However despite great improvements in insulin manufacture and delivery options, people with diabetes still face considerable inconvenience and early death because of diabetes complications. [REDACTED] in California has developed a potentially unlimited supply of pancreatic cells from human embryonic stem cells that reverse diabetes in mice. Our proposed research will focus on overcoming the four bottlenecks below to permit us to bring this cell therapy to clinical trials in humans within 3 years (1) To make pancreatic beta cells from hES cells so that they will function in a retrievable encapsulation system that will prevent rejection and tumor development in the recipient. (2) To establish the dosage of cells required to reverse diabetes. (3) To establish how long the cells last before we need to replace them. (4) To be sure that there is no tendency for the cells to make too much insulin and cause a low blood sugar. The first bottleneck will be overcome by implanting cells in a synthetic capsule already proven to protect cells from the immune system in humans and prevent the escape of any tumor cells that develop. The second and third bottlenecks will be addressed by a series of test studies in animals to establish the most appropriate dose of implanted cells, and how durable they are. The fourth will again be addressed in animal studies by creating the conditions most likely to lead to a low blood sugar to ensure that the cells function safely.
Statement of Benefit to California:
The strategy being developed to treat diabetes in this application would be applicable to both of the most common forms of diabetes (type 1 and 2 diabetes). Diabetes is the single greatest cost in health care dollars in the state of California. Many of the ethnic groups that are highly represented in California (Chinese, Indian, Japanese, Korean, Hispanic, African American) are at particularly high risk of type 2 diabetes while type 1 diabetes is increasing in Caucasians, and particularly in young children. The proposed research is designed to overcome the remaining obstacles before this cell based therapy can be applied in clinical trials to humans with diabetes. The hurdles are important since it would not be safe to perform clinical studies in humans until we have overcome them. Fortunately the hurdles that remain can all readily be addressed; they are just labor intensive and need to be done. Once a cell based therapy for diabetes (developed in California) is available, the potential benefits to the State of California are tremendous. First, there is the obvious direct benefit to those whose lives are affected by diabetes and their families. A six year old girl with type 1 diabetes now faces a life of painful finger jabs (5-10 per day) to measure blood sugar and at least four insulin injections per day. If she is able to live her full life expectancy, she faces more than 250,000 jabs, and the constant uncertainty of her state of health. With cell based therapy that lasted perhaps three years before replacement, we could reduce 250,000 jabs with one every three years and complete freedom between times. Second, the benefit of reduced health care costs and improved productivity would benefit all those in the State of California. Since diabetes is the single greatest cost to health care in California, and this cost is growing rapidly, we must find more cost effective ways to treat this disease. Third, the potential for economic growth, new highly paid jobs and tax revenue from the resulting California based therapy for export world wide would be huge. It is estimated that 80 million people will have diabetes in China alone within ten years. Type 2 diabetes in China requires insulin therapy and would be highly amenable to beta cell replacement. While there is hope that Federal spending on embryonic stem cells may be introduced shortly, the investment by California tax payers through CIRM has given the State of California a scientific lead that now needs to be translated into a clinical product to provide what in the case of diabetes would be a huge financial as well as social return on investment. The proposed studies are focused entirely on accelerating the delivery of beta cell therapy to patient care, and as such we believe will be of great benefit to the state of California.
This proposal addresses several bottlenecks to bringing a human embryonic stem cell (hESC)-derived cell therapy for diabetes into clinical trials within three years. The bottlenecks identified in the application include: 1) immune mediated rejection. 2) risk of teratoma formation; 3) dosage, durability and adaptability of hESC-derived progenitors and 4) risk of insulin over-secretion. The Principal Investigator (PI) addresses the first two bottlenecks by encapsulation of the hESC-derived pancreatic progenitor cells into a device that has been previously tested in humans. In the first aim, the research team will test whether hESC-derived pancreatic progenitors can develop into functional endocrine cells within the devices in vivo under normal and diabetic conditions. In the second aim, the team will determine the dose range of encapsulated pancreatic progenitors that can reverse diabetes. In the third aim, the team will determine the durability of the encapsulated cells and their adaptability to subsequent changes in insulin resistance. In the final aim, the team will test the metabolic control achieved with hESC-derived pancreatic progenitors including the risk of hypoglycemia. All studies will be performed in two preclinical models of diabetes. In general, the reviewers felt the rationale for the proposed studies of encapsulated pancreatic progenitors was strong and the preclinical models chosen were good. One reviewer argued this application is better described as pursuing a potential development candidate, namely encapsulated insulin-producing cells derived from hESC, rather than addressing solutions to bottlenecks highlighted in the RFA. A reviewer commented that the encapsulation strategy was a strength of the design, and expressed disappointment that the application did not focus on the opportunities presented by encapsulation, namely protection from allogeneic rejection and containment of any teratoma-forming cells. Instead, the proposal primarily addresses endocrine function of encapsulated cells. Though the application presented an interesting research opportunity, reviewers identified a number of issues with the proposal. The tone of the proposal was thought to be descriptive and at times, reiterative. Reviewers commented that the pancreatic endocrine functional studies were covered admirably but noted the relative lack of assessment for either immune responses or teratoma formation, key bottlenecks identified by the applicant. A major concern was that the applicant did not adequately address the likelihood of immune rejection in the proposed models, which raises questions about feasibility of the proposed functional studies. Reviewers noted that the cited published studies did not adequately support the PI’s contention that the device will allow the encapsulated cells to avoid rejection, particularly in the proposed xenogenic settings with only modest immunosuppression and even in the genetically immunodeficient model. Reviewers also criticized that the applicant did not consider the possibility that metabolic responses may be limited because of the subcutaneous implantation of the pancreatic tissue, resulting in a lack of access to the splanchnic circulation. Alternative proposals were not discussed. Thus, a number of assumptions are made by the applicant, and one false assumption carries serious ramifications for the rest of the proposal. The PI is an established leader in the field of islet developmental biology and clinical physiology and is well qualified to lead the proposed research. The research team and collaborators are also extremely qualified, and the environment is conducive to conducting the proposed research. The reviewers were divided on the proposed budget, some considering it reasonable while one considered it excessive citing the large number of FTEs requested, as well as high preclinical costs. In summary, this proposal seeks to address several considerations necessary prior to moving into clinical trials in humans using hESC-derived pancreatic progenitors to treat type 1 diabetes. Despite its potential impact and an excellent research team, the proposal does not adequately address key concerns, especially immunogenicity and teratoma formation, resulting in a lukewarm reception by the reviewers.