Neuroscience Laboratory, The Cyprus Institute of Neurology and Genetics and Cyprus School of Molecular Medicine, Nicosia, Cyprus.
Neuroscience Laboratory, The Cyprus Institute of Neurology and Genetics and Cyprus School of Molecular Medicine, Nicosia, Cyprus; Neurology Clinics, The Cyprus Institute of Neurology and Genetics and Cyprus School of Molecular Medicine, Nicosia, Cyprus.
Brain Res. 2020 Feb 1;1728:146572. doi: 10.1016/j.brainres.2019.146572. Epub 2019 Nov 29.
Charcot-Marie-Tooth disease (CMT) encompasses numerous genetically heterogeneous inherited neuropathies, which together are one of the commonest neurogenetic disorders. Axonal CMT types result from mutations in neuronally expressed genes, whereas demyelinating CMT forms mostly result from mutations in genes expressed by myelinating Schwann cells. The demyelinating forms are the most common, and may be caused by dominant mutations and gene dosage effects (as in CMT1), as well as by recessive mutations and loss of function mechanisms (as in CMT4). The discovery of causative genes and increasing insights into molecular mechanisms through the study of experimental disease models has provided the basis for the development of gene therapy approaches. For demyelinating CMT, gene silencing or gene replacement strategies need to be targeted to Schwann cells. Progress in gene replacement for two different CMT forms, including CMT1X caused by GJB1 gene mutations, and CMT4C, caused by SH3TC2 gene mutations, has been made through the use of a myelin-specific promoter to restrict expression in Schwann cells, and by lumbar intrathecal delivery of lentiviral viral vectors to achieve more widespread biodistribution in the peripheral nervous system. This review summarizes the molecular-genetic mechanisms of selected demyelinating CMT neuropathies and the progress made so far, as well as the remaining challenges in the path towards a gene therapy to treat these disorders through the use of optimal gene therapy tools including clinically translatable delivery methods and adeno-associated viral (AAV) vectors.
腓骨肌萎缩症（CMT）包括多种遗传异质性的神经病变，是最常见的神经遗传疾病之一。轴索 CMT 类型是由神经元表达基因的突变引起的，而脱髓鞘 CMT 形式主要是由少突胶质细胞表达的基因的突变引起的。脱髓鞘形式最为常见，可能由显性突变和基因剂量效应引起（如 CMT1），也可能由隐性突变和功能丧失机制引起（如 CMT4）。致病基因的发现以及通过实验性疾病模型研究对分子机制的深入了解，为基因治疗方法的发展提供了基础。对于脱髓鞘 CMT，基因沉默或基因替代策略需要针对施旺细胞。通过使用髓鞘特异性启动子来限制施旺细胞中的表达，以及通过腰椎鞘内递送慢病毒病毒载体来实现更广泛的外周神经系统生物分布，在两种不同的 CMT 形式（包括由 GJB1 基因突变引起的 CMT1X 和由 SH3TC2 基因突变引起的 CMT4C）的基因替代方面取得了进展。本文综述了选定的脱髓鞘 CMT 神经病变的分子遗传机制以及迄今为止取得的进展，以及在使用最佳基因治疗工具（包括临床可转化的递送方法和腺相关病毒（AAV）载体）通过基因治疗治疗这些疾病的道路上仍然存在的挑战。
