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

描述（由申请人提供）：阿尔茨海默病（AD）是最常见的神经退行性疾病，仅在美国就有500万人受到折磨。这份U基金申请 将支持导致向FDA提交研究性新药（IND）申请的研究，用于AD中的脑源性神经营养因子（BDNF）基因递送。我们已经在小鼠、大鼠和非人类灵长类动物中完成了概念验证研究，证明BDNF可防止内嗅皮质神经元细胞丢失，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。这些影响延伸到海马体，从而治疗大脑的关键记忆回路。重要的是，这种方法为目前正在开发的淀粉样蛋白修饰疗法提供了一种急需的替代方案，如果两者都被证明部分有效，则为联合疗法提供了未来的可能性。我们提出BDNF的基因递送，因为需要将这种蛋白质直接施用到大脑中并随着时间的推移维持其递送。拟议 根据工作计划，我们将在GMP设施中生产表达人BDNF的腺相关病毒血清型2（AAV 2）载体，然后使用这种临床级材料在两个物种（大鼠和灵长类动物）中进行IND研究。此外，我们还将利用实时MR引导成像技术，将AAV 2-BDNF准确定位和递送到灵长类动物的内嗅皮层。目的1：生产AAV 2-BDNF用于IND使能安全性/毒性/给药研究。目的2：使用对流增强递送和实时MR引导优化AAV 2-BDNF基因递送至非人灵长类动物的内嗅皮层。目的3：啮齿类动物和非人灵长类动物的安全性/毒性/给药/生物分布研究。目标4：起草并提交IND申请。相关性：这项工作的成功完成将导致一种新方法的临床转化，以防止细胞丢失并刺激常见，严重和致残性神经退行性疾病的神经功能。

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.