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

描述(申请人提供)：胰岛素输送的闭环系统--包括胰岛素泵、连续血糖监测仪和基于反馈的控制算法--提供了一种前景看好的技术，能够在改善患者便利性和依从性的情况下，对1型糖尿病患者进行严格的血糖控制。这种耦合设备(也称为“人工胰腺”)的安全性和有效性将通过开发新的胰岛素类似物配方而得到提高，这种配方将结合快速吸收和迅速“关闭”胰岛素信号。虽然目前正在研究多种加速吸收的技术(基于药代动力学的方法；PK)，但尚不清楚如何缩短胰岛素信号的内在细胞持续时间，一旦在靶组织中形成了有效的激素-受体复合体(基于药效学的方法；PD)。因为闭环系统中的一个关键挑战是从瞬时过量交付事件中恢复。理想的胰岛素泵应结合快速的PK和缩短的PD。我们发明了一种双PK-PD优化的胰岛素类似物配方，灵感来自于最近对胰岛素与胰岛素受体(IR)结合的分子基础的结构洞察。一个由学术调查人员组成的国际团队，共同领导 凯斯西储大学医学院M.A.Weiss的实验室已经定义了胰岛素如何与其IR胞外区域中的主要结合位点(指定的位点1)结合(《自然》杂志2013年出版)。在1型糖尿病啮齿动物模型(链脲佐菌素治疗的SpragueDawley大鼠)中，结合辅助位点2的生化探针的阐明使新型胰岛素类似物的设计具有缩短的PD持续时间。Dual Site 1/Site 2联合优化为胰岛素类似物设计提供了创新范例。我们的产品被命名为Tryptolog，作为一个基本元素是用色氨酸取代亮氨酸A13位(胰岛素与2位相邻的胰岛素背面的非保守残基)。我们假设，这种较大的芳香族残基缩短了激素触发的IR胞外结构域与其细胞内酪氨酸激酶结构域之间的分子通信，进而缩短了胰岛素信号。在此PHAE 1 SBIR应用中，我们寻求以下支持：(I)通过联合修饰第1位点A8和B24来进一步优化和表征Tryptolog产品，以及(Ii)在猪模型中对它们进行比较验证，该猪模型更接近于人类患者，而不是Spraogue-Dawley大鼠。猪的研究将在Legacy Health Systems(波特兰，或俄勒冈州)由W.K.Ward博士进行，他是闭环系统专家和经验丰富的猪调查员。

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.