Long Acting Native GLP-1 formulations for Type 1 Diabetes

DESCRIPTION (provided by applicant): New therapies are desperately needed to relieve patients with Type 1 diabetes from the neuropathy, nephropathy and retinopathy associated with the current standard of treatment, injected insulin. The recent finding that islet cells can be regenerated in diabetic animals by the peptide hormone Glucagon- like peptide 1 (GLP-1) has raised the exciting possibility of a new approach for a cure. GLP-1 has a very short half life in vivo necessitating the use of potentially immunogenic analogues (exenatide) with extended half lives for evaluation of efficacy. However, 38% of type 2 diabetic patients that used exenatide in clinical trial have developed antibody against this GLP-1 analogue which could potentially limit efficacy of the hormone in the future. In our Phase I project we have succeeded in formulating native GLP-1 in our proprietary nanocarrier (PGC-HC) to extend its circulation half-life more than 200 fold (from ~ 5 min to > 24h) offering the potential to perform islet regeneration studies without the development of neutralizing antibody and with the added potential for targeted delivery to the pancreas. This Phase 2 SBIR proposal is focused on validating the efficacy of long acting native GLP-1 (developed in Phase I) to regenerate beta cells in an animal model of Type 1 diabetes and to bring the formulated native GLP-1 closer to clinical trial. In Aim 1 we propose to scale up synthesis of our nanocarrier in a cGLP-like manner, characterize the formulation and determine its shelf stability. In Aim 2 the acute and chronic maximum tolerated dose of carrier and GLP-1 formulation will be determined in mice prior to the optimization of dosing planned in Aim 3 to maximize diabetes prevention and regeneration of beta cell mass in vivo. Pre-diabetic NOD mice and diabetic NOD mice will be treated with formulated GLP-1 at three different concentrations administered at two different frequencies, with or without an immunosuppressive agent. Blood glucose and C-peptide levels will be monitored during and after treatment. At the end of the study, an IP glucose tolerance test will be done. The C-peptide, hemoglobin 1c and pancreatic insulin content will be determined and tissue histology will be done to determine the integrity of pancreatic function. The envisioned GLP-1 product, being a native peptide and requiring administration only every few days or once a week, would have significant advantages over current GLP-1 analogues recently approved by the FDA and those under development.