EGF/Gastrin for Islet Regeneration

描述(申请人提供)：迫切需要新的治疗方法，以减轻1型糖尿病患者与目前治疗标准相关的神经病变、肾病和视网膜病变，注射胰岛素。胰岛细胞移植，结合免疫抑制剂以避免免疫排斥反应，仅限于糖尿病患者的一小部分，并受到供体胰岛供应不足的限制。联合使用表皮生长因子受体激动剂(EGFRA)和胃泌素(G17)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的半衰期都很短(分钟)，这两种药物都是通过输注(大鼠)或频繁每日注射(小鼠)给药的，这种联合治疗的临床试验效果有限。第一阶段SBIR的结果证明，通过使用带有保护接枝共聚物(PGC)赋形剂的EGFRA(PGC-EGFRA)，可以显著改善使用EGFRA和G17联合使用的实验性糖尿病治疗。PGC与治疗胃酸过多的非处方质子泵抑制剂奥美拉唑(OPZ)联合使用，可以保护和稳定血液中的EGFRA(10倍稳定性)。这一组合中的OPZ可持续提高(高达基线的1000倍)血G17水平(超过24小时，而不是注射G17的几分钟)，而不会出现相关的胃酸过多。第二阶段SBIR的目标是1)生产具有良好特性的PGC制剂，2)找到这些制剂的最大耐受量(MTD)和治疗STZ糖尿病小鼠的最有效剂量方案，3)为每个制剂找到治疗NOD小鼠的最有效的剂量方案，无论是否使用抗CD3，以达到60%以上的治愈率，以及4)评价每个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.