Development of an exon skipping therapy for X-linked Alport syndrome with truncating variants in COL4A5

Tomohiko Yamamura, Tomoko Horinouchi, Tomomi Adachi, Maki Terakawa, Yutaka Takaoka, Kohei Omachi, Minoru Takasato, Kiyosumi Takaishi, Takao Shoji, Yoshiyuki Onishi, Yoshito Kanazawa, Makoto Koizumi, Yasuko Tomono, Aki Sugano, Akemi Shono, Shogo Minamikawa, China Nagano, Nana Sakakibara, Shinya Ishiko, Yuya AotoMisato Kamura, Yutaka Harita, Kenichiro Miura, Shoichiro Kanda, Naoya Morisada, Rini Rossanti, Ming Juan Ye, Yoshimi Nozu, Masafumi Matsuo, Hirofumi Kai, Kazumoto Iijima, Kandai Nozu*

*この論文の責任著者

研究成果: ジャーナルへの寄稿学術論文査読

64 被引用数 (Scopus)

抄録

Currently, there are no treatments for Alport syndrome, which is the second most commonly inherited kidney disease. Here we report the development of an exon-skipping therapy using an antisense-oligonucleotide (ASO) for severe male X-linked Alport syndrome (XLAS). We targeted truncating variants in exon 21 of the COL4A5 gene and conducted a type IV collagen α3/α4/α5 chain triple helix formation assay, and in vitro and in vivo treatment efficacy evaluation. We show that exon skipping enabled trimer formation, leading to remarkable clinical and pathological improvements including expression of the α5 chain on glomerular and the tubular basement membrane. In addition, the survival period was clearly prolonged in the ASO treated mice group. This data suggests that exon skipping may represent a promising therapeutic approach for treating severe male XLAS cases.

本文言語英語
論文番号2777
ジャーナルNature Communications
11
1
DOI
出版ステータス出版済み - 2020/12/01

ASJC Scopus 主題領域

  • 化学一般
  • 生化学、遺伝学、分子生物学一般
  • 物理学および天文学一般

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