Alternating Hemiplegia of Childhood (AHC) is a devastating autosomal dominant disorder caused by ATP1A3 mutations, resulting in severe hemiplegia and dystonia spells, ataxia, debilitating disabilities, and premature death. Here, we determine the effects of delivering an extra copy of the normal gene in a mouse model carrying the most common mutation causing AHC in humans, the D801N mutation. We used an adeno-associated virus serotype 9 (AAV9) vector expressing the human ATP1A3 gene under the control of a human Synapsin promoter. We first demonstrated that intracerebroventricular (ICV) injection of this vector in wild-type mice on postnatal day 10 (P10) results in increases in ouabain-sensitive ATPase activity and in expression of reporter genes in targeted brain regions. We then tested this vector in mutant mice. Simultaneous intracisterna magna and bilateral ICV injections of this vector at P10 resulted, at P40, in reduction of inducible hemiplegia spells, improvement in balance beam test performance, and prolonged survival of treated mutant mice up to P70. Our study demonstrates, as a proof of concept, that gene therapy can induce favorable effects in a disease caused by a mutation of the gene of a protein that is, at the same time, an ATPase enzyme, a pump, and a signal transduction factor.

中文翻译：

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Mashlool 中的腺相关病毒介导的基因治疗，Atp1a3Mashl/+，儿童交替性偏瘫小鼠模型

儿童交替性偏瘫 (AHC) 是由ATP1A3突变引起的破坏性常染色体显性遗传疾病，导致严重的偏瘫和肌张力障碍、共济失调、衰弱性残疾和过早死亡。在这里，我们确定了在携带人类 AHC 最常见突变 D801N 突变的小鼠模型中提供额外的正常基因副本的效果。我们使用了表达人类ATP1A3的腺相关病毒血清型 9 (AAV9) 载体基因在人突触蛋白启动子的控制下。我们首先证明，在出生后第 10 天 (P10) 在野生型小鼠中脑室内 (ICV) 注射该载体会导致哇巴因敏感 ATP 酶活性和靶脑区域报告基因的表达增加。然后我们在突变小鼠中测试了这个载体。在 P10 时同时在大脑池内和双侧 ICV 注射该载体导致，在 P40 时，可诱导性偏瘫发作减少，平衡木测试性能提高，治疗突变小鼠的存活期延长至 P70。我们的研究证明，作为概念证明，基因治疗可以在由蛋白质基因突变引起的疾病中诱导有利的效果，该蛋白质同时是一种 ATP 酶、泵和信号转导因子.