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Title: Branchpoints as potential targets of exon-skipping therapies for genetic disorders
Authors: Ohara, Hiroaki  kyouindb  KAKEN_id
Hosokawa, Motoyasu
Awaya, Tomonari  kyouindb  KAKEN_id  orcid 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  kyouindb  KAKEN_id
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

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