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：
10522566
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/10522566
关键词：
Address Adult Adverse effects Affect Agonist 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 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 Non-Insulin-Dependent Diabetes Mellitus Oral Outcome Measure Pancreas Pancreas Transplantation Persons Pharmaceutical Preparations Pharmacology 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 pre-clinical preclinical study primary outcome psychologic receptor regenerative cell regenerative therapy restoration secondary outcome small molecule stem cell replacement stem cells type I and type II diabetes volunteer

Address Adult Adverse effects Affect Agonist 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 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 Non-Insulin-Dependent Diabetes Mellitus Oral Outcome Measure Pancreas Pancreas Transplantation Persons Pharmaceutical Preparations Pharmacology 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 pre-clinical preclinical study primary outcome psychologic receptor regenerative cell regenerative therapy restoration secondary outcome small molecule stem cell replacement stem cells type I and type II diabetes volunteer

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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.

该修订的应用对FOA PAS-20-160“针对临床试验的小型R-01”响应 Niddk的任务”。 1型糖尿病（T1D）和2型糖尿病（T2D）最终是由于正常数量不足而导致的功能性，产生胰岛素的β细胞，但本质上，每个患有T1D或T2D的人都有残留的β细胞。这个beta 细胞不足是糖尿病中胰腺和胰岛移植的使用以及干细胞衍生的发展替代糖尿病的β细胞的方法。这些方法是有效的或可行的，但不能扩展到全球有4.63亿人患有糖尿病。尽管β单元格的缺乏率有充分，尽管大量临床上可用的糖尿病药物，目前没有诱导人β细胞的药物复制或再生。我们和其他人已经确定了一类新型的口服小分子，即dyRK1a抑制剂，它们是高度的有效刺激人β细胞增殖，体外和体内数量增加，以增强人类 β细胞分化，并在边缘质量人类胰岛移植设置中体内反向糖尿病。此外， DYRK1A抑制剂诱导的人β细胞增殖是由GLP1受体激动剂显着的临床用途，例如艾替肽，利拉格肽，semaglutide，lixisenatide等。那，人类beta的再生糖尿病中的细胞现在是可行的，可以开始分析DYRK1A抑制剂的安全。在几种已知的DYRK1A抑制剂中，大多数是合成的，几乎没有或没有临床前数据支持。在对比，一个，harmine是一种天然的植物衍生分子，在人类中已经使用了几个世纪的混合物称为Ayahuasca。 Ayahuasca包含许多生物学和神经心理活性化合物，除Harmine外，包括可能的精神活性化合物5--二甲基苯丙胺（DMT）。大多数作者表明Ayahuasca的精神活性成分是DMT，而不是Harmine。 Harmine-在治疗中β细胞 - 小鼠的再生剂量 - 在三个月的研究中没有造成不利影响。但是，未知是否口头施用的纯壁球会导致人类的不良影响，如果是这样，可能会发生这些剂量。由于Harmine在体外和体内非常有效的人类β细胞再生，因此临床前数据表明Harmine是安全的，并且由于Ayahuasca尚不在人类中具有慢性不良影响，所以我们提案一个开放标签，第1阶段，单剂量升级研究，对口服纯净harmine。有一个具体目的：具体目标。用纯Harmine进行单一剂量人类1期临床试验。我们的主要结果度量是人类Harmine的最大耐受剂量（MTD）的鉴定。次要结果措施包括定义人类在人类中的不利影响，并产生对糖尿病人类的后续研究的试验数据。