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

AAV2-BDNF 基因治疗阿尔茨海默病的临床试验

基本信息

批准号：
10185291
负责人：
MARK H. TUSZYNSKI
金额：
$ 120.15万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-15 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10185291
关键词：
Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease therapy Amyloid Amyloid beta-Protein Animal Experiments Animal Model Area Autopsy Biochemical Biodistribution Biological Biological Markers Blood - brain barrier anatomy Brain Brain-Derived Neurotrophic Factor Cell Death Cessation of life Clinic Clinical Clinical Trials Clinical trial protocol document Cognitive Collaborations Combined Modality Therapy Conduct Clinical Trials Convection Data Development Disease Disease Progression Dose Enrollment Exhibits Future Gene Delivery Gene Transfer Gene therapy trial Genes Growth Factor Hippocampus (Brain)Human Impaired cognition Intervention Learning Leber&apos s Hereditary Optic Neuropathy Life Macaca mulatta Magnetic Resonance Imaging Measures Mediating Medical Memory Memory Disorders Memory Loss Methodology Methods Molecular Mus Nerve Degeneration Nervous system structure Neurons Ohio Outcome Measure Parkinson Disease Pathology Patients Phase I Clinical Trials Primates Procedures Proteins Quality of life Rattus Research Safety Serotyping Serum Short-Term Memory Spinal Muscular Atrophy Standardization Synapses Technology Testing Therapeutic Effect Time Toxic effect Translating Universities Vision Work base clinical research site cognitive benefits cognitive function cohort efficacy study entorhinal cortex first-in-human fluorodeoxyglucose fluorodeoxyglucose positron emission tomography gene replacement gene therapy imaging biomarker improved interest mild cognitive impairment neural circuit neuroimaging neuron loss nonhuman primate phase II trial prevent primary outcome programs recruit response safety assessment targeted delivery tau Proteins trafficking vector

项目摘要

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.

项目摘要/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。因子）在整个生命过程中在皮质回路中积极产生和利用，以维持神经在 AD 动物模型中，BDNF 构建新的突触，阻止神经元的功能和回路。死亡并激活神经元；因此，BDNF 具有减缓或实际上逆转的潜力。认知能力下降已在 AD 和 MCI 中进行了概念验证研究。小鼠、大鼠和恒河猴。由于BDNF是一种比较大的极性蛋白，不能穿过血脑屏障，我们将使用实质内基因疗法将 BDNF 直接输送到内嗅皮层。 BDNF 将通过神经转运至海马体，并使用腺苷酸传递。相关血清型 2 载体（AAV2）现已在数百名患者中使用我们将利用最先进的方法进行中枢神经系统基因治疗试验。与世界各地合作进行实时 MR 引导和对流增强传输 (CED) 俄亥俄州立大学 (OSU) 是该技术的领导者。将从两个临床中心招募总共 12 名患者（6 名 AD 和 6 名 MCI）：UCSD 和 Case 所有患者都将在 OSU 接受基因递送。安全性，以及反映特定记忆和记忆的次要认知结果测量如果 AAV2-，将收集血清、脑脊液和影像生物标志物。 BDNF 基因传递是安全且耐受性良好的，并且表现出可能的认知益处，我们将 FDA 正在审查该项目的 IND，该试验将进入 2 期试验。 FDA 批准后开始研究两个剂量组：3x1011 vg/ml 和 1x1012 vg/ml。相关性：尚未确定针对 AD 和 MCI 的有效疾病缓解疗法。 BDNF 基因传递具有减缓或逆转 AD 认知衰退的潜力通过构建新的突触，刺激神经元功能并减少神经元死亡。该方法还提供了淀粉样蛋白和 tau 修饰联合治疗的潜力疗法。