Novel Design of a Fast-On/Fast-Off Insulin Analog for Closed-Loop Systems

用于闭环系统的快速启动/快速关闭胰岛素模拟物的新颖设计

• 批准号: 8592770
• 负责人: Bruce Hill Frank
• 金额: $ 30万
• 依托单位: THERMALIN DIABETES, LLC
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8592770
• 关键词: Algorithms; Anabolism; Artificial Pancreas; Back; Beryllium; Binding; Binding Sites; Biochemical; Blood Glucose; Budgets; Buffers; Clinical; Clinical Research; Clinical Trials; Communication; Complex; Coupled; Development; Devices; Digestion; Dose; Drug Formulations; Drug Kinetics; Enzyme-Linked Immunosorbent Assay; Event; Exhibits; Family suidae; Feedback; Health system; Hormone Receptor; Hormones; Human; Hypoglycemia; Insulin; Insulin Infusion Systems; Insulin Receptor; Insulin, Lispro, Human; Insulin-Dependent Diabetes Mellitus; International; Investigation; Ions; Kinetics; Laboratories; Lead; Leucine; Life; Mediating; Modeling; Modification; Molecular; NPM1 gene; National Institute of Diabetes and Digestive and Kidney Diseases; Nature; NovoLog; Octreotide; Parents; Patients; Pharmacodynamics; Phase; Physical condensation; Pichia; Positioning Attribute; Production; Property; Proteins; Pump; Rattus; Recovery; Relative (related person); Research Personnel; Rodent Model; Safety; Sampling; Serum; Signal Transduction; Site; Small Business Innovation Research Grant; Solubility; Sprague-Dawley Rats; Streptozocin; Structure; Surface; System; Technology; Testing; Time; TimeLine; Tissues; Trypsin; Tryptophan; Tyrosine Kinase Domain; Universities; Validation; Yeasts; Zinc; absorption; analog; base; career; chemical stability; chemical synthesis; comparative; design; experience; glucose monitor; glycemic control; improved; in vivo; innovation; insight; insulin dimers; insulin signaling; medical schools; miniproinsulin; monomer; non-diabetic; novel; novel strategies; pre-clinical; programs; public health relevance; receptor binding; response; subcutaneous; ward

DESCRIPTION (provided by applicant): Close-loop systems of insulin delivery-comprising an insulin pump, continuous glucose monitor, and feedback-based control algorithm-provide a promising technology to enable tight glycemic control in Type 1 diabetes mellitus with improved patient convenience and compliance. The safety and efficacy of such coupled devices (also known as an "artificial pancreas") would be enhanced by the development of novel insulin analog formulations that coupled rapid absorption with prompt "turn off" of insulin signaling. Whereas multiple technologies are under investigation to accelerate absorption (approaches based on pharmacokinetics; PK), it is not known how to foreshorten the intrinsic cellular duration of insulin signaling once a productive hormone- receptor complex has been formed in target tissues (approaches based on pharmacodynamics; PD). Because a key challenge in closed-loop systems is recovery from transient over-delivery events. An ideal pump insulin would combine rapid PK with foreshortened PD. Our invention of a dual PK-PD optimized insulin analog formulation was inspired by recent structural insights into the molecular basis of how insulin binds to the insulin receptor (IR). An international team of academic investigators, co-led by the laboratory of M. A. Weiss at Case Western Reserve University School of Medicine, has defined how insulin binds to its primary binding site (designated Site 1) in the IR ectodomain (in press in Nature (2013)). Elucidation of Site 1 coupled with biochemical probes of ancillary Site 2 enabled design of novel insulin analogs with abbreviated PD duration in a rodent model of Type 1 diabetes (streptozotocin- treated Sprague-Dawley rats). Dual Site 1/Site 2 co-optimization provides an innovative paradigm for insulin analog design. Our product is designated Tryptolog as an essential element is substitution of leucine position A13 (a non- conserved residue on the back surface of insulin adjoining Site 2) by tryptophan. We hypothesize that this bulkier aromatic residue foreshortens molecular communication between the hormone-triggered IR ectodomain and its intracellular tyrosine-kinase domains, in turn abbreviating the insulin signal. In this Phae 1 SBIR application we seek support for (i) the further optimization and characterization of Tryptolog products by co- modification of Site 1 sites A8 and B24 and (ii) their comparative validation in a pig model more relevant to human patients than Sprague-Dawley rats. Pig studies will be conducted at Legacy Health Systems (Portland, OR) by Dr. W. K. Ward, an expert on closed-loop systems and experienced pig investigator.

描述（由申请人提供）：胰岛素递送及胰岛素泵的近环系统，连续的葡萄糖监测仪和基于反馈的控制算法提供了有前途的技术，可以在1型糖尿病中进行紧密的血糖控制，并具有改善的患者便利性和合规性。这种耦合设备（也称为“人造胰腺”）的安全性和功效将通过新型胰岛素模拟制剂的发展增强，从而增强了胰岛素信号传导的迅速吸收和迅速的“关闭”的“关闭”。尽管正在研究多种技术以加速吸收（基于药代动力学； PK），但一旦在靶靶组织中形成了生产性激素受体复合物，尚不清楚如何预测如何预测胰岛素信号传导的内在细胞持续时间（基于药物动力学的方法； PD）。因为闭环系统中的关键挑战是从瞬态过度交付事件中恢复。理想的泵浦胰岛素将快速PK与预先的PD结合使用。我们对双PK-PD优化胰岛素模拟制剂的发明是受胰岛素如何与胰岛素受体（IR）结合的分子基础的最新结构见解的启发。国际学术研究人员团队，共同领导 由Case Western Reserve University医学院的M. A. Weiss实验室定义了胰岛素如何与IR Ectodomain中的主要结合部位（指定位点1）结合（在自然界中（2013年）中）。在1型糖尿病的啮齿动物模型中，阐明位点1与辅助部位2的生化探针2启用了具有缩写的PD持续时间的新型胰岛素类似物（链蛋白酶治疗的Sprague-Dawley大鼠）。双站点1/站点2合作化为胰岛素模拟设计提供了创新的范例。我们的产物被指定为基本元素，是替代亮氨酸位置A13（通过胰岛素邻接位点2）替代亮氨酸位置A13（一种非保守的残基2）。我们假设这种较大的芳族残基预示了激素触发的IR胞外域与其细胞内酪氨酸激酶结构域之间的分子通信，而胰岛素信号则缩写。在此PHAE 1 SBIR应用中，我们寻求支持（i）通过对位点1个位点A8和B24的合作进行进一步优化和表征，以及（ii）与Sprague-Dawley大鼠更相关的PIG模型中，它们的比较验证。 Pig研究将在闭环系统和经验丰富的Pig研究者的专家W. K. Ward博士在遗产卫生系统（OR OR）上进行。