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

Author

Listed:
  • Tomohiko Yamamura

    (Kobe University Graduate School of Medicine)

  • Tomoko Horinouchi

    (Kobe University Graduate School of Medicine)

  • Tomomi Adachi

    (Rare Disease Laboratories, Daiichi Sankyo Co., Ltd.)

  • Maki Terakawa

    (Rare Disease Laboratories, Daiichi Sankyo Co., Ltd.)

  • Yutaka Takaoka

    (Kobe University Hospital)

  • Kohei Omachi

    (Kumamoto University)

  • Minoru Takasato

    (RIKEN Center for Developmental Biology)

  • Kiyosumi Takaishi

    (Rare Disease Laboratories, Daiichi Sankyo Co., Ltd.)

  • Takao Shoji

    (Modality Research Laboratories, Daiichi Sankyo Co., Ltd.)

  • Yoshiyuki Onishi

    (Modality Research Laboratories, Daiichi Sankyo Co., Ltd.)

  • Yoshito Kanazawa

    (Modality Research Laboratories, Daiichi Sankyo Co., Ltd.)

  • Makoto Koizumi

    (Modality Research Laboratories, Daiichi Sankyo Co., Ltd.)

  • Yasuko Tomono

    (Division of Molecular Cell Biology, Shigei Medical Research Institute)

  • Aki Sugano

    (Kobe University Hospital)

  • Akemi Shono

    (Kobe University Graduate School of Medicine)

  • Shogo Minamikawa

    (Kobe University Graduate School of Medicine)

  • China Nagano

    (Kobe University Graduate School of Medicine)

  • Nana Sakakibara

    (Kobe University Graduate School of Medicine)

  • Shinya Ishiko

    (Kobe University Graduate School of Medicine)

  • Yuya Aoto

    (Kobe University Graduate School of Medicine)

  • Misato Kamura

    (Kumamoto University)

  • Yutaka Harita

    (The University of Tokyo)

  • Kenichiro Miura

    (Tokyo Women’s Medical University)

  • Shoichiro Kanda

    (The University of Tokyo)

  • Naoya Morisada

    (Kobe University Graduate School of Medicine)

  • Rini Rossanti

    (Kobe University Graduate School of Medicine)

  • Ming Juan Ye

    (Kobe University Graduate School of Medicine)

  • Yoshimi Nozu

    (Kobe University Graduate School of Medicine)

  • Masafumi Matsuo

    (Kobe Gakuin University)

  • Hirofumi Kai

    (Kumamoto University)

  • Kazumoto Iijima

    (Kobe University Graduate School of Medicine)

  • Kandai Nozu

    (Kobe University Graduate School of Medicine)

Abstract

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.

Suggested Citation

  • Tomohiko Yamamura & Tomoko Horinouchi & Tomomi Adachi & Maki Terakawa & Yutaka Takaoka & Kohei Omachi & Minoru Takasato & Kiyosumi Takaishi & Takao Shoji & Yoshiyuki Onishi & Yoshito Kanazawa & Makoto, 2020. "Development of an exon skipping therapy for X-linked Alport syndrome with truncating variants in COL4A5," Nature Communications, Nature, vol. 11(1), pages 1-8, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16605-x
    DOI: 10.1038/s41467-020-16605-x
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    Cited by:

    1. Angelo Miskalis & Shraddha Shirguppe & Jackson Winter & Gianna Elias & Devyani Swami & Ananthan Nambiar & Michelle Stilger & Wendy S. Woods & Nicholas Gosstola & Michael Gapinske & Alejandra Zeballos , 2024. "SPLICER: a highly efficient base editing toolbox that enables in vivo therapeutic exon skipping," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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