Long Acting Native GLP-1 formulations for Type 1 Diabetes

描述（由申请人提供）：迫切需要新的治疗方法来缓解1型糖尿病患者与当前标准治疗（注射胰岛素）相关的神经病变、肾病和视网膜病变。最近的发现，胰岛细胞可以再生糖尿病动物的肽激素胰高血糖素样肽1（GLP-1）提出了令人兴奋的可能性，一种新的方法来治疗。GLP-1在体内的半衰期非常短，因此需要使用半衰期延长的潜在免疫原性类似物（艾塞那肽）进行疗效评价。然而，在临床试验中使用艾塞那肽的2型糖尿病患者中，38%已产生针对这种GLP-1类似物的抗体，这可能会限制该激素未来的功效。在我们的I期项目中，我们成功地在我们专有的纳米载体（PGC-HC）中配制了天然GLP-1，将其循环半衰期延长了200倍以上（从约5分钟至> 24小时），提供了在不产生中和抗体的情况下进行胰岛再生研究的潜力，并增加了靶向递送至胰腺的潜力。这项2期SBIR提案的重点是验证长效天然GLP-1（在I期开发）在1型糖尿病动物模型中再生β细胞的功效，并使配制的天然GLP-1更接近临床试验。在目标1中，我们提出以类似cGLP的方式扩大我们的纳米载体的合成，表征制剂并确定其货架稳定性。在目标2中，在目标3中计划的剂量优化之前，将在小鼠中确定载体和GLP-1制剂的急性和慢性最大耐受剂量，以最大限度地预防糖尿病和体内β细胞群的再生。前驱糖尿病NOD小鼠和糖尿病NOD小鼠将用以两种不同频率施用的三种不同浓度的配制的GLP-1治疗，有或没有免疫抑制剂。治疗期间和治疗后将监测血糖和C肽水平。研究结束时，将进行IP葡萄糖耐量试验。将测定C肽、血红蛋白1c和胰腺胰岛素含量，并进行组织组织学检查，以确定胰腺功能的完整性。设想的GLP-1产品是一种天然肽，仅需要每隔几天或每周一次给药，与FDA最近批准的当前GLP-1类似物和正在开发的类似物相比具有显着优势。

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.