EGF/Gastrin for Islet Regeneration

EGF/胃泌素促进胰岛再生

基本信息

批准号：
8730624
负责人：
Gerardo M. Castillo
金额：
$ 74.96万
依托单位：
PHARMAIN CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8730624
关键词：
Acidity Acute Address Affect Agonist Animals Binding Blood Blood Glucose CD3 Antigens Caliber Canis familiaris Cell physiology Cells Chronic Clinical Treatment Clinical Trials Combined Modality Therapy Communication Complex DTR gene Data Data Collection Development Diabetes Mellitus Diabetic mouse Dissociation Dose Drug Formulations Drug Kinetics Economic Burden Endotoxins Enzymes Epidermal Growth Factor Epidermal Growth Factor Receptor Excipients Experimental Diabetes Mellitus Failure Gastrins Glycosylated hemoglobin A Goals Half-Life Human Hyperglycemia Immune Immune Tolerance Immunosuppressive Agents Inbred NOD Mice Infusion procedures Injection of therapeutic agent Insulin Insulin-Dependent Diabetes Mellitus Islet Cell Kidney Diseases Modality Mus Natural regeneration Neuropathy Non-Insulin-Dependent Diabetes Mellitus Omeprazole Organ Pancreas Patients Peptides Pharmaceutical Preparations Phase Polyethylene Glycols Polymers Preparation Production Property Proton Pump Inhibitors Publishing Rattus Recommendation Recovery Regimen Retinal Diseases Rodent Safety Site Small Business Innovation Research Grant Societies Stomach Streptozocin Subcutaneous Injections Subgroup Syringes Technology Testing Transplantation Treatment Protocols Vascular Permeabilities analog copolymer cost diabetic diabetic rat glucagon-like peptide human study improved islet nonhuman primate pre-clinical prevent public health relevance scale up standard care success trafficking treatment duration tumor

项目摘要

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.

描述（由申请人提供）：迫切需要新的疗法来缓解 1 型糖尿病患者与当前治疗标准（注射胰岛素胰岛移植）相关的神经病、肾病和视网膜病。 -细胞与免疫抑制剂联合使用以避免免疫排斥，仅限于糖尿病患者亚组，并且由于供体胰岛的缺乏而受到限制。使用表皮生长因子受体激动剂（EGFRA）和胃泌素（G17）的联合治疗会导致糖尿病。增加 ¿由于 G17 和 EGFRA 的半衰期较短（分钟），因此通过输注（大鼠）或每日频繁注射（小鼠）进行给药，并对该治疗组合进行了临床试验。 1 期 SBIR 的结果证明了联合使用 EGFRA 和 G17 的实验性糖尿病治疗可以通过联合使用 EGFRA 得到显着改善。受保护的移植物共聚物 (PGC) 赋形剂 (PGC-EGFRA) 与奥美拉唑 (OPZ)（一种用于治疗胃病的非处方质子泵抑制剂）相结合，可保护和稳定血液中的 EGFRA（稳定性提高 10 倍）。该组合中的 OPZ 可使血液 G17 水平持续升高（比基线高 1000 倍）（超过 24 小时而不是几分钟）。 2 期 SBIR 的目的是 1) 生产特征良好的 PGC 制剂，2) 找到制剂的最大耐受剂量 (MTD) 和最有效的给药方案。治疗 STZ 糖尿病小鼠，以及 3) 找到含有或不含抗 CD3 的每种制剂最有效的给药方案，用于治疗 NOD 小鼠，以达到高于60%，以及 4) 评估每种制剂的稳定性和安全性在第 2 阶段结束时，我们将有一个单一的治疗方案，我们将用它来收集 IND 备案的数据。