Long Acting Native GLP-1 formulations for Type 1 Diabetes

治疗1型糖尿病的长效GLP-1首席研究员：Bolotin，Elijah 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， 肾病和视网膜病变相关的治疗按现行标准，注射胰岛素。这个 最近发现，糖尿病动物的胰岛细胞可以通过多肽激素胰高血糖素再生。 与多肽1(GLP-1)一样，GLP-1也提出了一种令人兴奋的治疗方法。GLP-1具有非常强的 体内半衰期短，需要使用潜在的免疫原性类似物(艾塞那肽)。 延长了疗效评估的半衰期。然而，38%的2型糖尿病患者使用 临床试验中的埃克塞那肽已经开发出针对这种GLP-1类似物的抗体，可能会 限制激素在未来的疗效。在我们的第一阶段项目中，我们成功地制定了 我们专利的纳米载体(PGC-HC)中的天然GLP-1将其循环半衰期延长超过200 折叠(从~5分钟到&gt；24小时)，提供了在没有 开发中和抗体，并增加靶向胰腺递送的潜力。 该第二阶段SBIR建议的重点是验证长效天然GLP-1(开发的)的有效性 在第一阶段)在1型糖尿病动物模型中再生β细胞，并将配方 国产GLP-1更接近临床试验。在目标1中，我们建议放大合成我们的纳米载体 以类似于cGLP的方式，对配方进行表征并确定其货架稳定性。在目标2中，急性和 将在小鼠体内确定载体和GLP-1制剂的慢性最大耐受量 优化目标3中的剂量计划，以最大限度地预防糖尿病和促进β细胞再生 体内质量。糖尿病前期NOD小鼠和糖尿病NOD小鼠将在 三种不同的浓度，以两种不同的频率给药，有或没有 免疫抑制剂。血糖和C肽水平将在治疗期间和治疗后进行监测 治疗。在研究结束时，将进行IP糖耐量测试。C-肽， 将测定血红蛋白1c和胰腺胰岛素含量，并进行组织学检查 判断胰腺功能的完整性。设想的GLP-1产品是一种天然多肽和 只要求每隔几天或一周给药一次，比起 目前的GLP-1类似物最近被FDA批准，以及那些正在开发中的类似物。 Pharmain机密-摘要-

Long Acting GLP-1 for Type 1 diabetes Principal Investigator: BOLOTIN, Elijah 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. The recent finding that islet cells can be regenerated in diabetic animals by the peptide hormone Glucagon- like peptide 1 (GLP-1) has raised the exciting possibility of a new approach for a cure. GLP-1 has a very short half life in vivo necessitating the use of potentially immunogenic analogues (exenatide) with extended half lives for evaluation of efficacy. However, 38% of type 2 diabetic patients that used exenatide in clinical trial have developed antibody against this GLP-1 analogue which could potentially limit efficacy of the hormone in the future. In our Phase I project we have succeeded in formulating native GLP-1 in our proprietary nanocarrier (PGC-HC) to extend its circulation half-life more than 200 fold (from ~ 5 min to > 24h) offering the potential to perform islet regeneration studies without the development of neutralizing antibody and with the added potential for targeted delivery to the pancreas. This Phase 2 SBIR proposal is focused on validating the efficacy of long acting native GLP-1 (developed in Phase I) to regenerate beta cells in an animal model of Type 1 diabetes and to bring the formulated native GLP-1 closer to clinical trial. In Aim 1 we propose to scale up synthesis of our nanocarrier in a cGLP-like manner, characterize the formulation and determine its shelf stability. In Aim 2 the acute and chronic maximum tolerated dose of carrier and GLP-1 formulation will be determined in mice prior to the optimization of dosing planned in Aim 3 to maximize diabetes prevention and regeneration of beta cell mass in vivo. Pre-diabetic NOD mice and diabetic NOD mice will be treated with formulated GLP-1 at three different concentrations administered at two different frequencies, with or without an immunosuppressive agent. Blood glucose and C-peptide levels will be monitored during and after treatment. At the end of the study, an IP glucose tolerance test will be done. The C-peptide, hemoglobin 1c and pancreatic insulin content will be determined and tissue histology will be done to determine the integrity of pancreatic function. The envisioned GLP-1 product, being a native peptide and requiring administration only every few days or once a week, would have significant advantages over current GLP-1 analogues recently approved by the FDA and those under development. PharmaIn Confidential - Abstract -