Improved Intrathecal BDNF Gene Therapy for Alzheimer's Disease

摘要 脑源性神经营养因子（BDNF）是一种神经系统生长因子， 增强突触可塑性并调节神经元功能。BDNF基因治疗 阿尔茨海默病（AD）是淀粉样蛋白和tau蛋白靶向治疗的一种有前途的替代方案。 治疗：BDNF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。直接注射腺病毒- 相关病毒（AAV）载体进入内嗅皮层介导安全和持久 BDNF的表达，并将很快开始人体临床试验。虽然前景看好， 脑实质内AAV-BDNF注射是侵入性的， 大脑皮层的一部分。将AAV 9-BDNF鞘内施用至脑脊髓 液体可以解决这些问题，从一个单一的广泛治疗整个皮层， 微创输液我们最近报道了两个小时的特伦德伦堡 体位，身体仰卧在斜躺床上，头部呈30° 在脚下，大大增加了基因转移的强度和一致性， 在大鼠中鞘内AAV 9输注后，95%以上 皮层中的转导细胞是神经元，并且脱靶脑中的基因表达 区域和脊髓是最小的。这种新的交付方法具有很强的潜力 用于AD的临床治疗。 我们建议对鞘内AAV 9-BDNF基因治疗进行系统的临床前试验， 对于AD。目的1将通过直接比较鞘内注射和 在AD的转基因小鼠模型中的实质内AAV 9-BDNF输注和 分析行为和解剖结果。目标2将测试 递增剂量和延长治疗的鞘内AAV 9-BDNF输注 在非人类灵长类动物中。目的3将增强鞘内注射的特异性 AAV 9-BDNF疗法通过测试细胞特异性启动子以减少或消除脱- 靶基因表达。这些研究旨在简化交付，提高疗效， 增加BDNF基因治疗AD临床可行性，并将支持 即将进行的临床试验和临床前开发的新的基因治疗AD。

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.