A non-permanent treatment for genetic disorders that result in a missing enzyme has been the focus for many disorders over the last few decades through enzyme replacement therapy (ERT). These types of drugs have been approved by the FDA for various conditions (Pompe disease, MPS, Gaucher’s disease, etc). Angelman syndrome is a disorder that results from a dysfunctional, or missing, UBE3A gene, which results in the lack of a functional UBE3A protein, which is an enzyme. Replacing or activating the missing, or silent, gene, will ultimately result in production of a functional UBE3A enzyme. This leaves the potential for the UBE3A enzyme to be replaced, without the need for genetic manipulation, with the ultimate goal being the same. This grant is to investigate this approach to see if this is a vial option for the treatment of AS and if this enzyme can be replaced, and functional, in neurons of the central nervous system (CNS). ERT is considered well tolerated and has a good safety profile in other conditions. Typically, these proteins are infused intravenously either weekly, biweekly, or monthly, and is often performed at home for these conditions. There is an FDA approved therapy where the enzymes are infused into the CNS through a port in the lumbar spine for intermittent CSF infusions. ERT has not been investigated for AS. Based on data with HSC-Lentiviral delivery of a secreted UBE3A protein, this protein has been shown to be highly effective in the IL2- AS mouse model. This grant will develop an ERT for AS and demonstrate its efficacy using in-vitro cell models, as well as efficacy in AS-ERT in-vivo mouse models. This project will serve as a proof of concept to see if an ERT could achieve rescue of AS phenotypes in mice.