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

项目摘要 我们寻求开发一种超稳定的、超快速的胰岛素类似物配方，用于先进的智能泵 糖尿病的治疗。一种在人体内稳定的商业胰岛素制剂 至少180天的温度和一年的室温将分别使(A) 埋藏式腹膜腔内闭式泵治疗T1 DM/T2 DM和(B)预充补片 治疗2型糖尿病的泵。后一种市场的经济使发展一种 与持续葡萄糖相连的植入型人工胰腺(AP)设备的关键使能技术 监视器。超快药代动力学/动力学(PK/PD)有望提高阿司匹林的安全性和有效性 在这种闭环系统中使用的反馈算法。 目前开发更稳定的胰岛素制剂的障碍是温度依赖 胰岛素易发生纤颤；这种物理降解导致致炎的淀粉样蛋白。 在体温下，在温和的条件下，商业胰岛素制剂在短短一周内就可以形成纤维 搅动(如在泵储液器中)。一旦纤颤开始，种子成核-生长过程就会促进 天然胰岛素分子迅速转化为淀粉样蛋白；活性呈指数下降，使剂量 不准确，留下沉淀物，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，完全有效，但不易发生纤颤和化学降解。这个的设计 Platform是基于(I)最近关于胰岛素如何与其主要结合部位相互作用的结晶学研究。 胰岛素受体(“位点1”)和(Ii)胰岛素原纤维的分子模型。特别是，我们发现一个 在B链的C-端(ThrB30)和A的N-端之间正确构建6-8个残基接头 链(GlyA1)在37℃的温和搅拌下可以防止&gt；1年的纤维形成，同时保持天然的 生物活性。这种SCI在无锌单体配方和基于锌的配方中都是稳定的 六聚体配方，从而在选择辅料方面提供了显著的灵活性 稳定性和吸收速率的优化(快开)。我们将把这种优化扩展到FAST工程- 通过修饰胰岛素的辅助受体结合表面的药效学(PD)，同源于 在受体亚基的纤维连接蛋白同源域中的第2位。 一种超稳定的快速开启/快速关闭SCI配方将提供AP技术的重大进步。我们 因此，建议合成和表征五个这样的SCI作为候选配方。B.H.弗兰克博士 (首席研究员)在礼来公司之前的职业生涯中是Humalog的共同发明者。热敏糖尿病， 有限责任公司拥有SCI相关知识产权的独家许可证，该知识产权归CWRU所有。

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.