Design of an Implantable Pump Insulin

植入式胰岛素泵的设计

• 批准号: 7600456
• 负责人: MICHAEL Aaron WEISS
• 金额: $ 31.4万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7600456
• 关键词: Adhesives; Affinity; Agitation; Air; Animals; Arizona; Artificial Endocrine Pancreas; Binding; Biochemistry; Biological; Biological Assay; Biophysics; Blood Glucose; C-Peptide; Cardiovascular system; Cell Culture Techniques; Cell Nucleus; Chemicals; Chimera organism; Classification; Clinical; Clinical Investigator; Clinical Trials; Collaborations; Cystine; Data; Development; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Neuropathies; Dimerization; Disease; Doctor of Medicine; Drug Formulations; Drug Kinetics; Electron Microscopy; Employee Strikes; Epidemiology; Event; Exhibits; FDA approved; Family suidae; Figs - dietary; Fluorescence Spectroscopy; Foundations; Future; Glass; Glycerol; Goals; Greater sac of peritoneum; Hepatic; Human; Hypoglycemia; Implant; Implantable Pump; In Vitro; Incidence; Inflammation; Injection of therapeutic agent; Insulin; Insulin Infusion Systems; Insulin Receptor; Insulin-Dependent Diabetes Mellitus; Insulin-Like Growth Factor I; Insulin-Like Growth Factor Receptor; Insulin-Like-Growth Factor I Receptor; Intervention; Isotopes; Kidney Diseases; Kidney Failure; Knowledge; Label; Length; Letters; Liquid substance; Maintenance; Mechanics; Mediating; Microscopy; Modeling; Molecular; NMR Spectroscopy; Non-Insulin-Dependent Diabetes Mellitus; Obstruction; Oranges; Outcome; Patients; Peritoneal; Phenols; Physiological; Play; Preparation; Problem Solving; Proinsulin; Property; Protein Engineering; Proteins; Pump; Rattus; Recipe; Refractory; Relative (related person); Replacement Therapy; Research; Resistance; Resolution; Retinal Diseases; Risk; Safety; Series; Site; Solid; Solutions; Solvents; Structure; Study Section; Surface; System; Technology; Testing; Time; Translations; United Kingdom; Universities; Wound Healing; X-Ray Crystallography; Zinc; absorption; amyloid formation; amyloidogenesis; analog; base; blood glucose regulation; chemical synthesis; crosslink; design; diabetes control; follow-up; frontier; globular protein; glycemic control; in vitro Assay; in vivo; innovation; interest; meetings; miniproinsulin; monomer; novel; novel strategies; polypeptide; prevent; prospective; protein aggregation; protein aminoacid sequence; protein misfolding; protein structure; psychologic; public health relevance; receptor binding; small molecule; solid state nuclear magnetic resonance; success; surfactant; therapeutic protein; trend

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.

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) 以及后续糖尿病干预和并发症流行病学研究 (DCCT/EDIC)，已经在 1 型糖尿病中记录了严格血糖控制在降低风险和延迟糖尿病发生方面的益处。长期心血管和微血管并发症的进展，包括糖尿病神经病变、视网膜病变和肾脏疾病。在 2 型糖尿病中也观察到类似的趋势。这些数据促使人们广泛努力开发用于调节腹膜输送的植入式胰岛素泵。然而，迄今为止，由于与胰岛素颤动相关的泵阻塞问题，植入式泵仍处于实验阶段。该应用的目的是设计最佳的胰岛素类似物和胰岛素制剂，以便在植入式泵中安全有效地使用。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。尽管植入式胰岛素泵具有许多理论优势和有希望的临床试验，但目前尚未获得 FDA 批准。一个主要问题是现有胰岛素制剂在腹膜腔内37℃的泵储存器内储存1-3个月时稳定性有限。这种不稳定性会导致异常的蛋白质聚集，这通常会由于泵的部分或完全阻塞而损害胰岛素的输送。使用速效胰岛素类似物（HumalogTM（礼来）和 NovalogTM（诺和诺德））时，这个问题更加严重，其良好的药代动力学特性为外部胰岛素泵的使用提供了显着的优势。用于植入系统的完美泵胰岛素应将快速药代动力学与高蛋白质浓度下的长期稳定性结合起来，存储在泵储存器中并在 37 oC 下轻轻搅拌。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：开发新型管道材料或小分子表面活性剂以添加到胰岛素溶液中。尽管取得了一些进展，但临床成功仍难以实现。我们基于异常胰岛素聚集和纤维颤动的拓扑要求，提出了一种设计胰岛素类似物的新方法。基本思想基于我们最近对胰岛素原和胰岛素纤维颤动机制的基础研究（Huang, K. et al. J. Biol. Chem. 280, 42345-55 (2005) 和 Huang, K. et al. 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具有深远的影响，包括在 37°C 下发生的表面诱导的纤维颤动（如泵堵塞时发生的情况）。我们建议利用这些观察结果来设计最佳的泵胰岛素，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的同时消除颤动。设计原理将通过一系列功能测定和分子研究得到验证，为临床转化提供坚实的科学基础。公众健康相关性：胰岛素替代疗法治疗糖尿病的核心目标是血糖控制，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广泛努力开发植入体内的胰岛素泵，以提供胰岛素的调节腹膜输送；然而，迄今为止，由于与胰岛素聚集相关的泵堵塞，植入式泵仍处于试验阶段。该应用的目的是设计一种最佳的胰岛素类似物，以便在植入式泵中安全有效地使用。