A Clinical Trial of AAV2-BDNF Gene Therapy in Alzheimer's Disease

项目摘要/摘要：我们建议进行BDNF的首个人体临床试验 阿尔茨海默病(AD)和轻度认知障碍(MCI)的基因治疗，旨在 减少神经元丢失，激活神经元功能。脑源性神经营养 因子)在一生中活跃地产生并在皮质回路中被利用，以维持神经元 功能和电路。在AD动物模型中，BDNF建立新的突触，阻止神经元 死亡并激活神经元；因此，BDNF提供了减缓或实际上逆转的可能性 已建立的AD和MCI患者的认知功能下降。概念验证研究已在#年进行 老鼠、老鼠和恒河猴。 因为BDNF是一种相对较大的极性蛋白质，不会穿过血脑屏障， 我们将使用实质内基因疗法将BDNF直接转移到内嗅皮层。 脑源性神经营养因子将通过神经运输进入海马体。脑源性神经营养因子将使用腺病毒载体- 相关的血清2型载体(AAV2)，现在已经在数百名患者中使用 中枢神经系统基因治疗试验。我们将利用最先进的方法进行基因传递，使用 与世界协作的实时磁共振引导和对流增强交付(CED) 俄亥俄州立大学(OSU)这项技术的领先者。 共有12名患者(6名AD和6名MCI)将从两个临床地点招募：UCSD和CASE 西部的。所有患者都将在俄亥俄州立大学接受基因输送。主要结果衡量标准将是 安全性，以及第二次认知结果测量，反映记忆特异性和 全球认知测量。将收集血清、脑脊液和成像生物标记物。如果AAV2- BDNF基因传递是安全和耐受性良好的，并显示出可能的认知益处，我们将 进入第二阶段试验。该项目的IND正在接受FDA的审查，该试验将 从FDA批准开始。将研究两个剂量组：3x1011Vg/ml和1x1012Vg/ml。 相关性：治疗AD和MCI的有效疾病修正疗法尚未确定。 脑源性神经营养因子基因治疗有可能减缓或逆转已确诊的阿尔茨海默病患者的认知功能衰退 通过建立新的突触，刺激神经元功能，减少神经元死亡。我们的 该方法也为淀粉样蛋白和tau修饰的联合治疗提供了可能性。 治疗。

Project Summary/Abstract: We propose to conduct a first-in-human clinical trial of BDNF gene therapy in Alzheimer’s Disease (AD) and Mild Cognitive Impairment (MCI), aiming to reduce neuronal loss and to activate neuronal function. BDNF (Brain-Derived Neurotrophic Factor) is actively produced and utilized in cortical circuits throughout life to sustain neuronal function and circuits. In animal models of AD, BDNF builds new synapses, prevents neuronal death and activates neurons; thus, BDNF offers the potential to slow or actually reverse cognitive decline in established AD and MCI. Proof-of-concept studies have been performed in mice, rats and rhesus monkeys. Because BDNF is a relatively large and polar protein that does not cross the blood brain barrier, we will use intraparenchymal gene therapy to deliver BDNF directly into the entorhinal cortex. BDNF will be neuronally trafficked into the hippocampus. BDNF will be delivered using adeno- associated serotype 2 vectors (AAV2), which have now been utilized in hundreds of patients in CNS gene therapy trials. We will utilize start-of-the-art methods for gene delivery, employing real-time MR guidance and convection-enhanced delivery (CED) in collaboration with the world leaders in this technology at Ohio State University (OSU). A total of 12 patients (6 AD and 6 MCI) will be recruited from two clinical sites: UCSD and Case Western. All patients will undergo gene delivery at OSU. The primary outcome measure will be safety, together with secondary cognitive outcome measures that reflect memory-specific and global cognitive measures. Serum, CSF and imaging biomarkers will be collected. If AAV2- BDNF gene delivery is safe and well-tolerated, and exhibit possible cognitive benefits, we will advance to Phase 2 trials. An IND for this program is under review by the FDA, and the trial will begin upon FDA clearance. Two dose groups will be studied: 3x1011 vg/ml and 1x1012 vg/ml. Relevance: Effective disease-modifying therapies for AD and MCI have not been identified. BDNF gene delivery offers the potential to slow or reverse cognitive decline in established AD by building new synapses, stimulating neuronal function and reducing neuronal death. Our approach also offers the potential for combination therapy with amyloid- and tau-modifying therapies.