Diabetes mellitus is a disease that results from insufficient insulin production and affects approximately two million people in the state of California. Currently, the most widely-used therapy involves direct insulin injection to supplement the insulin that is naturally produced in the pancreas. This therapy diminishes the quality of life for diabetes patients, particularly because lifelong injections are required. Drugs that could either increase production of insulin-producing beta-islet cells or upregulate endogenous insulin would provide an alternative to current insulin injection therapy and dramatically decrease morbidity. In order to more accurately and quickly identify these candidate drugs, it would be very advantageous to have cells that reliably mimic a developing pancreas “in a dish” for drug screening. Human embryonic stem (hES) cells can provide a renewable source of normal cells that can be differentiated into pancreas-like cells, thus providing a good model for studying the effects of various compounds on insulin production.
The applicant institution has significant expertise and intellectual property in engineering mouse embryonic stem cells to differentiate into pancreatic-like cells that strongly resemble cells in the body. We propose engineering a similar design in human ES cells to facilitate their differentiation into pancreas-like cells. This will allow for scaled production of large quantities of pancreatic-like cells, sufficient for screening drug screening. One key advance in the proposal is the ability to detect the effect of a given drug specifically on insulin production in these cells using fluorescence monitoring. Because small changes in fluorescence can be easily detected, drugs can be optimized to increased potency and reduce unwanted side effects. Another key element in this ES cell design is the ability to easily screen for developmental genes and growth factors that can stimulate beta-islet cell growth and insulin expression. The institution maintains a proprietary set of candidate genes that will be evaluated in this fashion to identify novel therapeutic molecules for treating diabetes.
Diabetes and related diseases constitute a significant portion of healthcare expenditures in California. Direct and indirect costs are estimated to be approximately 16 billion USD a year based on population (http://www.cdc.gov/nccdphp/overview.htm). Furthermore, incidence in minority groups in California is disproportionately higher. Diabetes associated diseases such as stroke and cardiovascular disease are complicated and are often underestimated in cross-sectional assessments of State health.
Tragically, the percentage of adults diagnosed with diabetes continues to rise. In 2005 seven percent were diagnosed with diabetes, compared to 6.1% in 2001 (Diamant et al, 2007). To address this alarming health issue, the pharmaceutical industry needs more efficient and clinically-relevant (i.e. human-based) drug discovery and development tools focused on the biology of beta-islet cell growth and response, and insulin regulation.
The present proposal describes an engineered human cell line that will serve as a first-tier commercial drug discovery and screening platform that could yield many diabetes-relevant drug candidates. The proposal is by a California company that has many years of experience in commercializing human and mouse ES cell-based tools for drug discovery and development, and that has previously developed an analogous mouse insulin reporter ES cell line currently being used in commercial cell-based screening assays with a pharmaceutical partner, which is currently bringing revenue to California. Similar clinically relevant screening partnerships will be sought with the proposed hES line systems, bringing revenue and new jobs to California. In addition, commercialization of new diabetes drugs developed with the proposed hES cell line system will help relieve the burden on healthcare. Intellectual property gains for California are also potentially significant.
Publication of the results derived from the described research project will continue to support the advancement of California and human embryonic stem cell technology and stimulate new academic and commercial collaborations for recruiting and job growth.