Ultralong-acting insulin for diabetes

项目摘要 胰岛素替代疗法自2000年问世以来，已经挽救了许多1型糖尿病患者的生命。 20世纪20年代。目前，患者可获得多种速效、中效和长效胰岛素。然而，在这方面， 许多接受胰岛素替代治疗的患者不能达到足够的血糖控制， 未达到目标HbA 1c水平（<7%）。患者间和患者内变异性是限制 基础胰岛素治疗的有效性;这种变异性增加了低血糖的可能性，并降低了 可以安全处方的胰岛素剂量。胰岛素治疗更方便， 诱导低血糖症将导致更大的患者顺应性。因此，提供更平坦、更均匀的 胰岛素剂量的可变性较小，并且以方便的形式增加依从性，有可能 显著改善糖尿病患者血糖控制。Extend Biosciences正在利用人体自身的 天然系统，以延长半衰期，并增加生物利用度的肽皮下注射后， 注射在第一阶段SBIR资助中，我们建议使用我们的 技术，并将其配制为缓释贮库，以实现每周一次的基础胰岛素替代。 初步结果表明，我们的技术具有更长的半衰期和更高的生物利用度， 影响胰岛素受体的胰岛素功能。我们建议建立每周一次的可行性 基础胰岛素用于治疗糖尿病通过实现以下三个具体目标。首先，我们要准备 长效胰岛素的三种长效给药方式。然后，我们将在大鼠模型中测试这些制剂。 1型糖尿病我们还将研究这些制剂在小型猪（一种动物模型）中的药代动力学 更能预测人类的行为一旦完全开发，这种胰岛素衍生物将大大受益于 帮助糖尿病患者使用一种持久的、对患者友好的药物来管理他们的疾病。更 即使剂量增加，也会降低低血糖的风险，同时改善血糖控制， 长期糖尿病并发症，如心血管疾病、视网膜病变、神经病变、胃轻瘫，以及 肾病

Project Summary Insulin replacement therapy has saved numerous lives of Type 1 diabetic patients since it was established in the 1920's. Currently, multiple fast-, intermediate- and longer-acting insulins are available to patients. However, many patients on insulin replacement therapy do not achieve adequate blood glucose control as indicated by not reaching target HbA1c levels (<7%). Inter- and intra-patient variability is a major factor limiting the effectiveness of basal insulin therapy; this variability enhances the likelihood of hypoglycemia and reduces the dose of insulin that may be safely prescribed. An insulin therapy that is more convenient and less likely to induce hypoglycemia would lead to greater patient compliance. Thus, methods to deliver a flatter, more even dose of insulin, with smaller variability, and in a convenient format to increase compliance, has the potential to significantly improve glycemic control in diabetes patients. Extend Biosciences is harnessing the body's own natural systems to extend the half-life and increase the bioavailability of peptides following subcutaneous injection. In this Phase I SBIR grant, we propose to develop an ultralong-acting version of insulin using our technology and formulate it as a slow-release depot to achieve a once-weekly basal insulin replacement. Preliminary results show that our technology confers a longer half-life and increased bioavailability without affecting the function of insulin at the insulin receptor. We propose to establish the feasibility of a once-weekly basal insulin for the treatment of diabetes by achieving the following three specific aims. First, we will prepare three depot delivery methods with our long-acting insulin. Then, we will test these formulations in a rat model of type 1 diabetes. We will also examine the pharmacokinetics of these formulations in minipigs, an animal model that is more predictive of behavior in humans. Once fully developed, this insulin derivative would greatly benefit patients with diabetes by helping them manage their disease using a long-lasting, patient-friendly drug. More even dosing would lower the risks of hypoglycemia while improving control of blood glucose, thus reducing long-term diabetic complications such as cardiovascular disease, retinopathy, neuropathy, gastroparesis, and nephropathy.