This program is designed to support a full pre-clinical plan to develop a novel gene replacement therapy for Angelman syndrome. This program will start with evaluating the natural history of the AS mouse model to fully assess neurobehavioral functional deficits at different ages from 2-6 months of age postpartum. The most robust behaviors will then be focused upon when AAV-Ube3a is used to replace the deficient gene and assess for behavioral rescue. The most commonly known Ube3a isoforms will be evaluated independently to assess for most robust behavioral rescue to determine the best gene therapy candidate. Then the transgenes will be optimized and neurotoxicity evaluated. Once that is completed then NHP feasibility studies will be evaluated to explore the preliminary safety profile for high dose AAV.UBE3A for the human gene therapy candidate which will drive conversation with the FDA in moving this gene therapy forward toward a clinical trial.