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的首次人类临床试验阿尔茨海默氏病（AD）和轻度认知障碍（MCI）的基因疗法，旨在减少神经元丧失并激活神经元功能。 BDNF（脑衍生的神经营养性因子）在一生中积极生产和使用，以维持神经元功能和电路。在AD的动物模型中，BDNF构建了新的突触，可防止神经元死亡并激活神经元；因此，BDNF提供了减速或实际逆转的潜力已建立的AD和MCI认知能力下降。概念证明研究已在老鼠，老鼠和恒河猴。因为BDNF是一种相对较大的极性蛋白质，不会越过血脑屏障，所以我们将使用掌内基因疗法将BDNF直接输送到内嗅皮层中。 BDNF将被神经贩运到海马。 BDNF将使用adeno- 相关的血清型2载体（AAV2），现在已在数百名患者中使用中枢神经系统基因治疗试验。我们将利用基因输送的开始方法实时MR指导和连接增强的交付（CED）与世界合作俄亥俄州立大学（OSU）这项技术的领导者。总共将从两个临床部位招募12例患者（6 AD和6个MCI）：UCSD和CASE 西。所有患者将在OSU进行基因递送。主要结果度量将是安全，以及次要认知结果指标，反映了特定记忆和全球认知测量值。将收集血清，CSF和成像生物标志物。如果AAV2- BDNF基因的传递是安全且耐受良好的，并且暴露了可能的认知益处，我们将前进到第二阶段试验。 FDA正在审查该计划的IND，审判将从FDA清除开始。将研究两个剂量组：3x1011 VG/mL和1x1012 VG/ml。相关性：尚未确定有效的AD和MCI疾病修改疗法。 BDNF基因递送提供了减慢或反向认知能力下降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。我们的方法还提供了与淀粉样蛋白和tau修改的联合疗法的潜力疗法。