Small Molecule Drug Therapy for Parkinson's Disease

描述（由申请人提供）：在美国，每年治疗帕金森病的总费用约为250亿美元。对于神经元和运动功能衰弱的患者，迫切需要一种有效的治疗方法，但尚未得到满足。神经再生疗法的发展是一个重要的目标，因为全世界每年有数百万人因神经退行性疾病而致残和死亡，但目前还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，激发了人们对开发新方法的兴趣，这些新方法可以增强人体从内源性干细胞中产生健康新细胞的自然能力。最近，我们偶然发现一种小分子杂环嘧啶衍生物可以加速培养的人神经干细胞的生长。随后对啮齿动物的初步分析表明，该分子还能加速老年大脑的神经发生，改善多巴胺能损伤小鼠（帕金森病模型）的运动功能，显然没有任何副作用。基于这些初步的观察，我们假设给药杂环嘧啶衍生物会刺激新的脑细胞形成，从而改善运动功能。为了验证这一概念，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有可能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，使用免疫组织学分析、Western blot和行为测试。实验完成后，我们期望在不产生明显有害影响的情况下，证实在帕金森病动物模型中使用杂环嘧啶衍生物促进与神经发生相关的运动功能的剂量依赖性改善的可行性。在II期，我们将在非人类灵长类动物Perkinson病模型中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启用研究做准备。这个项目是创新的，因为我们的测试化合物为神经退行性疾病患者诱导新的脑细胞生长提供了一种新方法。公共卫生相关性：我们建议测试一种新的小分子候选药物，它可以增强人体从内源性干细胞中再生脑细胞的自然能力。如果成功，我们的候选药物将为帕金森病、阿尔茨海默病和肌萎缩侧索硬化症等神经退行性疾病患者提供新的治疗选择。

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.