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

一种治疗 1 型糖尿病的双重作用小分子

• 批准号: 10699206
• 负责人: Craig S Nunemaker
• 金额: $ 60.92万
• 依托单位: ASAKE BIOTECHNOLOGY, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10699206
• 关键词: Age; Alberta province; American; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Beta Cell; Biotechnology; Blood; Blood Glucose; Cell Death; Cell Death Induction; Cells; Cessation of life; Chromatography; Clinical; Clinical Trials; Collaborations; Cytoprotection; Data; Development; Diabetes Mellitus; Diabetic mouse; Diagnosis; Disease; Disease Progression; Drug Kinetics; Energy Metabolism; Excretory function; Food; Glucose; Goals; Grant; Health; Hormones; Human; Hypoglycemia; Immune; Immune system; Immunologic Markers; Implant; In Vitro; Inbred NOD Mice; Incubated; Indiana; Inflammatory; Insulin; Insulin-Dependent Diabetes Mellitus; Interferon Type II; Intramuscular; Intraperitoneal Injections; Islets of Langerhans; Islets of Langerhans Transplantation; Laboratories; Lead; Measurement; Mediating; Metabolism; Mus; Non-Insulin-Dependent Diabetes Mellitus; Ohio; Oral; Pancreas; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Pharmacology Study; Phase; Population; Procedures; Proteins; Research Personnel; Residual state; Risk Reduction; Rodent; Route; Series; Signal Transduction; Small Business Technology Transfer Research; Stat5 protein; Structure of beta Cell of islet; TNF gene; Tail; Techniques; Testing; Therapeutic; Time; Transplantation; Universities; Validation; Veins; Work; absorption; analog; blood glucose regulation; clinical application; cytokine; diabetes mellitus therapy; drinking water; effective therapy; exhaustion; improved; improved outcome; inhibitor; insulin secretion; insulitis; islet; liquid chromatography mass spectrometry; mouse model; novel; pharmacokinetics and pharmacodynamics; prevent; product development; small molecule; small molecule therapeutics; subcutaneous

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.

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