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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.

此修订后的应用程序响应 FOA PAS-20-160“针对以下疾病的临床试验的小型 R-01”： NIDDK 的使命”。 1 型糖尿病 (T1D) 和 2 型糖尿病 (T2D) 最终都是由于正常细胞数量不足造成的。功能正常、能产生胰岛素的 β 细胞，但基本上每个 1 型糖尿病或 2 型糖尿病患者都有残留的 β 细胞。这个测试版细胞缺陷是胰腺和胰岛移植在糖尿病中的应用以及干细胞衍生细胞的开发的基础 β细胞替代治疗糖尿病的方法。这些方法是有效或可行的，但无法推广到全球有 4.63 亿人患有糖尿病。尽管有充分记录的β细胞数量不足，并且尽管临床上可用的糖尿病药物众多，但目前临床使用的药物尚无诱导人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，它具有高度的有效刺激人类β细胞增殖，增加体外和体内数量，增强人类 β细胞分化，并在边缘质量人类胰岛移植环境中逆转体内糖尿病。此外， GLP1 受体激动剂可显着增强 DYRK1A 抑制剂诱导的人 β 细胞增殖临床应用如艾塞那肽、利拉鲁肽、司马鲁肽、利西拉肽等。因此，人类β的再生细胞治疗糖尿病现在是可行的，现在是时候开始分析 DYRK1A 抑制剂的安全性了。在几种已知的 DYRK1A 抑制剂中，大多数是合成的，并且很少或没有临床前数据支持。在相比之下，去氢骆驼蓬碱是一种天然的植物源性分子，几个世纪以来一直以混合物的形式用于人类称为死藤水。死藤水含有许多具有生物和神经心理活性的化合物，除了去氢骆驼蓬碱外，还包括可能具有精神活性的化合物 5-,5'-二甲基色胺 (DMT)。大多数作者表明死藤水的精神活性成分是 DMT，而不是骆驼蓬碱。骆驼蓬碱 - 治疗性 β 细胞 - 小鼠再生剂量 - 在三个月的研究中没有造成任何不良影响。但是否口服尚不清楚服用纯去氢骆驼蓬碱会对人体产生不良影响，如果是的话，在什么剂量下可能会发生这些不良影响。由于去氢骆驼蓬碱在体外和体内诱导人类 β 细胞再生非常有效，因为临床前数据表明去氢骆驼蓬碱是安全的，并且由于尚不清楚死藤水对人类有慢性副作用，我们提出了一项口服纯去氢骆驼蓬碱的开放标签、第一阶段、单剂量递增研究。有一个具体目标：具体目标。使用 Pure Harmine 进行单剂量递增人体 1 期临床试验。我们的主要结果指标是确定人体中去氢骆驼蓬碱的最大耐受剂量 (MTD)。次要结果指标包括确定去氢骆驼蓬碱对人类的不利影响（如果存在），并产生后续对人类糖尿病患者进行研究的试点数据。