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 d...
Saved in:
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2021-11-01
|
| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.202114599 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849761839826599936 |
|---|---|
| author | Srinivasarao Repudi Irina Kustanovich Sara Abu‐Swai Shani Stern Rami I Aqeilan |
| author_facet | Srinivasarao Repudi Irina Kustanovich Sara Abu‐Swai Shani Stern Rami I Aqeilan |
| author_sort | Srinivasarao Repudi |
| collection | DOAJ |
| description | 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 (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. |
| format | Article |
| id | doaj-art-b0c97a48d8e64ff2bf3b116d611d7e9f |
| institution | DOAJ |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2021-11-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-b0c97a48d8e64ff2bf3b116d611d7e9f2025-08-20T03:05:53ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842021-11-01131211510.15252/emmm.202114599Neonatal neuronal WWOX gene therapy rescues Wwox null phenotypesSrinivasarao Repudi0Irina Kustanovich1Sara Abu‐Swai2Shani Stern3Rami I Aqeilan4The Concern Foundation Laboratories, The Lautenberg Center for Immunology and Cancer Research, Immunology and Cancer Research‐IMRIC, Hebrew University‐Hadassah Medical SchoolSagol Department of Neurobiology, University of HaifaThe Concern Foundation Laboratories, The Lautenberg Center for Immunology and Cancer Research, Immunology and Cancer Research‐IMRIC, Hebrew University‐Hadassah Medical SchoolSagol Department of Neurobiology, University of HaifaThe Concern Foundation Laboratories, The Lautenberg Center for Immunology and Cancer Research, Immunology and Cancer Research‐IMRIC, Hebrew University‐Hadassah Medical SchoolAbstract 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 (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.https://doi.org/10.15252/emmm.202114599AAV9DEE28hypomyelinationseizuresWOREE syndrome |
| spellingShingle | Srinivasarao Repudi Irina Kustanovich Sara Abu‐Swai Shani Stern Rami I Aqeilan Neonatal neuronal WWOX gene therapy rescues Wwox null phenotypes EMBO Molecular Medicine AAV9 DEE28 hypomyelination seizures WOREE syndrome |
| title | Neonatal neuronal WWOX gene therapy rescues Wwox null phenotypes |
| title_full | Neonatal neuronal WWOX gene therapy rescues Wwox null phenotypes |
| title_fullStr | Neonatal neuronal WWOX gene therapy rescues Wwox null phenotypes |
| title_full_unstemmed | Neonatal neuronal WWOX gene therapy rescues Wwox null phenotypes |
| title_short | Neonatal neuronal WWOX gene therapy rescues Wwox null phenotypes |
| title_sort | neonatal neuronal wwox gene therapy rescues wwox null phenotypes |
| topic | AAV9 DEE28 hypomyelination seizures WOREE syndrome |
| url | https://doi.org/10.15252/emmm.202114599 |
| work_keys_str_mv | AT srinivasaraorepudi neonatalneuronalwwoxgenetherapyrescueswwoxnullphenotypes AT irinakustanovich neonatalneuronalwwoxgenetherapyrescueswwoxnullphenotypes AT saraabuswai neonatalneuronalwwoxgenetherapyrescueswwoxnullphenotypes AT shanistern neonatalneuronalwwoxgenetherapyrescueswwoxnullphenotypes AT ramiiaqeilan neonatalneuronalwwoxgenetherapyrescueswwoxnullphenotypes |