The goal of this project is to develop a new treatment for diabetes, based on increasing the number of insulin-producing cells in the pancreas, called beta-cells. In type I diabetes, the beta-cells are destroyed by the immune system, while in type II diabetes the beta-cells are more gradually lost due to the toxic effects of fat and glucose. Thus, in both major forms of diabetes, increasing the number of beta-cells would provide enormous benefit.
We have discovered recently that cells within the pancreas called alpha-cells that reside adjacent to the beta-cells can turn into beta-cells under certain conditions. Because the alpha-cells are not affected by either type I or type II diabetes, this finding opens the door to developing a therapy for diabetes based on stimulating the formation of new beta-cells from alpha cells. However, to achieve that goal, we would need to discover a drug that stimulates the alpha-cells to undergo such a conversion.
To that end, we will use high throughput screening, as done by pharmaceutical companies. For the screening, we will produce large numbers of alpha-like cells from human embryonic stem cells. Compounds that we discover will be tested in culture and then in animal models, with the goal of finding one that can be moved forward towards clinical testing in patients with diabetes. Such a therapy could be truly revolutionary in terms of its impact on the treatment of diabetes and on the lives of patients with diabetes.
Statement of Benefit to California:
Diabetes, particularly type II, but also type I, is increasing in incidence and prevalence. As of 2005, California had approximately three million people with diabetes. About one third of the population of California has prediabetes, suggesting that the incidence will continue to increase. Diabetes is particularly prevalent in regions of the state such as the Central Valley, which has a large Hispanic population, which is particularly prone to type II diabetes. In 2005, the cost of treating diabetes in California was estimated to be approximately 24.5 billion dollars. In addition to diabetes itself, diabetes is a major contributor to cardiovascular disease risk, and more recently has been recognized as a significant risk factor for a number of types of cancer. Thus, a novel therapy for diabetes such as that proposed here to generate new insulin-producing beta-cells would have an enormous impact on the health of the citizens of California, resulting in increased quality of life and decreased health care costs.
The goal of this Development Candidate Feasibility (DCF) proposal is to identify a molecule that could potentially be used for the treatment of diabetes. The applicant’s group and others have observed that under certain experimental conditions pancreatic alpha cells can transdifferentiate into pancreatic beta cells (the cells that are defective in diabetes). Based on this observation, the applicant seeks to identify a molecule that can induce transdifferentiation of human alpha cells into beta cells and to test that compound in proof-of-concept efficacy studies. Proposed studies include generation of human embryonic stem cells (hESC)-derived alpha cells (milestone 1), development of a high throughput screening (HTS) assay to monitor hESC-derived alpha cell transdifferentiation to beta cells (milestone 2), execution of a high throughput screen (milestone 3), verification of primary hits using secondary assays (milestone 4), and in vivo functional assessment of beta cells transdifferentiated from either hESC-derived or primary alpha cells using the verified hits (milestones 5 and 6).
Objective and Milestones
- Neither the molecular target nor the mechanism of action (MOA) of the proposed development candidate will be known, and an approach to resolve these issues is not described. The proposed target product profile (TPP) needs a plan to try to understand these important features that determine compound selectivity.
- The TPP is based on observations from the PI’s lab and others that alpha cells can convert to beta cells in vivo under specific conditions. However, whether this transdifferentiation is a compelling potential strategy for treatment of the disease remains to be seen.
- The basic strategies to develop a screen and test compounds are laid out with clear milestones.
Rationale and Significance
- Whether this would be a useful clinical approach seems somewhat uncertain. In Type I diabetes, the underlying conditions leading to loss of beta cell mass presumably remain, therefore possibly limiting the overall potential impact.
- A disease-modifying drug that addresses the loss of insulin-secreting pancreatic beta cells for diabetes does not exist. If successful, the proposed therapeutic might lead to a new type of treatment that could significantly improve the current standard of care for diabetes.
Research Project Feasibility and Design
- The critical first aim of the research plan, the development and validation of the hESC-based assay for conversion of alpha cells to beta cells, may be challenging, yet no alternative plans were discussed. Thus, failure to successfully format this cell-based screen would end the project.
- The proposed high throughput screen is unlikely to get hits that can easily be translated into development. It is extremely difficult to do structure-activity relationship (SAR) optimization using cell-based assays, so optimization of any lead compound(s) would be difficult to do in the absence of knowledge of their molecular target(s).
- Reviewers had mixed views as to how feasible the it would be to identify a single factor that can induce transdifferentiation of alpha cells into beta cells. While some reviewers felt that the preliminary data cited in the application helped validate this approach, others felt that the preliminary results were anecdotal and did not show a causal relationship between the treatment and the phenotype.
- The strategy of producing alpha-like cells (making glucagon or glucagon + insulin) from hESC is perhaps the best available, but it must be noted that the cells likely are not fully equivalent to mature alpha cells; rather they correspond to an earlier fetal stage.
- This project is highly speculative and high risk.
Qualification of the PI (Co-PI and Partner PI, if applicable) and Research Team
- The PI is a well-established investigator in the diabetes field.
- Together the PI and key members of the team have relevant qualifications, including experience to lead the proposed research project.
- The Co-I clearly is experienced in translational research. Thus, the skills of the PI and Co-I are nicely complementary.
Collaborations, Assets, Resources and Environment
- Resources, facilities and major equipment critical to the success of the project are available for conducting the proposed research. The environment facilitates the probability of success of the proposed research.
- The resources for high throughput/high content screening are available and there is appropriate expertise in the technology.
Responsiveness to the RFA
- Human stem cells are essential for the screening technology. The project fits within the RFA scope.