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 Aoto, Misato Kamura, Yutaka Harita, Kenichiro Miura, Shoichiro Kanda, Naoya Morisada, Rini Rossanti, Ming Juan Ye, Yoshimi Nozu, Masafumi Matsuo, Hirofumi Kai, Kazumoto Iijima and Kandai Nozu ()
Additional contact information
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

Nature Communications, 2020, vol. 11, issue 1, 1-8

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-16605-x

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