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.