Stimulation of Pancreatic Beta-Cell Stem Cells with a Small Molecule Antagonist of HNF4a

Funding Type: 
Disease Team Therapy Planning I
Grant Number: 
ICOC Funds Committed: 
Public Abstract: 

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 on the beta-cells. Thus, in both major forms of diabetes, increasing the number of beta-cells would have an enormous benefit on the course of disease.

We have used high-throughput screening technology to find small molecules that alter the expression of the insulin gene. Through that process, we discovered a molecule that acted on the insulin gene by inhibiting the activity of a protein called HNF4a. This protein is involved in gene regulation and is known to play an important role in the beta-cell. It is thought to be regulated in the body by fatty acids. Because fatty acids are one of the few stimuli that can increase the mass of beta-cells as an early response to obesity, we tested our HNF4a inhibitor for its ability to promote the formation of new beta-cells. Gratifyingly, the inhibitor caused new beta-cells to form and proliferate. This represents a fundamentally new approach to the treatment of diabetes, taking advantage of the ability of the pancreas to regenerate the cells that exist within it, particularly the beta-cells.

The next steps for this project include further studies in animal models of diabetes, development and testing of molecules related to our current inhibitor to improve its drug-like properties, testing for possible side effects of improved inhibitors, and preparation of the new drug application to the FDA. These activities will involve an integrated team at the Sanford-Burnham Medical Research Institute. Of significance, our Institute has one of the most sophisticated drug discovery and development centers in the country, the Conrad Prebys Center for Chemical Genomics. This Center is one of four comprehensive high-throughput drug screening centers established in the USA by the National Institutes of Health. It is led by Dr. Michael Jackson, a highly experienced drug development professional, who has led small biotech and large pharmaceutical drug development efforts. He will serve as the Planning Leader on this project. The medicinal chemists and other drug developmental experts in the Center will play important roles in the project.

In summary, we believe that this project has a high potential to result in a novel therapy for diabetes, based on the ability of an HNF4a inhibitor to induce the formation of new beta-cells. 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 would have an enormous impact on the health of the citizens of California, resulting in increased quality of life and decreased health care costs.