Neonatal neuronal WWOX gene therapy rescues Wwox null 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 adenoassociated viral vector (AAV9) 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, myelination deficits, and the premature lethality and behavioral deficits 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.

Antineoplastic Nature of WWOX in Glioblastoma Is Mainly a Consequence of Reduced Cell Viability and Invasion

“…Due to its genomic localization, WWOX tumor suppressor activity is much more frequently impaired by the loss of heterozygosity or homozygous deletion than by point mutations [ 37 , 38 , 39 ]. Initially recognized as a putative tumor suppressor in breast cancer, the WWOX gene is now in the spotlight for its possible role in, e.g., central nervous system (CNS) and related neurological disorders [ 2 , 9 , 32 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ] such as WWOX -related epileptic encephalopathy (WOREE), for which a WWOX gene therapy was recently suggested as a proof-of-concept [ 47 ].…”

Expansion of the clinical and molecular spectrum of WWOX‐related epileptic encephalopathy

“…Specific neuronal restoration of WWOX expression by injecting adeno‐associated virus (AAV) vector in the brain of Wwox ‐null mice rescued brain hyperexcitability, seizures, premature lethality, and behavioral deficits. These findings provide a proof‐of‐concept for WWOX gene therapy as a promising approach to treat children with WOREE (Repudi et al, 2021).…”

“…Wwox knock‐out mice recapitulate the neurological phenotypes of patients with WOREE: spontaneous seizures at ∼2 weeks of age, severe hypomyelination in both the peripheral nervous system and the brain, atrophy of the optic tract, and a short lifespan of only 3–4 weeks (Cheng et al, 2020; Mallaret et al, 2014). Studies performed in a Wwox knockout mouse model demonstrated spontaneous bursting activity in the neocortex which indicated that WWOX plays a fundamental role in balancing neocortical excitability (Breton et al, 2021; Repudi et al, 2021). Specific neuronal restoration of WWOX expression by injecting adeno‐associated virus (AAV) vector in the brain of Wwox ‐null mice rescued brain hyperexcitability, seizures, premature lethality, and behavioral deficits.…”

Rodent Models of Audiogenic Epilepsy: Genetic Aspects, Advantages, Current Problems and Perspectives

“…Wwox -null mutated mice were predisposed to brain hyperexcitability, intractable epilepsy, ataxia and postnatal lethality [ 183 ]. The restoration of Wwox expression by neonatal gene therapy using an adenoviral vector carrying Wwox cDNA under the control of the synapsin I gene promoter reduced premature mortality and predisposition to AE, as well as promoting partial normalization of the development of Wwox -mutated mice [ 187 ].…”