Improved Intrathecal BDNF Gene Therapy for Alzheimer's Disease

改进的鞘内 BDNF 基因疗法治疗阿尔茨海默病

• 批准号: 10581553
• 负责人: Michael Castle
• 金额: $ 39.44万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10581553
• 关键词: Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease therapy; Amyloid; Amyloid deposition; Anatomy; Antibody Response; Behavioral; Brain; Brain region; Brain-Derived Neurotrophic Factor; Cells; Cellular biology; Cerebral cortex; Cerebrospinal Fluid; Clinical; Clinical Treatment; Clinical Trials; Dependovirus; Disease model; Doctor of Medicine; Doctor of Philosophy; Dose; Gene Expression; Gene Transduction Agent; Gene Transfer; Gliosis; Growth Factor; Head; Hippocampus; Hour; Human; Immune response; Infusion procedures; Injections; Intravenous; Learning; Macaca mulatta; Mediating; Memory; Methods; Molecular Biology; Mus; Nerve Degeneration; Nervous System; Neuroglia; Neurons; Outcome; Pathologic; Patients; Peripheral; Pre-Clinical Model; Preclinical Testing; Principal Investigator; Production; Qualifying; Rattus; Reporting; Rodent; Rodent Diseases; Safety; Serotyping; Serum; Specificity; Spinal Cord; Supination; Synapses; Synaptic plasticity; Testing; Tissues; Transgenic Mice; Treatment Efficacy; Trendelenburg Position; Validation; adeno-associated viral vector; cellular transduction; clinical translation; cognitive function; design; enhancing factor; entorhinal cortex; experience; experimental study; foot; gene therapy; gene therapy clinical trial; improved; minimally invasive; nervous system disorder; neuron loss; neuroprotection; next generation; nonhuman primate; novel; novel strategies; pre-clinical; preclinical development; preservation; prevent; promoter; safety testing; side effect; targeted treatment; tau Proteins; therapeutic evaluation; translational potential; treatment duration; treatment effect

Abstract Brain-derived neurotrophic factor (BDNF) is a nervous system growth factor that enhances synaptic plasticity and regulates neuronal function. BDNF gene therapy for Alzheimer’s disease (AD) is a promising alternative to amyloid- and tau-targeted therapies: BDNF reduces neuronal degeneration and stimulates neuronal activity in rodent and non-human primate models of AD. Direct injection of an Adeno- Associated Virus (AAV) vector into entorhinal cortex mediates safe and long-lasting BDNF expression, and will soon begin human clinical trials. Although promising, intraparenchymal AAV-BDNF injection is invasive and treats only a small percentage of the cerebral cortex. Intrathecal administration of AAV9-BDNF to the cerebrospinal fluid could solve these problems by broadly treating the entire cortex from a single minimally invasive infusion. We recently reported that two hours of Trendelenburg positioning, in which the body lies supine on a reclining table with the head 30° below the feet, dramatically increases the strength and consistency of gene transfer to cerebral cortex after intrathecal AAV9 infusion in rats. More than 95% of transduced cells in cortex are neurons, and gene expression in off-target brain regions and spinal cord is minimal. This novel delivery method has strong potential for clinical treatment of AD. We propose systematic preclinical testing of intrathecal AAV9-BDNF gene therapy for AD. Aim 1 will test therapeutic efficacy by directly comparing intrathecal and intraparenchymal AAV9-BDNF infusion in a transgenic mouse model of AD and analyzing behavioral and anatomical outcomes. Aim 2 will test the safety of intrathecal AAV9-BDNF infusion at escalating doses and over prolonged treatment periods in the non-human primate. Aim 3 will enhance the specificity of intrathecal AAV9-BDNF therapy by testing cell-specific promoters to reduce or eliminate off- target gene expression. These studies aim to simplify delivery, enhance efficacy, and increase clinical feasibility of BDNF gene therapy for AD, and will support both upcoming clinical trials and preclinical development of new gene therapies for AD.

摘要 脑源性神经营养因子(BDNF)是一种神经系统生长因子 增强突触可塑性，调节神经元功能。脑源性神经营养因子的基因治疗 阿尔茨海默病(AD)是淀粉样蛋白和tau靶向治疗的一种有前途的替代方法 治疗方法：脑源性神经营养因子减少神经元变性并刺激神经元活动 AD的啮齿动物和非人灵长类动物模型。直接注射腺体- 内嗅皮质相关病毒载体介导的安全和持久 BDNF的表达，并将很快开始人体临床试验。尽管前景看好， 实质内注射AAV-BDNF是侵入性的，只能治疗一小部分 大脑皮层的。脑脊液鞘内注射AAV9-BDNF 液体可以解决这些问题，方法是从一个单一的 微创输液。我们最近报道，特伦德伦堡的两个小时 体位，身体仰卧在倾斜的桌子上，头部30° 脚下，极大地增加了基因转移的强度和一致性 鞘内注射AAV9对大脑皮层的影响。超过95%的 皮层中的转导细胞是神经元，基因在非靶向脑中的表达 区域和脊髓最小。这种新的递送方式具有很强的潜力 用于临床治疗阿尔茨海默病。 我们建议对鞘内AAV9-BDNF基因治疗进行系统的临床前试验 对于AD。AIM 1将通过直接比较鞘内和鞘内来测试治疗效果 脑实质内注射AAV9-BDNF治疗AD转基因小鼠模型 分析行为和解剖学结果。目标2将测试 AAV9-BDNF鞘内注射剂量递增和治疗时间延长 在非人类灵长类动物中的经期。目标3将增强鞘内注射的特异性 AAV9-BDNF治疗通过检测细胞特异性启动子来减少或消除Off- 靶基因表达。这些研究旨在简化交付，提高疗效，以及 增加脑源性神经营养因子基因治疗阿尔茨海默病的临床可行性，并将支持两者 阿尔茨海默病新基因疗法即将进行的临床试验和临床前开发。