Invention of an oral medication for cardiac Fabry disease caused by RNA mis-splicing.

Abstract

Pathogenic RNA splicing variants have emerged as promising therapeutic targets due to their role in disease while preserving coding sequences. In this study, we developed RECTAS-2.0, a small molecule designed to correct RNA mis-splicing caused by the <i>GLA</i> c.639+919G>A mutation, which leads to the inclusion of a 57-nucleotide poison exon, resulting in later-onset Fabry disease, particularly prevalent in East Asia. RECTAS-2.0 restored normal <i>GLA</i> mRNA splicing and α-galactosidase activity in patient-derived B-lymphoblastoid cell lines and induced pluripotent stem cell-derived cardiomyocytes. Furthermore, oral administration of RECTAS-2.0 effectively corrected splicing in a transgenic mouse model, demonstrating its substantial splice-switching activity and safety for clinical application. RECTAS-2.0 demonstrated potential applicability to other genetic disorders that involve similar exon competition. These findings underscore the therapeutic potential of RECTAS-2.0 for Fabry disease and highlight its broader implications for RNA splicing-targeted therapies in genetic disorders.