Small Molecule Drug Therapy for Parkinson's Disease

帕金森病的小分子药物治疗

基本信息

批准号：
7481709
负责人：
KIMINOBU SUGAYA
金额：
$ 28.25万
依托单位：
NEOCYTEX BIOPHARMA, INC.
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2009-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7481709
关键词：
Abnormal Cell Acute Adult Adverse effects Affect Age Aging Alzheimer&apos s Disease American Amyotrophic Lateral Sclerosis Animal Model Animals Behavioral Biological Assay Brain Brain Stem Bromodeoxyuridine Caring Cell Count Cell Nucleus Cell Proliferation Cell Transplantation Cells Cellular biology Cercopithecus pygerythrus Chemistry Chronic Clinical Clinical Trials Corpus striatum structure Daily Data Deep Brain Stimulation Defect Development Diagnosis Diathermy Disease Disease model Dopamine Dopaminergic Cell Dose Drug Formulations Drug Industry Drug Monitoring Electrodes Employee Strikes Equilibrium Exploratory Behavior Forelimb Funding Globus Pallidus Goals Grant Growth Healed Human Hyperactive behavior Impaired cognition Implanted Electrodes Injection of therapeutic agent Injury Involuntary Movements Lead Lesion Licensing MPTP Poisoning Macaca mulatta Magnetic Resonance Imaging Maleates Marketing Measurable Measures Medicine Methods Microscopy Modeling Monitor Morphology Motor Motor Activity Motor Neurons Mus Muscle Rigidity Natural regeneration Nerve Tissue Nervous system structure Neurodegenerative Disorders Neurons Neurophysiology - biologic function Operative Surgical Procedures Other Resources Parkinson Disease Pathology Patients Pattern Performance Persons Pharmaceutical Preparations Pharmacologic Substance Pharmacotherapy Phase Phase I Clinical Trials Placement Preparation Procedures Process Proliferating Property Public Health Pyrimidine Pyrimidines Recovery Research Risk Rodent Safety Series Small Business Technology Transfer Research Speech Speed Staging Stem cells Structure of subthalamic nucleus Substantia nigra structure Testing Therapeutic Tissues Toxic effect Tremor Tyrosine 3-Monooxygenase United States Universities Visual Week Western Blotting aged aging brain base behavior test brain cell cell growth cell type clinical application commercialization concept cost day design disabling disease dopamine transporter dopaminergic neuron experience healing improved in vivo innovation interest killings migration mouse model nerve stem cell nervous system disorder neurogenesis neuron loss neuroprotection nonhuman primate novel novel strategies professor relating to nervous system research study retinal rods small molecule success tool

项目摘要

DESCRIPTION (provided by applicant): The total cost of caring for Parkinson's disease is about $25 billion per year in the United States. There is an urgent and unmet need for an effective treatment for the patients who have suffered debilitating loss of neurons and motor function. Development of neuroregeneration therapy is an important goal because neurdegenerative diseases disable and kill millions of people worldwide each year, yet a viable therapeutic option is not available. Discovery of neural stem cells in the aging and diseased brain has sparked interest in the development of new approaches to boost the body's natural ability to create healthy new cells from endogenous stem cells. Recently, we made the serendipitous discovery that a small molecule heterocyclic pyrimidine derivative can speed up the growth of human neural stem cells grown in culture. Subsequent preliminary analysis in rodents suggested that the molecule also accelerate neurogenesis in aged brain and improve motor function in dopaminergic lesion mouse, a Parkinson's disease model, apparently without any side effects. Based on these preliminary observations, we are hypothesizing that administration of the heterocyclic pyrimidine derivative will stimulate new brain cell formation leading to improved motor function. To establish proof of concept, we are proposing to conduct a series of studies with a mouse model of Parkinson's disease. We investigate whether the heterocyclic pyrimidine derivative has a potential to protect and/or regenerate neurons by stimulating proliferation, migration and differentiation of endogenous neural stem cells using Immunohistological assays, Western blot, and behavioral tests. Upon the completion of these experiments, we expect to confirm the feasibility of using the heterocyclic pyrimidine derivative to promote dose dependent improvement in motor function associate with neurogenesis in animal model for Parkinson's disease without inducing obviously deleterious effects. In Phase II, we will conduct detailed safety, distribution, and efficacy studies on the molecule with non-human primate Perkinson's disease model, in preparation for carrying out IND enabling studies during Phase III. This project is innovative because our test compound offers a novel approach for inducing new brain cell growth in patients with neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: We are proposing to test a new small molecule drug candidate that can boost the body's natural ability to regenerate brain cells from endogenous stem cells. When successful, our drug candidate will offer a new treatment alternative for patients with neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and ALS.

描述（由申请人提供）：在美国，照顾帕金森氏病的总成本约为250亿美元。对于遭受神经元丧失和运动功能丧失的患者，需要有效治疗的紧急且未满足。神经疗法疗法的发展是一个重要的目标，因为每年神经疾病会禁用并杀死数百万人，但没有可行的治疗选择。在衰老和患病的大脑中发现神经干细胞的发现引发了人们对发展新方法的兴趣，以增强人体从内源性干细胞中创建健康的新细胞的自然能力。最近，我们提出了一个偶然的发现，即小分子杂环嘧啶衍生物可以加快在培养中生长的人类神经干细胞的生长。随后在啮齿动物中进行初步分析表明，该分子还加速了衰老的大脑的神经发生，并改善了多巴胺能病变小鼠的运动功能，多巴胺能病变小鼠是帕金森氏病模型，显然没有任何副作用。基于这些初步观察，我们假设给药杂环嘧啶衍生物将刺激新的脑细胞形成，从而改善运动功能。为了建立概念证明，我们建议通过帕金森氏病小鼠模型进行一系列研究。我们研究了杂环嘧啶衍生物是否具有通过使用免疫组织学测定，蛋白质印迹和行为测试刺激内源性神经干细胞的增殖，迁移和分化来保护和/或再生神经元的潜力。这些实验完成后，我们希望确认使用杂环嘧啶衍生物的可行性来促进帕金森氏病动物模型中与动物模型的运动功能相关的剂量依赖性改善，而不会诱导明显有害作用。在第二阶段，我们将使用非人类灵长类动物珀金森氏病模型对分子进行详细的安全性，分布和功效研究，以准备在第三阶段进行IND启用研究。该项目具有创新性，因为我们的测试化合物为诱导神经退行性疾病患者的新脑细胞生长提供了一种新颖的方法。公共卫生相关性：我们建议测试一种新的小分子候选药物，该药物可以提高人体从内源性干细胞中再生脑细胞的自然能力。成功后，我们的候选药物将为神经退行性疾病的患者（例如帕金森氏病，阿尔茨海默氏病和ALS）提供一种新的治疗方法。