Long Acting Native GLP-1 formulations for Type 1 Diabetes

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。最近发现糖尿病动物的胰岛细胞可以通过多肽激素GLP-1(GLP-1)再生，这增加了一种新的治疗方法的令人兴奋的可能性。GLP-1在体内的半衰期非常短，因此有必要使用具有潜在免疫原性的类似物(埃塞那肽)延长半衰期以评估疗效。然而，在临床试验中使用艾塞那肽的2型糖尿病患者中，有38%的人已经产生了针对这种GLP-1类似物的抗体，这可能会限制这种激素未来的疗效。在我们的第一阶段项目中，我们成功地在我们的专利纳米载体(PGC-HC)中配制了天然的GLP-1，将其循环半衰期延长了200倍以上(从~5分钟延长到&gt；24小时)，提供了在不开发中和抗体的情况下进行胰岛再生研究的可能性，并增加了定向递送到胰腺的可能性。这项第二阶段SBIR建议的重点是验证长效天然GLP-1(在第一阶段开发)在1型糖尿病动物模型中再生β细胞的有效性，并使配方的天然GLP-1更接近临床试验。在目标1中，我们建议以类似cGLP的方式放大合成我们的纳米载体，表征配方并确定其货架稳定性。在目标2中，载体和GLP-1制剂在小鼠体内的急性和慢性最大耐受量将在目标3中计划的剂量优化之前确定，以最大限度地预防糖尿病和体内β细胞团的再生。糖尿病前期NOD小鼠和糖尿病NOD小鼠将接受三种不同浓度、两种不同频率的GLP-1治疗，无论是否使用免疫抑制剂。在治疗过程中和治疗后将监测血糖和C肽水平。在研究结束时，将进行IP糖耐量测试。将测定C-肽、血红蛋白1c和胰腺胰岛素含量，并进行组织学检查以确定胰腺功能的完整性。设想中的GLP-1产品是一种原生肽，只需要每隔几天或一周给药一次，与FDA最近批准的GLP-1类似物和正在开发的类似物相比，将具有显著优势。

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. 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.