Angelman Syndrome (AS) is a rare neurodevelopmental disorder characterized by impaired communication skills, ataxia, motor deficits, intellectual disabilities, and seizures. The genetic cause of AS is the loss of UBE3A expression in the neurons. Currently, there is no cure or corrective therapies available to AS patients. A novel approach being advanced by our laboratories is the use of hematopoietic stem cells (HSC) to provide life-long delivery of functional UBE3A to neurons. Immunodeficient AS mice transplanted with Ube3a expressing human CD34+ HSCs showed significant improvement in several motor behavioral assays including open field, rotarod, beam walking, digigait, as well as in novel object recognition cognitive assay. The data demonstrate that this stem cell gene therapy approach offers a promising treatment strategy for Angelman Syndrome.