Leukoencephalopathy with vanishing white matter (VWM) is a progressive incurable white matter disease that most commonly occurs in childhood and presents with ataxia, spasticity, neurological degeneration, seizures, and premature death. A distinctive feature is episodes of rapid neurological deterioration provoked by stressors such as infection, seizures, or trauma. VWM is caused by autosomal recessive mutations in one of five genes that encode the eukaryotic initiation factor 2B complex, which is necessary for protein translation and regulation of the integrated stress response. The majority of mutations are in . Astrocytic dysfunction is central to pathophysiology, thereby constituting a potential therapeutic target. Herein we characterize two VWM murine models and investigate astrocyte-targeted adeno-associated virus serotype 9 (AAV9)-mediated gene supplementation therapy as a therapeutic option for VWM. Our results demonstrate significant rescue in body weight, motor function, gait normalization, life extension, and finally, evidence that gene supplementation attenuates demyelination. Last, the greatest rescue results from a vector using a modified glial fibrillary acidic protein (GFAP) promoter—AAV9-gfaABC(1)D-thereby supporting that astrocytic targeting is critical for disease correction. In conclusion, we demonstrate safety and early efficacy through treatment with a translatable astrocyte-targeted gene supplementation therapy for a disease that has no cure.

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评估 AAV 基因治疗在白质消失病小鼠模型中的安全性和早期疗效

伴白质消失的白质脑病 (VWM) 是一种进行性、无法治愈的白质疾病，最常见于儿童期，表现为共济失调、痉挛、神经退行性变、癫痫发作和过早死亡。一个显着特征是由感染、癫痫或创伤等应激源引起的神经系统快速恶化。 VWM 是由编码真核起始因子 2B 复合物的五个基因之一的常染色体隐性突变引起的，该复合物对于蛋白质翻译和综合应激反应的调节是必需的。大多数突变发生在 .星形胶质细胞功能障碍是病理生理学的核心，因此构成潜在的治疗靶点。在此，我们描述了两种 VWM 小鼠模型，并研究星形胶质细胞靶向腺相关病毒血清型 9 (AAV9) 介导的基因补充疗法作为 VWM 的治疗选择。我们的结果表明，对体重、运动功能、步态正常化、寿命延长有显着的拯救作用，最后，有证据表明基因补充可减轻脱髓鞘作用。最后，使用修饰的神经胶质原纤维酸性蛋白 (GFAP) 启动子 AAV9-gfaABC(1)D 的载体获得了最大的拯救结果，从而支持星形细胞靶向对于疾病纠正至关重要。总之，我们通过可翻译的星形胶质细胞靶向基因补充疗法治疗无法治愈的疾病，证明了安全性和早期疗效。