Establishment of radical therapy for Fukuyama Muscular Dystrophy

福山肌营养不良症（Fukuyama muscular dystrophy，FCMD）是日本最常见的常染色体隐性遗传病之一，是发现的第一种由祖先将SINE-VNTR-Alu逆转录酶元件（retrotranslation element，SVA）插入致病基因引起的人类疾病。在这里，我们表明，异常的mRNA剪接，诱导SVA外显子捕获，FCMD的分子发病机制的基础。在FCMD患者细胞和模型小鼠中引入靶向剪接受体、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）防止了SVA对致病性外显子的捕获，挽救了正常的fuklavin mRNA表达和蛋白质产生。AON治疗也恢复了fuketamine功能，包括作为O-糖基化。肌营养不良聚糖（. DG）和层粘连蛋白结合。DG我们已经证明了剪接调节疗法作为FCMD的第一种根治性临床治疗的前景。

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.