Design of an Implantable Pump Insulin

植入式胰岛素泵的设计

基本信息

批准号：
8003137
负责人：
MICHAEL Aaron WEISS
金额：
$ 5.69万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-15 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8003137
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 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

项目摘要

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.

描述（由申请人提供）：胰岛素替代疗法在治疗糖尿病（DM）中的核心目标是对血糖浓度的严格控制。临床试验，包括糖尿病干预和并发研究（DCCT/EDIC）的临床试验（DCCT）以及随访的流行病学（DCCT/EDIC），已在1型DM中记录了严格控制的益处，使糖尿病控制的益处在降低了长期心血管疾病的风险并延迟疾病的疾病中，包括疾病的疾病疾病，包括疾病的疾病，包括疾病的疾病，包括疾病的疾病疾病，包括疾病的疾病疾病，包括疾病的疾病疾病，包括疾病的疾病。在2型DM中观察到类似的趋势。这些数据激发了广泛的努力，以开发一种可植入的胰岛素泵来进行调节的腹膜。但是，迄今为止，由于与胰岛素纤颤相关的泵闭塞问题，可植入的泵仍保持实验性。该应用的目的是设计最佳的胰岛素类似物和胰岛素配方，以在可植入的泵中安全有效使用。根据蛋白质结构的一般科学原理，提出的设计策略采用单链胰岛素类似物。尽管具有许多理论上的优势和有前途的临床试验，但目前尚未获得FDA批准的可植入胰岛素泵。当前的胰岛素制剂的稳定性有限，在腹膜腔内37 oC中存储了1-3个月，这是一个主要的问题。这种不稳定性会导致异常的蛋白质聚集，从而经常由于泵的部分或完全阻塞而损害胰岛素的递送。使用快速作用胰岛素类似物（Humalogtm（Lilly）和Novalogtm（Novo-Nordisk）），该问题更加严重，其有利的药代动力学特性否则为外部胰岛素泵提供了显着的优势。用于植入系统的完美泵浦胰岛素将在高蛋白质浓度下将快速的药代动力学与长期稳定性相结合，并在泵储层中储存，并在37 oC中轻轻搅拌。由于胰岛素倾向于折叠和经历异常聚集的倾向似乎对其结构进行了内在的固有，因此过去的研究工作集中在替代方法上：新型管道材料或小分子表面活性剂的开发以添加到胰岛素溶液中。尽管已经取得了一些进展，但临床成功是难以捉摸的。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。基本思想是基于我们最近对促硫素的基础研究和胰岛素纤颤的机理（Huang，K。等人J. Biol。Chem。Chem。280，42345-55（2005）和Huang，K。等人的生物化学45，10278-93（2006（2006））。这些研究表明，连接肽对单链胰岛素类似物倾向的倾向是对异常聚集的倾向，包括在37 C时表面诱导的纤颤，如咬合泵中所发生的。我们建议利用这些观察结果来设计最佳的泵浦胰岛素，设计原纤维，而在}中进行}设计，具有高胰岛素活性和低IGF相关的有丝分裂性。设计原理将通过一系列功能测定和分子研究来验证，为临床翻译提供稳固的科学基础。