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; Kandai Nozu

doi:10.1038/s41467-020-16605-x

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Article number	2777
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-16605-x
State	Published - 2020/12/01

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Yamamura, T., Horinouchi, T., Adachi, T., Terakawa, M., Takaoka, Y., Omachi, K., Takasato, M., Takaishi, K., Shoji, T., Onishi, Y., Kanazawa, Y., Koizumi, M., Tomono, Y., Sugano, A., Shono, A., Minamikawa, S., Nagano, C., Sakakibara, N., Ishiko, S., ... Nozu, K. (2020). Development of an exon skipping therapy for X-linked Alport syndrome with truncating variants in COL4A5. Nature Communications, 11(1), Article 2777. https://doi.org/10.1038/s41467-020-16605-x

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

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.",

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

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year = "2020",

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doi = "10.1038/s41467-020-16605-x",

language = "英語",

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Yamamura, T, Horinouchi, T, Adachi, T, Terakawa, M, Takaoka, Y, Omachi, K, Takasato, M, Takaishi, K, Shoji, T, Onishi, Y, Kanazawa, Y, Koizumi, M, Tomono, Y, Sugano, A, Shono, A, Minamikawa, S, Nagano, C, Sakakibara, N, Ishiko, S, Aoto, Y, Kamura, M, Harita, Y, Miura, K, Kanda, S, Morisada, N, Rossanti, R, Ye, MJ, Nozu, Y, Matsuo, M, Kai, H, Iijima, K & Nozu, K 2020, 'Development of an exon skipping therapy for X-linked Alport syndrome with truncating variants in COL4A5', Nature Communications, vol. 11, no. 1, 2777. https://doi.org/10.1038/s41467-020-16605-x

TY - JOUR

T1 - Development of an exon skipping therapy for X-linked Alport syndrome with truncating variants in COL4A5

AU - Yamamura, Tomohiko

AU - Horinouchi, Tomoko

AU - Adachi, Tomomi

AU - Terakawa, Maki

AU - Takaoka, Yutaka

AU - Omachi, Kohei

AU - Takasato, Minoru

AU - Takaishi, Kiyosumi

AU - Shoji, Takao

AU - Onishi, Yoshiyuki

AU - Kanazawa, Yoshito

AU - Koizumi, Makoto

AU - Tomono, Yasuko

AU - Sugano, Aki

AU - Shono, Akemi

AU - Minamikawa, Shogo

AU - Nagano, China

AU - Sakakibara, Nana

AU - Ishiko, Shinya

AU - Aoto, Yuya

AU - Kamura, Misato

AU - Harita, Yutaka

AU - Miura, Kenichiro

AU - Kanda, Shoichiro

AU - Morisada, Naoya

AU - Rossanti, Rini

AU - Ye, Ming Juan

AU - Nozu, Yoshimi

AU - Matsuo, Masafumi

AU - Kai, Hirofumi

AU - Iijima, Kazumoto

AU - Nozu, Kandai

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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.

AB - 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.

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U2 - 10.1038/s41467-020-16605-x

DO - 10.1038/s41467-020-16605-x

M3 - 学術論文

C2 - 32488001

AN - SCOPUS:85085909694

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2777

ER -

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

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