New therapies are desperately needed for patients with Type 1 diabetes. Recent reports that the insulin-stimulating hormone Glucagon-Like Peptide (GLP-1), can increase pancreatic beta cell mass, offers the exciting prospect that beta cells can be regenerated in Type 1 diabetes, avoiding the need for islet transplantation. A number of modified analogues of GLP-1 are in development that are resistant to the peptidase DPP-IV that rapidly inactivates GLP-1 in the bloodstream. Our company proposes to apply a novel drug delivery nanotechnology Protected Graft Copolymers (PGC) coupled with Pharmaln's Reversible Binding (PRB) to reversibly associate native GLP-1 with the carrier. Since GLP-I in the carrier would be encased in a polymer; we anticipate protection of the peptide from cleavage by DPP-IV and thus an extended half-life. Importantly, since this carrier has been demonstrated to accumulate in sites of inflammation, the envisioned formulation would result in increased delivery to the pancreas, thus potentially minimizing gastrointestinal side effects. -to demonstrate the feasibility of the approach we propose to 1) formulate PGC/PRB:GLP-1 and measure the complex formation efficiency, binding constant and stability in serum; 2) determine the in vitro potency of PGC/PRB:GLP-1 receptor binding and sensitivity to degradation by DPP-IV ; 3) demonstrate the effect of PGC/PRB:GLP-1 on beta cell insulin secretion and glucose responsiveness as well as ability to induce neogenesis of new beta cells from ductal cells in vitro; 4) determine the PK, accumulation of the complex in the pancreas and its stability and 5) demonstrate efficacy in vivo in regeneration of beta cell mass in a rat model of streptozotocin-induced diabetes. The Phase II studies will involve the validation and optimization of the treatment to extended animal groups, including models of Type 1 diabetes in combination with immunosuppressants. The envisioned product, GLP-1 in an optimal pancreas-directed delivery system, should be of commercial interest not only for the treatment of Type 1 diabetes, but also for other applications being investigated for this peptide, including obesity, Alzheimer's and Type 2 diabetes.
| Castillo, Gerardo M; Reichstetter, Sandra; Bolotin, Elijah M (2012) Extending residence time and stability of peptides by protected graft copolymer (PGC) excipient: GLP-1 example. Pharm Res 29:306-18 |
| Medarova, Zdravka; Greiner, Dale L; Ifediba, Marytheresa et al. (2011) Imaging the pancreatic vasculature in diabetes models. Diabetes Metab Res Rev 27:767-72 |
