On-demand cell-autonomous gene therapy for brain circuit disorders.
On-demand cell-autonomous gene therapy for brain circuit disorders.
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DOI：
10.1126/science.abq6656
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发表时间：
2022-11-04
期刊：
影响因子：
--
通讯作者：
Lignani G
中科院分区：
文献类型：
--
作者：
Qiu Y;O'Neill N;Maffei B;Zourray C;Almacellas-Barbanoj A;Carpenter JC;Jones SP;Leite M;Turner TJ;Moreira FC;Snowball A;Shekh-Ahmad T;Magloire V;Barral S;Kurian MA;Walker MC;Schorge S;Kullmann DM;Lignani G
几种神经发育和神经精神障碍的特征在于病理活动的间歇性发作。虽然基因疗法提供了调节神经元兴奋性的能力，但限制因素是它们不能区分参与回路病理的神经元和“健康”的周围或混合的神经元。我们描述了一种基因治疗策略，下调过度活跃的神经元的兴奋性在闭环，我们测试癫痫模型。我们使用立即早期基因启动子来驱动Kv1.1钾通道的表达，特别是在过度活跃的神经元中，并且只有当它们表现出异常活动时。神经元兴奋性降低的癫痫相关活动，导致持续的抗癫痫作用，而不干扰正常行为。活性依赖性基因治疗是一种有前途的按需细胞自主治疗脑回路疾病。
Several neurodevelopmental and neuropsychiatric disorders are characterized by intermittent episodes of pathological activity. Although genetic therapies offer the ability to modulate neuronal excitability, a limiting factor is that they do not discriminate between neurons involved in circuit pathologies and “healthy” surrounding or intermingled neurons. We describe a gene therapy strategy that down-regulates the excitability of overactive neurons in closed loop, which we tested in models of epilepsy. We used an immediate early gene promoter to drive the expression of Kv1.1 potassium channels specifically in hyperactive neurons, and only for as long as they exhibit abnormal activity. Neuronal excitability was reduced by seizure-related activity, leading to a persistent antiepileptic effect without interfering with normal behaviors. Activity-dependent gene therapy is a promising on- demand cell-autonomous treatment for brain circuit disorders.
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