Establishment of radical therapy for Fukuyama Muscular Dystrophy

Fukuyama肌营养不良症(FCMD)是日本最常见的常染色体隐性遗传病之一，是第一种由祖先在致病基因中插入SVA-VNTR-Alu逆转录转座元件(SVA)引起的疾病。在这里，我们证明了SVA外显子捕获诱导的异常的mRNA剪接是FCMD分子发病的基础。针对剪接受体、预测的外显子剪接增强子和内含子剪接增强子的反义寡核苷酸(AON)的引入，阻止了SVA在FCMD患者细胞和模型小鼠中捕获致病外显子，拯救了FCMD患者细胞和模型小鼠正常的fukutin mRNA表达和蛋白生产。AON治疗还恢复了Fukutin的功能，包括-dystroglan(.-dg)的O-糖基化和.-dg与层粘连蛋白的结合。我们已经证明剪接调节疗法有望成为FCMD的第一个根治性临床治疗方法。

Fukuyama muscular dystrophy(FCMD), one of the most common autosomal recessive disorders in Japan, was the first human disease found to result from ancestral insertion of a SINE-VNTR-Alu retrotransposal element(SVA) into a causative gene. Here we show that aberrant mRNA splicing, induced by SVA exon trapping, underlies the molecular pathogenesis of FCMD. Introduction of antisense oligonucleotides(AONs) targeting the splice acceptor, the predicted exonic splicing enhancer, and the intronic splicing enhancer prevented pathogenic exon trapping by SVA in FCMD patient cells and model mice, rescuing normal fukutin mRNA expression and protein production. AON treatment also restored fukutin functions, including as O-glycosylation of.-dystroglycan(.-DG) and laminin binding by.-DG. We have demonstrated the promise of splicing modulation therapy as the first radical clinical treatment for FCMD.