A Translational Program of BDNF Gene Delivery in Alzheimer's Disease

阿尔茨海默病 BDNF 基因传递的转化计划

• 批准号: 8927970
• 负责人: MARK H. TUSZYNSKI
• 金额: $ 23.76万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-15 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8927970
• 关键词: Adult; Advisory Committees; Alzheimer' s Disease; Amyloid; Applications Grants; Area; Biochemical; Biodistribution; Brain; Brain-Derived Neurotrophic Factor; Caring; Cells; Cessation of life; Clinic; Clinical; Clinical Trials; Collaborations; Contracts; Convection; Dependovirus; Development; Disease; Disease Progression; Dopamine; Dose; Ensure; Future; Gene Delivery; Gene therapy trial; Growth Factor; Growth Factor Gene; Health; Hippocampus (Brain); Human; Investigational Drugs; Investigational New Drug Application; Lead; Learning; Magnetic Resonance; Magnetic Resonance Imaging; Medical; Medicine; Memory; Methods; Molecular; Monkeys; Multicenter Trials; Mus; Nature; Nervous system structure; Neurodegenerative Disorders; Neurons; Neurophysiology - biologic function; Parkinson Disease; Patients; Phase; Phase I Clinical Trials; Plasmid Cloning Vector; Preparation; Primates; Proteins; Publishing; Quality of life; Rattus; Recombinants; Research; Rodent; Safety; Serotyping; Synapses; Telephone; Testing; Therapeutic; Time; TimeLine; Toxic effect; Toxicology; Transgenic Organisms; Translating; Translations; Treatment Cost; United States; United States National Institutes of Health; Vision; Work; base; brain circuitry; cognitive function; cost; effective therapy; entorhinal cortex; experience; gene replacement therapy; gene therapy; image guided; improved; lot production; manufacturing facility; neuron loss; nonhuman primate; novel strategies; prevent; programs; safety study; symposium; vector

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common neurodegenerative disorder, afflicting 5 million people in the U.S. alone. This U grant application will support studies leading to the filing of an Investigational New Drug (IND) application to the FDA for Brain-Derived Neurotrophic Factor (BDNF) gene delivery in AD. We have completed proof-of-concept studies in mice, rats and non-human primates, demonstrating that BDNF prevents entorhinal cortical neuronal cell loss, enhances synaptic markers, reverses molecular and biochemical features associated with AD, and improves learning and memory. These effects extend into the hippocampus, thereby treating key memory circuitry of the brain. Importantly, this approach provides a much-needed alternative to amyloid-modifying therapeutics currently under development, providing future possibilities for combined therapies if both prove to be partly effective. We propose gene delivery of BDNF because of the need to administer this protein directly into the brain and sustain its delivery over time. In the proposed work plan, we will manufacture adeno-associated virus serotype 2 (AAV2) vectors expressing human BDNF at a GMP facility, then use this clinical-grade material to perform IND-enabling studies in two species (rat and primates). In addition, we will generate expertise in accurately targeting and delivering AAV2-BDNF to the primate entorhinal cortex using real-time, MR-guided imaging. The following aims will be performed: Aim 1: Produce AAV2-BDNF for IND-enabling safety/toxicity/dosing studies. Aim 2: Optimize AAV2-BDNF gene delivery to the entorhinal cortex in non-human primates using convection-enhanced delivery and real-time MR guidance. Aim 3: Safety/toxicity/dosing/biodistribution studies in rodents and non-human primates. Aim 4: Draft and Submit an IND Application. Relevance: Successful completion of this work will lead to clinical translation of a new approach to prevent cell loss and stimulate neural function in a common, severe and disabling neurodegenerative disorder.

描述（由申请人提供）：阿尔茨海默氏病（AD）是最常见的神经退行性疾病，仅在美国就遭受了500万人。这个U赠款申请 将支持在AD中向FDA提出研究新药物（IND）的研究（IND）的研究。我们已经完成了在小鼠，大鼠和非人类灵长类动物的概念验证研究，表明BDNF可以防止内hin骨皮层神经元细胞损失，增强突触标记，逆转与AD相关的分子和生化特征，并改善学习和记忆。这些效果延伸到海马，从而治疗大脑的钥匙内存电路。重要的是，这种方法为目前正在开发的淀粉样蛋白改良治疗剂提供了急需的替代方法，如果两者都被证明是部分有效的，则为联合疗法提供了未来的可能性。我们提出了BDNF的基因递送，因为需要将该蛋白直接施用到大脑中并随着时间的流逝而维持其递送。在提议中 工作计划，我们将生产与GMP设施表达人BDNF的腺相关病毒血清型2（AAV2）载体，然后使用该临床级材料在两个物种（大鼠和灵长类动物）中进行辅助研究。此外，我们还将使用实时的MR引导成像来准确靶向和传递AAV2-BDNF的专业知识。将执行以下目标：AIM 1：生产AAV2-BDNF，以实现安全/毒性/给药研究。 AIM 2：使用对流增强的递送和实时MR指导，优化非人类灵长类动物的AAV2-BDNF基因递送到内嗅皮层。 AIM 3：啮齿动物和非人类灵长类动物的安全性/毒性/剂量/生物分布研究。目标4：草稿并提交IND申请。相关性：成功完成这项工作将导致一种新方法的临床翻译，以防止细胞丧失并刺激常见，严重和残疾的神经退行性疾病中的神经功能。