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

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

  • Sci Adv. 2025 Apr 11;11(15):eadt9695. doi: 10.1126/sciadv.adt9695.
Tomonari Awaya 1,  Masahiko Ajiro 1 2,  Hiroko Kobayashi 1 2,  Teruo Sawada 1 2,  Kentoku Gotanda 3,  Toshiharu Noji 4,  Naohiro Takemoto 4,  Kei Iida 5,  Megumu K Saito 6,  Dau-Ming Niu 7 8,  Masatoshi Hagiwara 1 2
Affiliations

Affiliations

  • 1 Department of Anatomy and Developmental Biology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan.
  • 2 Department of Drug Discovery Medicine, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan.
  • 3 Modality Research Laboratories III, Shinagawa R&D Center, Daiichi Sankyo Co. Ltd., Tokyo 140-8710, Japan.
  • 4 Modality Research Laboratories I, Shinagawa R&D Center, Daiichi Sankyo Co. Ltd., Tokyo 140-8710, Japan.
  • 5 Medical Support Center, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan.
  • 6 Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan.
  • 7 Department of Pediatrics, Taipei Veterans General Hospital, Taipei 11217, Taiwan.
  • 8 Institute of Clinical Medicine, National Yang-Ming Chiao Tung University, Taipei 112304, Taiwan.
PMID: 40203112 DOI: 10.1126/sciadv.adt9695
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 GLA 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 GLA 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.

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