Gene therapy is emerging as a powerful tool to modulate abnormal gene expression, a hallmark of most CNS disorders. The transformative potentials of recently approved gene therapies for the treatment of spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS) and active cerebral adrenoleukodystrophy are encouraging further development of this approach. However, most attempts to translate gene therapy to the clinic have failed to make it to market. There is an urgent need not only to tailor the genes that are targeted to the pathology of interest but to also address delivery challenges and thereby maximize the utility of genetic tools. In this Review, we provide an overview of gene therapy modalities for CNS diseases, emphasizing the interconnectedness of different delivery strategies and routes of administration. Important gaps in understanding that could accelerate the clinical translatability of CNS genetic interventions are addressed, and we present lessons learned from failed clinical trials that may guide the future development of gene therapies for the treatment and management of CNS disorders.

基因治疗正在成为调节异常基因表达的强大工具，而异常基因表达是大多数中枢神经系统疾病的标志。最近批准的用于治疗脊髓性肌萎缩症（SMA）、肌萎缩侧索硬化症（ALS）和活动性脑肾上腺脑白质营养不良的基因疗法的变革潜力正在鼓励这种方法的进一步发展。然而，大多数将基因疗法转化为临床的尝试都未能成功推向市场。迫切需要不仅定制针对感兴趣的病理学的基因，而且还需要解决交付挑战，从而最大限度地提高遗传工具的效用。在这篇综述中，我们概述了中枢神经系统疾病的基因治疗方式，强调不同递送策略和给药途径的相互关联性。解决了可能加速中枢神经系统基因干预临床可转化性的重要理解差距，我们提出了从失败的临床试验中吸取的经验教训，这些经验教训可能会指导中枢神经系统疾病治疗和管理的基因疗法的未来发展。