Ultralong-acting insulin for diabetes

项目摘要 自#年建立以来，胰岛素替代疗法挽救了无数1型糖尿病患者的生命。 20世纪20年代的S。目前，患者可以使用多种速效、中效和长效胰岛素。然而， 许多接受胰岛素替代治疗的患者没有达到足够的血糖控制，如以下所示 未达到目标HbA1c水平(&lt；7%)。患者之间和患者内部的变异性是限制 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 可以安全开出的胰岛素剂量。一种更方便、更不可能发生的胰岛素疗法 诱导低血糖将导致患者更大的依从性。因此，提供更平坦、更均匀的方法 胰岛素剂量，具有较小的变异性，并以一种方便的形式增加顺应性，有可能 显著改善糖尿病患者的血糖控制。扩展生物科学正在利用人体自身的 天然系统延长多肽的半衰期并提高皮下注射后的生物利用度 注射。在这一阶段的SBIR赠款中，我们建议开发一种超长效胰岛素版本，使用我们的 技术并将其制定为缓释库，以实现每周一次的基础胰岛素替代。 初步结果表明，我们的技术提供了更长的半衰期和增加的生物利用度，而不需要 影响胰岛素受体上的胰岛素功能。我们建议建立一周一次的可行性 基础胰岛素通过实现以下三个特定目标来治疗糖尿病。首先，我们将做好准备 我们的长效胰岛素有三种仓库递送方式。然后，我们将在大鼠模型中测试这些配方 1型糖尿病。我们还将在小型猪的动物模型上检查这些制剂的药代动力学。 这更能预测人类的行为。一旦完全开发，这种胰岛素衍生品将大大受益 通过帮助糖尿病患者使用一种长效、患者友好的药物来管理他们的疾病。更多 即使是剂量也会降低低血糖的风险，同时改善血糖的控制，从而减少 糖尿病的长期并发症，如心血管疾病、视网膜病变、神经病变、胃瘫和 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.