EGF/Gastrin for Islet 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。胰岛细胞的移植，结合免疫抑制剂以避免免疫排斥，仅限于糖尿病患者的一个亚群，并受到供体胰岛供应不足的限制。使用表皮生长因子受体激动剂（EGFRA）和胃泌素（G17）联合治疗可增加糖尿病小鼠和大鼠的细胞质量并逆转高血糖。由于G17和EGFRA的半衰期（分钟）都很短，因此通过输注（大鼠）或频繁的每日注射（小鼠）给药，并且这种治疗组合的临床试验疗效有限。1期SBIR的结果证明，EGFRA和G17联合使用的实验性糖尿病治疗可以通过使用受保护接枝共聚物（PGC）赋形剂（PGC-EGFRA）得到显著改善。PGC与奥美拉唑（OPZ）联合使用时可保护和稳定血液中的EGFRA（10倍稳定），奥美拉唑是一种用于治疗胃酸过多的非处方质子泵抑制剂。这种组合的OPZ提供了血液G17水平的持续升高（比基线高1000倍）（注射G17后超过24小时，而不是几分钟），而没有相关的胃酸升高。2期SBIR的目标是：1)生产表征良好的PGC制剂；2)找到治疗stz -糖尿病小鼠的制剂的最大耐受剂量（MTD）和最有效的给药方案；3)找到治疗NOD小鼠的每种制剂加或不加Anti-CD3的最有效给药方案，使治愈率高于60%；4)评估每种制剂的稳定性和安全性。在第二阶段结束时，我们将有一个单一的治疗方案，我们将使用它来收集IND申请的数据。

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. Combination treatment using Epidermal Growth Factor Receptor Agonist (EGFRA) and Gastrin (G17) results in an increase in ¿-cell mass and reverses hyperglycemia in diabetic mice and rats. Because of short half-life (minutes) of both G17 and EGFRA, these were administered by infusion (rats) or frequent daily injection (mice) and a clinical trial of this treatment combination suffered from limited efficacy. Results from Phase 1 SBIR demonstrated the proof of concept that the experimental diabetes treatment using a combination of EGFRA and G17 can be improved significantly by the use of EGFRA with Protected-graft-copolymer (PGC) excipient (PGC-EGFRA). The PGC protects and stabilizes EGFRA in the blood (10- fold stabilization) in combination with Omeprazole (OPZ), an over the counter proton pump inhibitor for the treatment of stomach hyperacidity. The OPZ in this combination provides sustained elevation (up to 1000 fold over the baseline) of blood G17 level (over 24hr versus few minutes from G17 injection) without the associated hyperacidity of the stomach. The aims of the Phase 2 SBIR are to 1) produce well characterized PGC formulations, 2) find the maximum tolerable dose (MTD) of the formulations and the most effective dosing regimen for the treatment of STZ-diabetic mice, and 3) find the most effective dosing regimen for each formulation with or without Anti-CD3 for the treatment of NOD mice to achieve a cure rate of higher than 60%, and 4) to evaluate stability and safety of each formulation. At the end of Phase 2, we will have a single treatment regimen which we will use to collect data for an IND filing.