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

项目概要/摘要：我们建议进行BDNF的首次人体临床试验 阿尔茨海默病（AD）和轻度认知障碍（MCI）的基因治疗，旨在 减少神经元损失并激活神经元功能。脑源性神经营养因子 因子）在整个生命过程中在皮层回路中被积极地产生和利用，以维持神经元 功能和电路。在AD的动物模型中，BDNF建立新的突触，阻止神经元 死亡并激活神经元;因此，BDNF提供了减缓或实际逆转 确诊的AD和MCI的认知能力下降。概念验证研究已在 小鼠、大鼠和恒河猴。 由于BDNF是一种相对较大的极性蛋白，不能穿过血脑屏障， 我们将使用脑实质内基因疗法将BDNF直接输送到内嗅皮层。 脑源性神经营养因子会通过神经传递进入海马体。BDNF将通过腺- 相关的血清型2载体（AAV 2），其现在已经在数百名患者中使用， CNS基因治疗试验。我们将利用最先进的基因传递方法， 实时MR引导和对流增强输送（CED）与世界合作 俄亥俄州州立大学（OSU）的技术领导者。 将从两个临床研究中心（UCSD和Case）共招募12例患者（6例AD和6例MCI） 西部片所有患者将在OSU接受基因递送。主要结局指标将是 安全性，以及反映记忆特异性和 全球认知测量。将采集血清、CSF和影像学生物标志物。如果AAV 2- BDNF基因传递是安全的，耐受性良好，并表现出可能的认知益处，我们将 进入第二阶段试验。FDA正在审查该项目的IND，该试验将 FDA批准后开始。将研究两个剂量组：3x 1011 vg/ml和1x 1012 vg/ml。 相关性：尚未确定AD和MCI的有效疾病缓解疗法。 BDNF基因传递提供了减缓或逆转已建立的AD认知下降的潜力 通过建立新的突触，刺激神经元功能和减少神经元死亡。我们 这种方法还提供了与淀粉样蛋白和tau蛋白修饰的联合治疗的可能性， 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.