Neonatal neuronal WWOX gene therapy rescuesWwoxnull phenotypes

Abstract

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.

Uncovering convergence and divergence between autism and schizophrenia using genomic tools and patients’ neurons

“…iPSC-based models offer an alternative to understanding the effect of genomic mutations and associations on neural cells 6,16,21,[43][44][45][46][47][48] . The majority of studies investigated NPCs and neurons derived from ASD patient-specific iPSC in vitro and only a few havestudied the role of glial cells from ASD patients using iPSC technology.…”

“…Over the last decade, induced pluripotent stem cells (iPSC) based models of SCZ and ASD [14][15][16][17][18][19][20][21][22] have provided important clues about the pathophysiological processes affected in neural cells, especially since the animal models do not fully recapitulate the complex genetics and clinical features of neuropsychiatric disorders 23 . We recently performed a quantitative metaanalytical study of the progress done in the field of SCZ genetics and the findings of SCZ phenotypes in iPSC-derived neural cells 6 .…”

Uncovering convergence and divergence between autism and schizophrenia using genomic tools and patients’ neurons

“…Hence from this analysis, we can infer that variation and mutations resulting in functional dysregulation of these genes could affect these brain areas and circuits resulting in ASD symptoms. iPSC-based models offer an alternative to understanding the effect of genomic mutations and associations on neural cells 6,16,21,[43][44][45][46][47][48] . The majority of studies investigated NPCs and neurons derived from ASD patient-speci c iPSC in vitro and only a few havestudied the role of glial cells from ASD patients using iPSC technology.…”

“…Over the last decade, induced pluripotent stem cells (iPSC) based models of SCZ and ASD [14][15][16][17][18][19][20][21][22] have provided important clues about the pathophysiological processes affected in neural cells, especially since the animal models do not fully recapitulate the complex genetics and clinical features of neuropsychiatric disorders 23 . We recently performed a quantitative meta-analytical study of the progress done in the eld of SCZ genetics and the ndings of SCZ phenotypes in iPSC-derived neural cells 6 .…”