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Title: | Branchpoints as potential targets of exon-skipping therapies for genetic disorders |
Authors: | Ohara, Hiroaki Hosokawa, Motoyasu Awaya, Tomonari https://orcid.org/0000-0002-9004-3172 (unconfirmed) Hagiwara, Atsuko Kurosawa, Ryo Sako, Yukiya Ogawa, Megumu Ogasawara, Masashi Noguchi, Satoru Goto, Yuichi Takahashi, Ryosuke Nishino, Ichizo Hagiwara, Masatoshi |
Author's alias: | 大原, 寛明 細川, 元靖 粟屋, 智就 萩原, 厚子 黒澤, 凌 佐古, 有季哉 髙橋, 良輔 萩原, 正敏 |
Issue Date: | 12-Sep-2023 |
Publisher: | Elsevier BV |
Journal title: | Molecular Therapy - Nucleic Acids |
Volume: | 33 |
Start page: | 404 |
End page: | 412 |
Abstract: | Fukutin (FKTN) c.647+2084G>T creates a pseudo-exon with a premature stop codon, which causes Fukuyama congenital muscular dystrophy (FCMD). We aimed to ameliorate aberrant splicing of FKTN caused by this variant. We screened compounds focusing on splicing regulation using the c.647+2084G>T splicing reporter and discovered that the branchpoint, which is essential for splicing reactions, could be a potential therapeutic target. To confirm the effectiveness of branchpoints as targets for exon skipping, we designed branchpoint-targeted antisense oligonucleotides (BP-AONs). This restored normal FKTN mRNA and protein production in FCMD patient myotubes. We identified a functional BP by detecting splicing intermediates and creating BP mutations in the FKTN reporter gene; this BP was non-redundant and sufficiently blocked by BP-AONs. Next, a BP-AON was designed for a different FCMD-causing variant, which induces pathogenic exon trapping by a common SINE-VNTR-Alu-type retrotransposon. Notably, this BP-AON also restored normal FKTN mRNA and protein production in FCMD patient myotubes. Our findings suggest that BPs could be potential targets in exon-skipping therapeutic strategies for genetic disorders. |
Rights: | © 2023 The Authors. This is an open access article under the CC BY-NC-ND license. |
URI: | http://hdl.handle.net/2433/287214 |
DOI(Published Version): | 10.1016/j.omtn.2023.07.011 |
PubMed ID: | 37547287 |
Appears in Collections: | Journal Articles |
This item is licensed under a Creative Commons License