The Concern Foundation Laboratories, The Lautenberg Center for Immunology and Cancer Research, Immunology and Cancer Research-IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Sagol Department of Neurobiology, University of Haifa, Haifa, Israel.
EMBO Mol Med. 2021 Dec 7;13(12):e14599. doi: 10.15252/emmm.202114599. Epub 2021 Nov 7.
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.
WW 结构域包含氧化还原酶（WWOX）是一种新兴的神经基因调节中枢神经系统的内稳态。WWOX 种系双等位基因突变导致 WWOX 相关癫痫性脑病（WOREE）综合征和脊髓小脑共济失调和常染色体隐性 12（SCAR12），这两种破坏性的神经发育障碍具有高度异质性的临床结局，最常见的是严重的癫痫性脑病和严重的全球发育迟缓。我们最近证明，小鼠 Wwox 的神经元消融可重现 Wwox 缺失小鼠的表型，导致难治性癫痫、少突胶质细胞发育不良和出生后致死。在这里，我们设计并产生了携带小鼠 Wwox 或人 WWOX cDNA 的腺相关病毒载体（AAV9），并由人神经元突触素 I 启动子（AAV-SynI-WWOX）驱动。测试 AAV-SynI-WWOX 在 Wwox 缺失小鼠中的递送效果表明，特定神经元中 WWOX 表达的恢复可挽救大脑过度兴奋和癫痫发作、低血糖、髓鞘形成缺陷以及 Wwox 缺失小鼠的过早致死和行为缺陷。这些发现为 WWOX 基因治疗提供了概念验证，作为治疗 WOREE 和 SCAR12 患儿的一种有前途的方法。
