Molecular targeting therapy and pathomechanism for Fukuyama muscular dystrophy and related disorders

福山肌营养不良症（FCMD）是发现的第一个由祖先将sin - vntr - alu （SVA）反转录转座子插入致病基因引起的人类疾病。本研究表明，SVA外显子捕获诱导的异常mRNA剪接是口蹄疫分子发病机制的基础。引入靶向剪接受体、预测外显子剪接增强子和内含子剪接增强子的反义寡核苷酸（AONs），可阻止SVA在口蹄疫患者和模型小鼠细胞中诱捕致病性外显子，恢复正常的fukutin mRNA表达和蛋白生成。AON处理也恢复了fukutin功能，包括a-DG的o糖基化和a-DG的层粘连蛋白结合。因此，我们发现了sva介导的外显子捕获在人类疾病中的作用，并证明了剪接调节疗法有望成为口蹄疫和其他sva介导疾病的第一个根治临床治疗方法。

Fukuyama muscular dystrophy (FCMD) is the first human disease found to result from ancestral insertion of a SINE-VNTR-Alu (SVA) retrotransposon 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 cells of patients with FCMD and model mice, rescuing normal fukutin mRNA expression and protein production. AON treatment also restored fukutin functions, including O-glycosylation of a-DG and laminin binding by a-DG. Thus, we have discovered in human disease a role for SVA-mediated exon-trapping and demonstrated the promise of splicing modulation therapy as the first radical clinical treatment for FCMD and other SVA-mediated diseases.