AbstractWW domain-containing oxidoreductase (WWOX) is an emerging neural gene regulating homeostasis of the central nervous system. Germline biallelic mutations inWWOXcause WWOX-related epileptic encephalopathy (WOREE) syndrome and spinocerebellar ataxia, and autosomal recessive 12 (SCAR12), two devastating neurodevelopmental disorders with highly heterogenous clinical outcomes, the most common being severe epileptic encephalopathy and profound global developmental delay. We recently demonstrated that neuronal ablation of murineWwoxrecapitulates phenotypes ofWwox-null mice leading to intractable epilepsy, hypomyelination and postnatal lethality. Here, we designed and produced an adeno-associated viral vector harboring murineWwoxor humanWWOXcDNA and driven by the human neuronal Synapsin I promoter (AAV-SynI-WWOX). Testing the efficacy of AAV-SynI-WWOX delivery inWwoxnull mice demonstrated that specific neuronal restoration of WWOX expression rescued brain hyperexcitability and seizures, hypoglycemia, and myelination deficits as well as the premature lethality ofWwox-null mice. These findings provide a proof-of-concept forWWOXgene therapy as a promising approach to curing children with WOREE and SCAR12.