Research Center for Myology, UPMC Univ Paris 06 and INSERM UMRS 974, Institute of Myology, Sorbonne Universités, Paris, France.
Department of Translational Medicine and Neurogenetics, IGBMC, INSERM U964, CNRS UMR7104, Collège de France, University of Strasbourg, Illkirch, France.
EMBO Mol Med. 2018 Feb;10(2):239-253. doi: 10.15252/emmm.201707988.
Rapid advances in allele-specific silencing by RNA interference established a strategy of choice to cure dominant inherited diseases by targeting mutant alleles. We used this strategy for autosomal-dominant centronuclear myopathy (CNM), a rare neuromuscular disorder without available treatment due to heterozygous mutations in the gene encoding Dynamin 2. Allele-specific siRNA sequences were developed in order to specifically knock down the human and murine -mRNA harbouring the p.R465W mutation without affecting the wild-type allele. Functional restoration was achieved in muscle from a knock-in mouse model and in patient-derived fibroblasts, both expressing the most frequently encountered mutation in patients. Restoring either muscle force in a CNM mouse model or DNM2 function in patient-derived cells is an essential breakthrough towards future gene-based therapy for dominant centronuclear myopathy.
RNA 干扰的等位基因特异性沉默的快速进展为通过靶向突变等位基因来治疗显性遗传疾病建立了一种首选策略。我们使用这种策略治疗常染色体显性中轴性肌病（CNM），这是一种罕见的神经肌肉疾病，由于编码肌球蛋白重链 2 的基因突变，目前尚无治疗方法。为了特异性敲低携带 p.R465W 突变的人类和小鼠 -mRNA，而不影响野生型等位基因，开发了等位基因特异性 siRNA 序列。在携带最常见突变的敲入小鼠模型和患者来源的成纤维细胞中的肌肉中实现了功能恢复。在 CNM 小鼠模型中恢复肌肉力量或在患者来源的细胞中恢复 DNM2 功能，是朝着针对显性中轴性肌病的未来基因治疗迈出的重要一步。
