Design of an Implantable Pump Insulin

描述（由申请人提供）：胰岛素替代疗法治疗糖尿病（DM）的中心目标是严格控制血糖浓度。临床试验，包括具有里程碑意义的糖尿病控制和并发症试验（DCCT）和后续糖尿病干预和并发症流行病学研究（DCCT/EDIC），已经证明了1型糖尿病严格控制血糖在降低风险和延缓长期心血管和微血管并发症（包括糖尿病神经病变、视网膜病变和肾脏疾病）进展方面的益处。在2型糖尿病中也观察到类似的趋势。这些数据促使人们努力开发一种用于调节腹膜输送的植入式胰岛素泵。然而，到目前为止，由于与胰岛素颤动相关的泵闭塞问题，植入式泵仍处于实验阶段。本应用程序的目的是设计一个最佳的胰岛素模拟物和胰岛素配方安全有效地使用在植入式泵。该设计策略基于蛋白质结构的一般科学原理，采用单链胰岛素类似物。尽管植入式胰岛素泵有许多理论上的优势和有前景的临床试验，但目前还没有得到FDA的批准。一个主要的问题是，目前的胰岛素制剂在腹腔内37℃的泵库中储存1-3个月时，稳定性有限。这种不稳定性导致异常的蛋白质聚集，由于泵的部分或完全阻塞而经常损害胰岛素的输送。使用速效胰岛素类似物（HumalogTM（礼来公司）和NovalogTM（诺和诺德公司））时，这个问题更为严重，它们良好的药代动力学特性为外部胰岛素泵的使用提供了显著的优势。用于植入系统的完美泵胰岛素将结合快速药代动力学和高蛋白浓度下的长期稳定性，储存在泵库中，在37℃下温和搅拌。由于胰岛素错误折叠和异常聚集的倾向似乎是其结构固有的，过去的研究工作集中在替代方法上：开发新的管道材料或小分子表面活性剂来添加到胰岛素溶液中。虽然取得了一些进展，但临床的成功仍是难以捉摸的。我们提出了一种基于异常胰岛素聚集和纤颤的拓扑要求来设计胰岛素类似物的新方法。基本观点是基于我们最近对胰岛素原和胰岛素颤动机制的基础研究（Huang， K. et al.）。生物。黄凯等。化学学报，2005,42345-55。生物化学45,10278-93(2006))。这些研究表明，连接肽对单链胰岛素类似物发生异常聚集的倾向有深远的影响，包括37℃时发生在闭塞泵中的表面诱导的纤颤。我们建议利用这些观察结果来设计一种最佳泵胰岛素，设计出纤颤，同时设计出具有高胰岛素活性和低igf相关有丝分裂性的快速作用。设计原则将通过一系列功能分析和分子研究进行验证，为临床翻译提供坚实的科学基础。公共卫生相关性：胰岛素替代疗法治疗糖尿病的中心目标是血糖控制，即将血糖调节到接近生理水平。这种严格控制的临床重要性促使人们努力开发一种植入体内的胰岛素泵，以提供可调节的胰岛素腹腔输送；然而，到目前为止，由于泵堵塞与胰岛素聚集有关，植入式泵仍处于实验阶段。本应用程序的目的是设计一个最佳的胰岛素模拟物安全有效地使用在植入式泵。

DESCRIPTION (provided by applicant): The central goal of insulin replacement therapy in the treatment of diabetes mellitus (DM) is tight control of blood glucose concentrations. Clinical trials, including the landmark Diabetes Control & Complications Trial (DCCT) and follow-up Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC), have documented in Type 1 DM the benefit of tight glycemic control in reducing the risk and delaying the progression of long-term cardiovascular and microvascular complications, including diabetic neuropathy, retinopathy, and renal disease. Similar trends are observed in Type 2 DM. These data have motivated extensive efforts to develop an implantable insulin pump for regulated peritoneal deliver. To date, however, implantable pumps remain experimental due to the problem of pump occlusion associated with insulin fibrillation. The objective of this application is to design an optimal insulin analog and insulin formulation for safe and effective use in an implantable pump. The proposed design strategy, based on general scientific principles of protein structure, employs single-chain insulin analogs. Despite their many theoretical advantages and promising clinical trials, implantable insulin pumps are presently not approved by the FDA. A major problem is posed by the limited stability of present insulin formulations as stored for 1-3 months within the pump reservoir at 37 oC within the peritoneal cavity. Such instability causes aberrant protein aggregation, which frequently impairs insulin delivery due to partial or complete obstruction of the pump. This problem is more severe with use of rapid-acting insulin analogs (HumalogTM (Lilly) and NovalogTM (Novo-Nordisk)), whose favorable pharmacokinetic properties otherwise offer significant advantages for use in external insulin pumps. The perfect pump insulin for an implantable system would combine rapid pharmacokinetics with long-term stability at high protein concentration as stored in a pump reservoir with gentle agitation at 37 oC. Because the propensity of insulin to misfold and undergo aberrant aggregation has seemed intrinsic to its structure, past research efforts have focused on alternative approaches: development of novel tubing materials or small-molecule surfactants to add to the insulin solution. Although some progress has been obtained, clinical success has been elusive. We propose a novel approach to the design of insulin analogs based on the topological requirements of aberrant insulin aggregation and fibrillation. The essential idea is based on our recent foundational studies of proinsulin and the mechanism of insulin fibrillation (Huang, K. et al. J. Biol. Chem. 280, 42345-55 (2005) and Huang, K. et al. Biochemistry 45, 10278-93 (2006)). These studies demonstrate a profound effect of the connecting peptide on the propensity of single-chain insulin analogs to undergo aberrant aggregation, including surface-induced fibrillation at 37 C as occurs in occluded pumps. We propose to exploit these observations to design an optimal pump insulin, designing out fibrillation while } designing in} rapid action with high insulin activity and low IGF-related mitogenicity. Design principles will be validated through a series of functional assays and molecular studies to provide a solid scientific foundation for clinical translation. PUBLIC HEALTH RELEVANCE: The central objective of insulin replacement therapy in the treatment of Diabetes is glycemic control, i.e., regulation of blood glucose to near-physiological levels. The clinical importance of this tight control has motivated extensive efforts to develop an insulin pump implanted in the body to provide regulated peritoneal delivery of insulin; however, to date, implantable pumps remain experimental due to pump blockage associated with insulin aggregation. The objective of this application is to design an optimal insulin analog for safe and effective use in an implantable pump.