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.
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