Design of an Implantable Pump Insulin

描述（由申请方提供）：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型糖尿病患者严格血糖控制在降低风险和延迟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DM中观察到类似的趋势。这些数据促使人们做出了大量努力来开发用于调节腹膜输送的可植入胰岛素泵。然而，迄今为止，由于与胰岛素纤维性颤动相关的泵阻塞问题，可植入泵仍处于实验阶段。本申请的目的是设计一种最佳的胰岛素类似物和胰岛素制剂，以安全有效地用于植入式泵。所提出的设计策略，基于蛋白质结构的一般科学原理，采用单链胰岛素类似物。尽管有许多理论优势和有前途的临床试验，但植入式胰岛素泵目前尚未获得FDA批准。一个主要的问题是现有的胰岛素制剂在腹膜腔中37 ℃下在泵储液器中储存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，这经常由于泵的部分或完全阻塞而损害胰岛素输送。使用速效胰岛素类似物（HumalogTM（Lilly）和NovalogTM（Novo-Nordisk））时，该问题更加严重，其有利的药代动力学特性另外提供了用于外部胰岛素泵的显著优势。用于植入式系统的完美泵胰岛素将联合收割机快速药代动力学与在高蛋白浓度下的长期稳定性相结合，储存在37 ℃下温和搅拌的泵储液器中。由于胰岛素错误折叠和发生异常聚集的倾向似乎是其结构所固有的，因此过去的研究工作集中在替代方法上：开发新型管材或小分子表面活性剂以添加到胰岛素溶液中。虽然取得了一些进展，但临床成功一直难以捉摸。我们提出了一种新的方法来设计胰岛素类似物的基础上异常胰岛素聚集和纤维化的拓扑要求。基本思想是基于我们最近对胰岛素原和胰岛素纤维化机制的基础研究（Huang，K.等人J. Biol. Chem. 280，42345-55（2005）和Huang，K.等人Biochemistry 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，包括在37 ℃下发生在阻塞泵中的表面诱导的纤维化。我们建议利用这些观察结果来设计最佳泵胰岛素，设计出纤维性颤动，同时设计出具有高胰岛素活性和低IGF相关促有丝分裂性的快速作用。设计原则将通过一系列功能测定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，将血糖调节至接近生理水平。这种严格控制的临床重要性促使人们做出了大量努力来开发植入体内的胰岛素泵，以提供胰岛素的调节性腹膜递送;然而，迄今为止，由于与胰岛素聚集相关的泵堵塞，植入式泵仍处于实验阶段。本申请的目的是设计一种最佳胰岛素类似物，用于植入式胰岛素泵中安全有效。

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.