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Phase 1 Translational Diabetes Research Using The DYRK1A inhibitor, Harmine

使用 DYRK1A 抑制剂 Harmine 进行的 1 期转化糖尿病研究

基本信息

批准号：
10665783
负责人：
James Warren Murrough
金额：
$ 33.8万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10665783
关键词：
Address Adult Adverse effects Affect Agonist Agreement Autopsy Banisteriopsis Beta Cell Cause of Death Cell Count Cell Differentiation process Cell Proliferation Chronic Clinical Clinical Data Clinical Trials Consumption Data Diabetes Mellitus Disease Dose Dose Limiting Drug Kinetics End stage renal failure Enrollment Face Foundations Future GCG gene Glucose Glycosylated hemoglobin A Goals Harmine Human In Vitro Individual Infusion procedures Inhibition of Cell Proliferation Insulin Insulin-Dependent Diabetes Mellitus Islets of Langerhans Transplantation Life Maximum Tolerated Dose Mission Modeling Mus Myocardial Infarction N,N-Dimethyltryptamine National Institute of Diabetes and Digestive and Kidney Diseases Natural Products Natural regeneration Neuropsychology Non-Insulin-Dependent Diabetes Mellitus Oral Oral Administration Outcome Measure Pancreas Pancreas Transplantation Persons Pharmaceutical Preparations Pharmacotherapy Phase Phase I Clinical Trials Phosphotransferases Plants Proliferating Psychotropic Drugs Public Health Reagent Research Research Personnel Residual state Rodent Safety Stem Cell Development Stroke Structure of beta Cell of islet Therapeutic Tissues Toxic effect Transplantation Tyrosine Phosphorylation Work bench-to-bedside translation beta cell replacement cell regeneration cost diabetes mellitus therapy engineered stem cells exenatide glycemic control human data improved in vitro regeneration in vivo inhibitor inhibitor therapy islet liraglutide novel open label personalized medicine pharmacologic pre-clinical preclinical study primary outcome receptor regenerative cell regenerative therapy restoration secondary outcome small molecule stem cell replacement stem cells type I and type II diabetes volunteer

项目摘要

This revised application is responsive to FOA PAS-20-160 “Small R-01’s for Clinical Trials Targeting Diseases Within the Mission of NIDDK”. Both Type 1 diabetes (T1D) and Type 2 diabetes (T2D) ultimately result from inadequate numbers of normally functioning, insulin-producing beta cells, yet essentially everyone with T1D or T2D has residual beta cells. This beta cell deficiency underlies the use of pancreas and islet transplant in diabetes and the development of stem cell-derived approaches for beta cell replacement for diabetes. These approaches are effective or feasible, but not scalable to the 463 million people globally with diabetes. Despite the well documented deficiency in beta cell numbers, and despite a plethora of clinically-available diabetes drugs, there are no drugs in current clinical use that induce human beta cells to replicate or regenerate. We and others have identified a novel class of orally available small molecules, the DYRK1A inhibitors, that are highly effective in stimulating human beta cells to proliferate, to increase in number in vitro and in vivo, to enhance human beta cell differentiation, and to reverse diabetes in vivo in a marginal mass human islet transplant setting. In addition, the human beta cell proliferation induced by DYRK1A inhibitors is markedly potentiated by GLP1 receptor agonists in clinical use such as exenatide, liraglutide, semaglutide, lixisenatide and others. Thus, regeneration of human beta cells in diabetes is now feasible, and it is appropriate to begin to analyze the safety of DYRK1A inhibitors. Among the several known DYRK1A inhibitors, most are synthetic and are supported by little or no preclinical data. In contrast, one, harmine, is a natural, plant-derived molecule that has been used in humans for centuries in a concoction called Ayahuasca. Ayahuasca contains a number of biologically and neuro-psychologically active compounds, in addition to harmine, including the likely psychoactive compound, 5-,5’-dimethyltryptamine (DMT). Most authors suggest that the psychoactive component of Ayahuasca is DMT, and not harmine. Harmine - in therapeutic beta cell- regenerative doses in mice - caused no adverse effects in three-month studies. However, it is unknown whether orally administered pure harmine leads to adverse effects in humans, and if so at what doses these might occur. Since harmine is very effective in inducing human beta cell regeneration in vitro and in vivo, since preclinical data suggest that harmine is safe, and since Ayahuasca is not known to have chronic adverse effects in humans, we propose an open label, Phase 1, single dose escalation study of orally administered pure harmine. There is one Specific Aim: Specific Aim. To Perform A Single Rising Dose Human Phase 1 Clinical Trial with Pure Harmine. Our Primary Outcome Measure is the identification of the Maximally Tolerated Dose (MTD) of harmine in humans. Secondary outcome measures include defining the adverse effects of harmine in humans, if they exist, and generating pilot data for subsequent studies in humans with diabetes.

本修订后的申请是对FOA PAS-20-160“针对内部疾病的临床试验的小R-01”的响应