PT  - JOURNAL ARTICLE
AU  - Srinivasarao Repudi
AU  - Irina Kustanovich
AU  - Sara Abu-Swai
AU  - Shani Stern
AU  - Rami I. Aqeilan
TI  - Neonatal neuronal WWOX gene therapy rescues <em>Wwox</em> null phenotypes
AID  - 10.1101/2021.04.27.441575
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.04.27.441575
4099  - http://biorxiv.org/content/early/2021/04/27/2021.04.27.441575.short
4100  - http://biorxiv.org/content/early/2021/04/27/2021.04.27.441575.full
AB  - WW domain-containing oxidoreductase (WWOX) is an emerging neural gene regulating homeostasis of the central nervous system. Germline biallelic mutations in WWOX cause 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 murine Wwox recapitulates phenotypes of Wwox-null mice leading to intractable epilepsy, hypomyelination and postnatal lethality. Here, we designed and produced an adeno-associated viral vector harboring murine Wwox or human WWOX cDNA and driven by the human neuronal Synapsin I promoter (AAV-SynI-WWOX). Testing the efficacy of AAV-SynI-WWOX delivery in Wwox null mice demonstrated that specific neuronal restoration of WWOX expression rescued brain hyperexcitability and seizures, hypoglycemia, and myelination deficits as well as the premature lethality of Wwox-null mice. These findings provide a proof-of-concept for WWOX gene therapy as a promising approach to curing children with WOREE and SCAR12.