A dual-acting small molecule for the treatment of type 1 diabetes

项目总结： 超过150万美国人患有1型糖尿病(T1D)，这是一种与胰岛素有关的自身免疫性疾病， 对血糖调节和整体能量代谢至关重要的激素。当第一次被诊断为 使用T1D，估计患者的胰岛素已经减少了70%-90%。在这一点上，免疫力 系统已经瞄准并摧毁了在胰岛中发现的绝大多数产生胰岛素的β细胞 胰腺内的朗格汉斯。这种破坏在很大程度上是通过一连串的促炎 细胞因子触发细胞死亡。自发现以来的一个世纪里，没有其他实质性的治疗方法 除了胰岛素治疗外，治疗T1D的研究也取得了进展。然而，最近的进展集中在 关于β细胞健康的研究已经导致了几项临床试验。Aake Biotech，与调查人员合作 俄亥俄大学正在开发一种小分子疗法，它可能能够在两个重要的方面治疗T1D 方式。在培养皿中对啮齿动物和人胰岛进行的测试中，我们的先导化合物MSB-3保护了β细胞 从细胞因子诱导的细胞死亡，也刺激这些细胞产生和分泌更多的胰岛素 耗尽了胰岛素储备。在我们的第一阶段资助中，我们收集了非肥胖糖尿病(NOD)小鼠的数据，一只小鼠 T1D模型显示，从12周龄开始每天服用MSB-3完全阻止了 血糖和胰岛素炎减少(自身免疫力降低的迹象)，而60%天真的对照组小鼠 开发了T1D。此外，在已经患有糖尿病(血糖300 mg/dL)的NOD小鼠中，每天服用MSB-3 治疗稳定了血糖，甚至似乎在没有其他治疗方法的情况下完全逆转了疾病。 在审判过程中的任何时候。尽管在疾病治疗方面有这些有希望的效果，但我们不确定如何 MSB-3工作正常。在这项提案的目标1中，Asake与一位领先的小型- 分子靶标鉴定利用光亲和层析等技术鉴定蛋白质 我们先导化合物的目标(S)。这些数据将被用于更好地为药物的化合物开发提供信息 并评估新化合物对胰岛素分泌和β细胞保护的影响。晋级 产品开发，我们还将测试几种给药途径，包括一种新的长效 目的2皮下给药，并测定目的3的药代动力学和药效学。 临床应用，目标4将确定MSB-3是否可以作为一种添加剂来提高疗效 人类胰岛移植程序。如果成功，这些研究将极大地帮助开发 治疗T1D的潜在新产品。

Project Summary: Over 1.5 million Americans suffer from type 1 diabetes (T1D), an autoimmune disorder involving insulin, a hormone that is essential for blood glucose regulation and overall energy metabolism. When first diagnosed with T1D, it is estimated that the patient’s insulin has been reduced by 70-90%. By this point, the immune system has already targeted and destroyed a vast majority of insulin-producing beta cells found in islets of Langerhans within the pancreas. This destruction occurs, in large part, through a barrage of pro-inflammatory cytokines triggering cell death. For a century since its discovery, no other substantial therapeutic advancements have occurred outside of insulin therapy to treat T1D. However, recent advancements focused on beta-cell health have resulted in several clinical trials. ASAKE Biotech, in collaboration with investigators at Ohio University, is developing a small-molecule therapeutic that may be able to treat T1D in two important ways. In tests of rodent and human pancreatic islets in a dish, our lead compound MSB-3 protected beta-cells from cytokine-induced cell death and also stimulated these cells to produce and secrete more insulin without depleting insulin reserves. In our phase 1 grant, we collected data in non-obese diabetic (NOD) mice, a mouse model of T1D, to show that giving MSB-3 daily beginning at 12-weeks of age completely blocked any rise in blood glucose and reduced insulitis (a sign of reduced autoimmunity), whereas 60% of naïve control mice developed T1D. Moreover, In NOD mice that already had diabetes (blood glucose >300 mg/dL), daily MSB-3 treatment stabilized blood glucose and even appeared to reverse the disease entirely with no other therapy given at any point in the trial. Despite these promising effects in disease treatment, we are not certain how MSB-3 works. In Aim 1 of this proposal, ASAKE has partnered with one of the leading experts in small- molecule target identification to use photoaffinity chromatography and other techniques to identify the protein target(s) of our lead compound. These data will be used to better inform compound development by medicinal chemistry and to assess effects of new compounds on insulin secretion and beta-cell protection. To advance product development, we will also test several routes of administration including a novel long-acting subcutaneous pellet in Aim 2 and determine pharmacokinetics and pharmacodynamics in Aim 3. As a possible clinical application, Aim 4 will determine whether MSB-3 could be a used as an additive to improve the efficacy of human islet transplantation procedures. If successful, these studies will greatly aid the development of a potential novel product to treat T1D.