Enabling implantable artificial pancreas pumps with heat-stable, ultra-rapid insulin

使用热稳定、超快速胰岛素实现植入式人工胰腺泵

• 批准号: 9185181
• 负责人: Bruce Hill Frank
• 金额: $ 7.65万
• 依托单位: THERMALIN DIABETES, LLC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-19 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9185181
• 关键词: Adoption; Agitation; Algorithms; Amyloid; Anabolism; Artificial Pancreas; Binding Sites; Biological; Blood Glucose; Body Temperature; Budgets; Catheters; Cell Culture Techniques; Cell Line; Chemicals; Clinical Trials; Deltastab; Deposition; Development; Devices; Diabetes Mellitus; Dose; Drug Kinetics; Economics; Engineering; Excipients; Family; Family suidae; Feedback; Fermentation; Fibronectins; Formulation; Glucose; Goals; Growth; Heating; Hepatic; Human; Implant; Implantable Pump; Inflammatory; Injection of therapeutic agent; Insulin; Insulin Infusion Systems; Insulin Receptor; Insulin, Lispro, Human; Insulin-Dependent Diabetes Mellitus; Intravenous Bolus; Lead; Left; Licensing; Life; Link; Mammalian Cell; Marketing; Methods; Microfluidics; Modeling; Modification; Molecular Models; National Institute of Diabetes and Digestive and Kidney Diseases; Non-Insulin-Dependent Diabetes Mellitus; Patients; Pharmacodynamics; Pharmacologic Substance; Pharmacy facility; Phase; Pichia; Positioning Attribute; Predisposition; Preparation; Principal Investigator; Process; Production; Proteins; Pump; Rattus; Refractory; Regulation; Research; Safety; Sampling; Serum; Signal Transduction; Site; Small Business Innovation Research Grant; Solubility; Streptozocin; Structure; Surface; System; Technology; Temperature; Testing; TimeLine; Tissues; Tromethamine; Variant; Work; Yeasts; Zinc; absorption; analog; base; career; cell bank; chemical stability; cost; design; diabetic rat; flexibility; glucose monitor; glycemic control; improved; in vivo; innovation; intraperitoneal; molecular modeling; neoplastic cell; non-diabetic; pre-clinical; prevent; programs; receptor; receptor binding; response; self assembly; subcutaneous

Project Summary We seek to develop an ultra-stable ultra-fast insulin analog formulation for use in advanced “smart” pumps in the treatment of diabetes mellitus. A commercially available insulin formulation that is stable at body temperature for at least 180 days and at room temperature for a year would respectively make practical (a) implantable intraperitoneal closed-loop pumps for the treatment of T1DM/T2DM and (b) pre-filled patch pumps for the treatment of T2DM. The economics of the latter market makes practical the development of a critical enabling technology for an implanted artificial pancreas (“AP”) device linked to a continuous glucose monitor. Ultra-fast pharmacokinetic/dynamic (PK/PD) promises to improve the safety and efficacy of the feedback algorithms employed in such closed-loop systems. The current barrier to the development of more stable insulin formulations is the temperature-dependent susceptibility of insulin to undergo fibrillation; such physical degradation leads to a pro-inflammatory amyloid. At body temperature fibrils can form in commercial insulin formulations in as little as one week on gentle agitation (as in a pump reservoir). Once fibrillation begins, a seeded nucleation-growth process promotes the rapid conversion of the native insulin molecules into amyloid; activity declines exponentially, making dosing inaccurate and leaving deposits that lead to catheter occlusion. To overcome this barrier, an innovative structural approach is proposed based on a single-chain insulin (SCI) platform that is fully potent and yet refractory to fibrillation and chemical degradation. Design of this platform is based on (i) recent crystallographic studies of how insulin interacts with its primary binding site in the insulin receptor (“Site 1”) and (ii) molecular models of insulin fibrils. In particular, we have discovered that a properly constructed 6-8 residue linker between the C-terminus of the B chain (ThrB30) and N-terminus of the A chain (GlyA1) can prevent fibril formation for >1 year on gentle agitation at 37 oC while preserving native biological activity. Such an SCI is stable both in a zinc-free monomeric formulation and in a zinc-based hexameric formulation, thus providing marked flexibility in choice of excipients for the simultaneous optimization of stability and rate of absorption (fast-ON). We will extend such optimization to engineer fast- OFF pharmacodynamics (PD) through modification of insulin’s ancillary receptor-binding surface, cognate to Site 2 in the fibronectin-homology domains of the receptor -subunit. An ultra-stable fast-ON/fast-OFF SCI formulation would provide a major advance in AP technology. We therefore propose to synthesize and characterize five such SCIs as candidate formulations. Dr. B.H. Frank (principal investigator) was co-inventor of Humalog during his prior career at Eli Lilly. Thermalin Diabetes, LLC has an exclusive license to SCI-related IP, which is owned by CWRU.

项目概要 我们寻求开发一种超稳定、超快速的胰岛素类似物配方，用于先进的“智能”泵 一种在体内稳定的市售胰岛素制剂。 温度下至少 180 天和室温下一年分别可行 (a) 用于治疗 T1DM/T2DM 的植入式腹腔内闭环泵和 (b) 预填充补片 治疗 T2DM 的泵 后一个市场的经济性使得开发一种实用的泵变得可行。 与连续血糖相关的植入式人工胰腺（“AP”）装置的关键使能技术 超快速药代动力学/动力学（PK/PD）有望提高药物的安全性和有效性。 此类闭环系统中采用的反馈算法。 目前开发更稳定的胰岛素制剂的障碍是温度依赖性 胰岛素对纤维颤动的敏感性；这种物理降解导致促炎淀粉样蛋白。 在体温下，商业胰岛素制剂中的原纤维可以在温和的情况下在短短一周内形成 搅动（如在泵储器中）一旦纤维化开始，种子成核生长过程就会促进纤维化。 天然胰岛素分子快速转化为淀粉样蛋白，活性呈指数下降，使得给药剂量增加； 不准确并留下沉积物，导致导管堵塞。 为了克服这一障碍，提出了一种基于单链胰岛素的创新结构方法 (SCI) 平台，功能强大且不易发生纤维颤动和化学降解。 平台基于 (i) 最近对胰岛素如何与其主要结合位点相互作用的晶体学研究 胰岛素受体（“位点 1”）和 (ii) 胰岛素原纤维的分子模型 特别是，我们发现了一个。 在 B 链 (ThrB30) 的 C 末端和 A 链的 N 末端之间正确构建 6-8 个残基接头 链 (GlyA1) 在 37 oC 温和搅拌下可防止原纤维形成超过 1 年，同时保留天然状态 这种 SCI 在无锌单体制剂和锌基制剂中都是稳定的。 六聚体配方，从而为同时进行的赋形剂选择提供了显着的灵活性 稳定性和吸收率的优化（fast-ON）我们将把这种优化扩展到工程fast-ON。 通过修饰胰岛素的辅助受体结合表面来实现 OFF 药效学 (PD)，同源 受体 α 亚基纤连蛋白同源域中的位点 2。 超稳定的快速开启/快速关闭 SCI 配方将为 AP 技术带来重大进步。 因此，建议合成并表征 5 个此类 SCI 作为候选配方。 （首席研究员）在礼来公司 (Eli Lilly) 的职业生涯中是 Humalog 的共同发明者， LLC 拥有 SCI 相关 IP 的独家许可，该 IP 归 CWRU 所有。