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

福山肌营养不良症(FCMD)是第一种被发现的人类疾病，由祖先在致病基因中插入SVA逆转录转座子引起。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患者和模型小鼠细胞中的致病外显子捕获，拯救了正常的fukutin mRNA表达和蛋白生产。AON治疗还恢复了Fukutin的功能，包括a-DG的O-糖基化和a-DG与层粘连蛋白的结合。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，并展示了剪接调控疗法作为FCMD和其他SVA介导的疾病的第一个根本性临床治疗的前景。

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.