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. Transplantation of pancreatic islet cells in combination with immunosuppressant to avoid immune rejection is restricted to a subgroup of diabetics and is limited by the shortage in availability of donor islets. A recent reports demonstrate that a combination therapy of Epidermal Growth Factor (EGF) and gastrin increases beta cell mass and reverses hyperglycemia in diabetic mice and rats. Importantly, the islet neogenesis that resulted from the above experiment appears to result in cells that are resistant to autoimmunity, offering exciting prospects for the reversal of Type 1 diabetes. Because of short half-life (minutes) of both gastrin and EGF, these studies used analogues of EGF and gastrin which were administered twice daily by IP injection (mice) or by infusion (rats). The overall goal of this proposal is to formulate injectable native EGF and gastrin in a stable form with half-life of at least 24 hrs and would require only one injection every 2 days instead of frequent injections or infusion. Our company, PharmaIn, owns a proprietary set of technologies for the reversible binding of peptides and/or proteins to injectable drug nanocarriers. These nanocarriers protect drug from degradation and maintain fixed low concentration of free drugs minimizing side effects and toxicities. In addition, these nanocarriers tend to accumulate at sites of high vascular permeability or inflammations. Since Type 1 diabetic patients are believed to have a mild chronic pancreatic inflammation, the nanocarriers will localize in the pancreas, potentially minimizing side effects of growth factors in other areas. One of our goals is to develop this delivery system for native EGF and gastrin to cure diabetes. Additionally, we propose, in parallel, a second approach to improving EGF and gastrin combination therapy. We propose to indirectly induce gastrin secretion by the administration of an orally available proton pump inhibitor (omeprazole) shown previously to increase gastrin levels up to 10 fold. This approach, if successful, has the distinct advantage of replacing labile gastrin with an FDA-approved orally available OTC medication allowing for easy delivery, cost effective treatment and rapid FDA approval. We will quickly test EGF infusion and oral proton pump inhibitor for their ability to induce islet cell neogenesis (Aim1) and in parallel separately formulate EGF and gastrin (Aim 2).
In aim 3, we will determine in vivo pharmacokinetics of formulated EGF, and gastrin if needed. Phase II studies will involve comprehensive validation and evaluation of the combination treatment with either nanocarrier formulated EGF and gastrin or nanocarrier formulated EGF and oral proton pump inhibitor to larger groups of animals and to do safety study in two animal species (small and large) as required to prepare for IND.
This Phase I application is aimed toward developing an injectable nanocarrier-stabilized native EGF that can be used to treat and cure diabetes in combination with either nanocarrier- stabilized native gastrin or oral proton pump inhibitor available over the counter. This will be a cost saving treatment to cure or alleviate suffering of people with diabetes and reduce its economic burden to society. The eventual goal is FDA filing of an IND application.
| Castillo, Gerardo M; Nishimoto-Ashfield, Akiko; Banerjee, Aryamitra A et al. (2013) Omeprazole and PGC-formulated heparin binding epidermal growth factor normalizes fasting blood glucose and suppresses insulitis in multiple low dose streptozotocin diabetes model. Pharm Res 30:2843-54 |
