EGF/Gastrin for islet cell regeneration

描述（由申请人提供）：迫切需要新的治疗方法来缓解1型糖尿病患者的神经病变、肾病和视网膜病变，这些病变与目前注射胰岛素的治疗标准有关。胰岛细胞联合免疫抑制剂以避免免疫排斥的移植仅限于糖尿病患者，并受到供体胰岛供应不足的限制。最近的一项报告表明，表皮生长因子（EGF）和胃泌素联合治疗可增加糖尿病小鼠和大鼠的β细胞质量并逆转高血糖。重要的是，由上述实验产生的胰岛新生似乎产生了抵抗自身免疫的细胞，为逆转1型糖尿病提供了令人兴奋的前景。由于胃泌素和EGF的半衰期都很短（分钟），这些研究使用了EGF和胃泌素的类似物，每天两次通过IP注射（小鼠）或输注（大鼠）给药。本提案的总体目标是制备可注射的天然EGF和胃泌素，其半衰期至少为24小时，并且只需每2天注射一次，而不是频繁注射或输注。我们的公司PharmaIn拥有一套专有技术，用于多肽和/或蛋白质与可注射药物纳米载体的可逆结合。这些纳米载体保护药物免受降解，并保持固定的低浓度游离药物，最大限度地减少副作用和毒性。此外，这些纳米载体往往积聚在高血管通透性或炎症部位。由于1型糖尿病患者被认为有轻微的慢性胰腺炎症，纳米载体将定位于胰腺，潜在地减少生长因子在其他部位的副作用。我们的目标之一是开发这种天然EGF和胃泌素的输送系统来治疗糖尿病。此外，我们同时提出了第二种改善EGF和胃泌素联合治疗的方法。我们建议通过口服质子泵抑制剂（奥美拉唑）间接诱导胃泌素分泌，该药物先前显示可将胃泌素水平提高10倍。这种方法，如果成功，具有明显的优势，用FDA批准的口服可获得的OTC药物取代不稳定的胃泌素，允许易于递送，成本有效的治疗和快速FDA批准。我们将快速测试EGF输注和口服质子泵抑制剂诱导胰岛细胞新生（Aim1）的能力，并同时分别配制EGF和胃泌素（Aim 2）。在目标3中，我们将确定制剂EGF和胃泌素的体内药代动力学。II期研究将包括对纳米载体配制的EGF和胃泌素或纳米载体配制的EGF和口服质子泵抑制剂的联合治疗进行全面验证和评估，并根据IND的需要在两种动物物种（小型和大型）中进行安全性研究。该I期申请旨在开发一种可注射的纳米载体稳定的天然EGF，可与纳米载体稳定的天然胃泌素或口服质子泵抑制剂联合治疗和治愈糖尿病。这将是一种节省成本的治疗方法，可以治愈或减轻糖尿病患者的痛苦，减轻其对社会的经济负担。最终目标是向FDA提交IND申请。

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. 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. PUBLIC HEALTH RELEVANCE: 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.