A Phase 2 Trial of AAV-NGF Gene Delivery in Alzheimer's Disease

AAV-NGF 基因传递治疗阿尔茨海默病的 2 期试验

基本信息

批准号：
8292069
负责人：
Paul S. Aisen
金额：
$ 63.98万
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：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8292069
关键词：
Adverse event Affect Aftercare Age Aging Alzheimer&apos s Disease Amendment Amyloid beta-Protein Precursor Animal Model Autologous Basal Nucleus of Meynert Bilateral Biological Biological Markers Biometry Brain Cells Cessation of life Chronic Clinical Clinical Trials Clinical dementia rating scale Cognition Cognitive Data Data Collection Data Set Dependovirus Disease Double-Blind Method Evaluation Exhibits Fibroblasts Funding Gene Delivery Gene Expression Goals Growth Growth Factor Growth Factor Gene Health Human Image Implant Injection of therapeutic agent Injury Knowledge Measures Mechanics Multicenter Trials Nature Nerve Growth Factors Neurodegenerative Disorders Neurons Neuropsychological Tests Neurosurgeon Operative Surgical Procedures Outcome Outcome Measure Parkinson Disease Patients Pattern Performance Phase Phase I Clinical Trials Phase II Clinical Trials Population Positron-Emission Tomography Prevalence Procedures Property Randomized Randomized Clinical Trials Randomized Controlled Clinical Trials Reporting Research Infrastructure Risk Safety Scalp structure Site Stereotaxic Techniques Surgical incisions Techniques Technology Testing Therapeutic Toxic effect Trephine hole adeno-associated viral vector arm basal forebrain basal forebrain cholinergic neurons cholinergic neuron clinical research site cooperative study data management design efficacy trial excitotoxicity fluorodeoxyglucose fluorodeoxyglucose positron emission tomography follow-up gene therapy glucose uptake improved functioning in vivo neuropsychological new technology nonhuman primate novel novel strategies operation prevent prospective response sham surgery tool uptake vector

项目摘要

Nerve Growth Factor (NGF) potently prevents the death and augments the functional state of cholinergic neurons of the basal forebrain, a cell population that undergoes extensive degeneration in Alzheimer disease (AD). A recent Phase I clinical trial of ex vivo NGF gene delivery (via constitutively NGF secreting fibroblasts inserted into human basal forebrain) in early AD patients reported: 1) robust ¿trophic¿ (growth) responses of human cholinergic neurons to NGF in the AD brain, 2) intriguing possible effects on cognition sustained over at least a 22 month period, and 3) a significant increase in cortical glucose uptake on PET scan in treated subjects. A second phase I trial of in vivo NGF gene delivery has recently been conducted in 6 patients, utilizing Adeno-Associated Virus (AAV) vectors that exhibit superior properties of long-term gene expression in the brain compared to the vector used in the ex vivo NGF trial; this trial has confirmed the safety of in vivo AAV-NGF gene delivery in AD, with post-treatment follow-up ranging from six to 18 months in six subjects. We now propose a Phase II randomized clinical trial of AAV-NGF Gene Delivery in AD to test the hypothesis that NGF gene delivery, by preventing cell loss and augmenting neuronal function, will modify AD clinical progression. Given the novel nature of this technology and its requirement for stereotaxic delivery into patients, this trial will focus on objectives related to ¿scaling up¿ for larger efficacy trials, including: 1) expanding the technology's implementation to several new clinical sites, 2) assessing potential effect size, and 3) evaluating positron emission tomography (PET) as a potential marker of neurotrophic activity and correlate of efficacy. The proposed trial is a 24-month, prospective, randomized, double-blind, sham- controlled, multi-center Phase II clinical trial of AAV-NGF In Vivo Gene Therapy for AD. Fifty patients with mild to moderate AD will be randomly assigned to receive 2 intracerebral injections of AAV-NGF into each NBM of each hemisphere, or a sham- surgery control procedure (bilateral scalp incision and partial burr holes). Outcome measures include cognitive, clinical and safety assessments, as well as PET scanning measures. If the primary analysis is favorable, subjects assigned to the sham surgery arm will be offered active AAV-NGF treatment. Project Narrative This project is a randomized controlled clinical trial to determine the efficacy and safety of NGF gene delivery for the treatment of Alzheimer's disease. Alzheimer's disease is among the most important health problems worldwide, with steadily rising prevalence as populations age. Effective disease-modifying treatment is sorely needed.

神经生长因子（NGF）有效防止死亡并增强功能基底前脑的胆碱能神经元的状态，这是一种细胞群体的细胞群阿尔茨海默氏病的广泛退化（AD）。 Vivo NGF基因递送（通过组成性NGF分泌成纤维细胞插入到Humann中基础前脑）在早期的AD患者中报告：1）鲁棒� 奖杯» （增长）反应人类胆碱能神经元在AD大脑中的NGF，2）对可能对认知持续至少22个月，3）显着增加治疗受试者对PET扫描的皮质葡萄糖摄取。 NGF基因递送最近在6例患者中进行了在长期基因表达在与体内NGF试验中使用的载体相比，该试验证实了这项试验。 AD中体内AAVO-NGF基因递送的安全性，并带有后续后续范围在六个受试者中，我们提出了一个随机临床的六个月。 AAV-NGF基因递送在AD中的试验，以测试NGF基因递送的假设，通过预防细胞损失和增强神经元功能，将修改AD临床进展。分娩到患者中，该试验将集中于与„有关的目标扩展对于较大功效试验，包括：1）将技术的实施扩展到严重性新临床部位，2）评估潜在效应大小，3）评估正电子发射断层扫描（PET）作为神经营养活性的潜在标记，并相关功效。 AAV-NGF体内基因治疗的受控，多中心II期临床试验 AD。脑内注射AAV-NGF对每个半疗法的每个NBM或假手术控制程序（双侧头皮切口和部分毛刺孔）。措施包括认知，临床和安全评估以及PET扫描措施，如果主要分析是有利的，则分配给假手术将提供积极的AAV-NGF治疗该项目是一项随机对照临床试验，以确定功效和安全性 NGF基因的治疗是阿尔茨海默氏病的治疗。在世界范围内最重要的健康问题之一，稳步上升的患病率是人口年龄非常好。