Type I diabetes (also known as juvenile diabetes) is an autoimmune disease in which the body's white blood cells destroy the cells in the pancreas that produce the hormone insulin. Insulin is important in signaling to cells in the body that there is a lot of sugar circulating in the blood. Without insulin, the cells in the body cannot take up that sugar and use it for energy. This results in the body's cells essentially starving to death and also leads to persistently high levels of blood sugar, which causes damage to many organs in the body over time.
One approach to definitively treating type I diabetes is to replace the insulin-secreting cells, also known as beta-cells. We have been studying for many years the issue of whether there are endocrine stem cells in the adult human pancreas that can become beta-cells. A couple of years ago, we demonstrated that such cells exist. However, to turn that finding into a therapy, we need to be able to control the process by which the endocrine stem cells form new beta-cells.
To turn the endocrine stem cells into beta-cells, we propose to use a method called high-throughput screening. This is the same method that large pharmaceutical companies use to discover new drugs. Essentially, it involves testing thousands of small molecules for their ability to cause a certain biological process to occur, in our case causing endocrine stem cells to differentiate.
Once we have found initial candidates for molecules that can promote beta-cell formation, we will use chemical approaches to optimize the initial candidates. At the end of the process, we hope that have an efficient process that causes the stem cells to move along the path to becoming functional beta-cells.
The final part of solving the problem of developing a new treatment for type I diabetes is to find a way to reinsert the new beta-cells into the body. Because people with type I diabetes have an immune system that kills beta-cells, which is why they have diabetes in the first place, any transplanted beta-cells will also be eliminated by immune attach. Thus, we have been studying a device into which the cells can be placed and that protects them from immune attack. This device, called a macroencapsulation device, surrounds that cells with a semipermeable membrane that allows insulin to exit into the bloodstream and nutrients to enter, but keeps immune cells out. We have tested this device in a mouse model of type I diabetes and it works well to protect beta-cells from immune destruction.
By combining the human endocrine stem cells, high-throughput screening, chemical optimization, and macroencapsulation, we hope to be able to move towards a small human clinical trial.
Statement of Benefit to California:
Diabetes is a major public health problem that affect citizens throughout the world, including California. The goal of this proposal is to develop a new therapy for diabetes, based on transplanting human endocrine stem/progenitor cells in the context of a macroencapsulation device that will protect the cells from immune rejection. Successful development of this approach could lead to elimination of the need to inject insulin and also to elimination of diabetic complications such as blindness and kidney failure.
There are substantial economic benefits to California as well. The project is being led by a local biotechnology company that is focused on drug development. Success would lead to growth of that company and increased employment for scientists and other personnel involved in the project.
The goal of this development candidate proposal is to develop a beta cell therapy for diabetes derived from the non-endocrine fraction of adult human pancreas. In order to achieve this end, the applicant proposes to screen a library of small molecules for those that enable putative adult human endocrine stem cells derived from pancreatic exocrine tissues to differentiate into the endocrine lineage. The most promising compounds will be refined and optimized by a series of structure-activity studies, and tested in a panel of in vitro and in vivo analyses. Ultimately, endocrine progenitor cells that have been induced by these candidates will be tested for their ability to survive, fully differentiate and function in vivo using a microencapsulation device for transplantation into rodent models.
The reviewers agreed that the proposed research addresses an important, unmet need for improved therapies for type 1 diabetes, a destructive disease that affects a significant and growing number of individuals. If successful, this effort could be of very high impact.
In general, the reviewers found the scientific rationale for this effort to be plausible and expressed great confidence in the qualifications of the principal investigator, citing his/her more than twenty years experience in the biotechnology industry and track record in small molecule discovery using biological screens. While the premise was intriguing, reviewers concurred that the overall feasibility was limited. With no evidence to indicate otherwise, the reviewers were particularly concerned that the inductive milieu leading to reporter expression might be too complex to be observed in the single compound screening system described. In addition to this fundamental criticism, the reviewers expressed a number of technical concerns regarding the experimental design of the screening assay. For example, many questioned the extent to which the chosen reporters would be informative. In the case of one specific transcription factor, reviewers worried that transient expression might preclude useful analysis, a possibility that was acknowledged by the applicant. There were also fears that the proposed temporal windows for evaluating insulin promoter activity would be insufficient, as there have been precedents to indicate that longer lag times might be expected. Based on all of these concerns, the reviewers agreed that the proposed effort, while very exciting, was somewhat preliminary to that which would be considered for early translation. Most felt that the ambitious first aims were not likely to be achieved within this project’s timeline, and thus, the proposed transplantation with microencapsulation experiments were viewed as superfluous.
In summary, the reviewers agreed that the proposed effort was of sound rationale, addressed a critical need, and in theory could be of very high impact. While the premise was interesting, the overall feasibility was in doubt due to a number of practical and technical deficiencies. In addition, it was not clear that the relatively ambitious aims could be achieved within the timelines of this effort. Ultimately, the reviewers indicated that this project was in a more preliminary stage than that which would applicable to early translation.