研究人员描述了一种基因治疗策略，在闭合回路中下调过度活动的神经元的兴奋性，并在癫痫模型中进行了测试。研究人员使用一个即时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，并且只在它们表现出异常活动时才表达。神经元的兴奋性因癫痫相关活动而降低，导致持续的抗癫痫效果，而不干扰正常行为。活动依赖性的基因治疗是一种有希望的按需细胞自主治疗脑回路疾病的方法。
据介绍，一些神经发育和神经精神疾病的特点是病理活动的间歇性发作。尽管基因疗法提供了调节神经元兴奋性的能力，但一个限制性因素是它们不能区分参与回路病变的神经元和“健康”的周围或混合的神经元。
附：英文原文
Title: On-demand cell-autonomous gene therapy for brain circuit disorders
Author: Yichen Qiu, Nathanael O’Neill, Benito Maffei, Clara Zourray, Amanda Almacellas-Barbanoj, Jenna C. Carpenter, Steffan P. Jones, Marco Leite, Thomas J. Turner, Francisco C. Moreira, Albert Snowball, Tawfeeq Shekh-Ahmad, Vincent Magloire, Serena Barral, Manju A. Kurian, Matthew C. Walker, Stephanie Schorge, Dimitri M. Kullmann, Gabriele Lignani
Issue&Volume: 2022-11-04
Abstract: 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.
DOI: abq6656
Source: https://www.science.org/doi/10.1126/science.abq6656