Design of an Implantable Pump Insulin

描述(申请人提供)：胰岛素替代疗法治疗糖尿病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)和糖尿病干预和并发症后续流行病学研究(DCCT/EDIC)，已经在1型糖尿病患者中证明了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)进展方面的好处。在2型糖尿病中也观察到了类似的趋势。这些数据促使人们广泛努力开发一种植入式胰岛素泵，用于调节腹膜给药。然而，到目前为止，由于胰岛素颤动导致泵堵塞的问题，植入式泵仍处于实验阶段。本应用的目的是设计一种最佳的胰岛素类似物和胰岛素配方，以便在植入式泵中安全有效地使用。建议的设计策略基于蛋白质结构的一般科学原理，使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很有前景的临床试验，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37℃的腹膜腔内的泵储存库中储存1-3个月，稳定性有限。这种不稳定性会导致蛋白质的异常聚集，由于泵的部分或完全阻塞，这经常会损害胰岛素的输送。在使用快速作用的胰岛素类似物(HumalogTM(礼来公司)和NovalogTM(诺和诺德))时，这个问题更加严重，它们良好的药代动力学特性在其他方面为外部胰岛素泵的使用提供了显著的优势。用于植入型系统的完美的胰岛素泵将结合快速的药代动力学和在高蛋白浓度下的长期稳定性，将其储存在37℃的泵储存库中并进行温和的搅拌。由于胰岛素的错误折叠和异常聚集的倾向似乎是其结构所固有的，过去的研究努力集中在替代方法上：开发新型管状材料或小分子表面活性剂来添加到胰岛素溶液中。虽然已经取得了一些进展，但临床上的成功仍难以捉摸。我们根据胰岛素异常聚集和纤颤的拓扑要求，提出了一种新的设计胰岛素类似物的方法。这一基本思想是基于我们最近对胰岛素原和胰岛素纤颤机制的基础研究(Huang，K.等人)。J.Biol.化学。280,42345-55(2005年)和黄凯等人。生物化学45,10278-93(2006年))。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，包括在37℃时表面诱导的纤颤，就像闭塞泵中发生的那样。我们建议利用这些观察结果来设计一种最佳的胰岛素泵，设计出纤颤，同时设计出具有高胰岛素活性和低IGF相关有丝分裂活性的快速作用。设计原则将通过一系列功能分析和分子研究来验证，为临床翻译提供坚实的科学基础。与公共卫生相关：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广泛努力开发一种植入体内的胰岛素泵，以提供调节的胰岛素腹膜给药；然而，到目前为止，由于泵与胰岛素聚集相关的泵堵塞，植入泵仍处于实验阶段。这项应用的目的是设计一种安全有效地用于植入式泵的最佳胰岛素类似物。

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.