Small Molecule Drug Therapy for Parkinson's Disease

帕金森病的小分子药物治疗

• 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
• 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' 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

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，治疗帕金森病的总费用约为每年250亿美元。对于遭受神经元和运动功能的衰弱性丧失的患者，存在对有效治疗的迫切且未满足的需求。神经再生治疗的发展是一个重要的目标，因为神经退行性疾病每年使全球数百万人致残和死亡，但目前还没有可行的治疗选择。神经干细胞在衰老和患病大脑中的发现引发了人们对开发新方法的兴趣，以提高人体从内源性干细胞创造健康新细胞的自然能力。最近，我们偶然发现了一种小分子杂环嘧啶衍生物可以加速培养的人类神经干细胞的生长。随后对啮齿动物的初步分析表明，该分子还加速了老年大脑中的神经发生，并改善了多巴胺能损伤小鼠（帕金森病模型）的运动功能，显然没有任何副作用。基于这些初步观察，我们假设给予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。为了建立概念验证，我们建议用帕金森病的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，所述内源性神经干细胞使用免疫组织学测定、蛋白质印迹和行为测试。在完成这些实验后，我们期望确认使用杂环嘧啶衍生物在帕金森病动物模型中促进与神经发生相关的运动功能的剂量依赖性改善而不诱导明显有害作用的可行性。在II期，我们将在非人灵长类帕金森病模型上对该分子进行详细的安全性、分布和有效性研究，为III期开展IND使能研究做准备。这个项目是创新的，因为我们的测试化合物提供了一种新的方法，用于诱导神经退行性疾病患者的新脑细胞生长。公共卫生相关性：我们正在计划测试一种新的小分子候选药物，它可以增强人体从内源性干细胞再生脑细胞的自然能力。成功后，我们的候选药物将为帕金森病，阿尔茨海默病和ALS等神经退行性疾病患者提供新的治疗选择。