The product that will result from the proposed SBIR program, a consortium collaboration between BioPancreate (a small business) and Cornell University, will be an orally-administered insulin-replacement therapy for both type-1 and type-2 diabetes mellitus, utilizing a novel live biotherapeutic product that reprograms host intestinal stem cells into """"""""pancreatic ?-like"""""""" cells. Diabetes mellitus is one of the most compelling healthcare needs of our times. While curative approaches are likely deep in the future, injection of insulin has been a mainstay of therapy in addition to synergistic, but largely palliative oral therapies. There is a clear need for novel therapies for diabetes in particular for new oral therapies, as compliance and accurate dosing are at the root of exploding secondary complications. We, and others, have shown that intestinal stem cells can be programmed into glucose-responsive insulin-secreting cells by exposing them to an otherwise inactive GLP-1 peptide. We have developed a novel method for local and targeted delivery of GLP-1 peptide to adult enterocytes in situ, using genetically-modified commensal bacteria. These bacteria stimulate the re-programming of intestinal stem cells to insulin-secreting cells, relocating the center of glucose regulation in the body of diabetics from the pancreas to the GI tract. The technology is patented, low-cost to produce, and safe as it involves human bacterial probiotic strains. We have encouraging preliminary data in human epithelial cell lines and in vivo models. In response to GLP-1 secreted from commensal bacteria, isolated cells were reprogramed to become glucose-dependent insulin secretors. More importantly, we demonstrated this mechanism in diabetic animal models, which were returned to euglycemic levels after 30 days of treatment without any demonstrable side effects. Immunohistochemistry in these animals identified the cell type being transformed and the location of the new insulin depot. What is now needed is to complete fundamental pre-clinical product development that will enable IND-enabling studies to be finalized ahead of clinical evaluations.

Public Health Relevance

This proposal will provide a new strategy for treating type 1 diabetes mellitus. A cure for the disease is not currently available, and the mainstay of treatment is insulin injection. The product being developed here will be a novel oral therapy that stimulates cells in the intestine to secrete insulin in a glucose responsive manner, avoiding or significantly reducing the need for insulin injection and reducing the large daily swings in glucose levels typically occurring in a diabetic patient.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Small Business Technology Transfer (STTR) Grants - Phase I (R41)
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Special Emphasis Panel (ZRG1-EMNR-S (10))
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Arreaza-Rubin, Guillermo
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Biopancreate, Inc.
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Duan, Franklin F; Liu, Joy H; March, John C (2015) Engineered commensal bacteria reprogram intestinal cells into glucose-responsive insulin-secreting cells for the treatment of diabetes. Diabetes 64:1794-803
Costello, Cait M; Hongpeng, Jia; Shaffiey, Shahab et al. (2014) Synthetic small intestinal scaffolds for improved studies of intestinal differentiation. Biotechnol Bioeng 111:1222-32