EGF/Gastrin for Islet Regeneration

EGF/胃泌素促进胰岛再生

基本信息

批准号：
8455605
负责人：
Gerardo M. Castillo
金额：
$ 79.4万
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 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8455605
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 Islets of Langerhans Transplantation 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（由适用提供）：迫切需要新的疗法来从与当前治疗标准相关的神经病，肾病和视网膜病中挽救1型糖尿病患者。胰岛胰岛的移植与免疫抑制剂相结合以避免免疫反应，仅限于糖尿病患者的亚组，并且受供体胰岛可用性短缺的限制。使用表皮生长因子受体激动剂（EGFRA）和胃蛋白（G17）的联合处理导致糖质量增加并逆转糖尿病小鼠和大鼠的高血糖。由于G17和EGFRA的半衰期（分钟）短，因此通过输注（大鼠）或每天注射（小鼠）进行给药，而该治疗组合的临床试验受到有限的有效性。第1阶段SBIR的结果证明了概念证明，即通过将EGFRA与受保护的嫁接 - 聚合物（PGC）赋形剂（PGC-EGFRA）一起使用EGFRA，可以通过EGFRA和G17的结合进行实验性糖尿病治疗。 PGC与Omeprazole（Omeprazole（OPZ）结合使用，PGC保护并稳定了EGFRA（10倍稳定），Omeprazole（Omepz）是一种倒置质子泵抑制剂，用于治疗档次过度酸度。这种组合中的OPZ可提供血液G17水平的持续升高（在基线上最多1000倍）（超过24小时，而从G17注射中进行了几分钟），而没有摊位的相关性过高。第2阶段SBIR的目的是1）产生的PGC配方良好，2）找到公式的最大耐受剂量（MTD）和最有效的剂量方案，用于治疗STZ-糖尿病小鼠的治疗方案，以及3）3）找到对每种抗CD3的均衡率的最有效剂量的最有效的剂量，以使NOD 3的治疗率较高，以均与NOD级别的治疗率相比，该方案的率高于NOD3的均为nod的率，该率是NOD的40次。和每个公式的安全。在第2阶段结束时，我们将有一个单一的治疗方案，我们将使用该治疗方案来收集数据归档的数据。