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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.

SUBMITTER: Yamamura T

PROVIDER: S-EPMC7265383 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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

Yamamura Tomohiko T Horinouchi Tomoko T Adachi Tomomi T Terakawa Maki M Takaoka Yutaka Y Omachi Kohei K Takasato Minoru M Takaishi Kiyosumi K Shoji Takao T Onishi Yoshiyuki Y Kanazawa Yoshito Y Koizumi Makoto M Tomono Yasuko Y Sugano Aki A Shono Akemi A Minamikawa Shogo S Nagano China C Sakakibara Nana N Ishiko Shinya S Aoto Yuya Y Kamura Misato M Harita Yutaka Y Miura Kenichiro K Kanda Shoichiro S Morisada Naoya N Rossanti Rini R Ye Ming Juan MJ Nozu Yoshimi Y Matsuo Masafumi M Kai Hirofumi H Iijima Kazumoto K Nozu Kandai K

Nature communications 20200602 1

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 trim ...[more]

PMID: 32488001

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Project description:Background and objectivesX-linked Alport syndrome is caused by mutations in the COL4A5 gene. Although many COL4A5 mutations have been detected, the mutation detection rate has been unsatisfactory. Some men with X-linked Alport syndrome show a relatively mild phenotype, but molecular basis investigations have rarely been conducted to clarify the underlying mechanism.Design, setting, participants, & measurementsIn total, 152 patients with X-linked Alport syndrome who were suspected of having Alport syndrome through clinical and pathologic investigations and referred to the hospital for mutational analysis between January of 2006 and January of 2013 were genetically diagnosed. Among those patients, 22 patients had suspected splice site mutations. Transcripts are routinely examined when suspected splice site mutations for abnormal transcripts are detected; 11 of them showed expected exon skipping, but others showed aberrant splicing patterns. The mutation detection strategy had two steps: (1) genomic DNA analysis using PCR and direct sequencing and (2) mRNA analysis using RT-PCR to detect RNA processing abnormalities.ResultsSix splicing consensus site mutations resulting in aberrant splicing patterns, one exonic mutation leading to exon skipping, and four deep intronic mutations producing cryptic splice site activation were identified. Interestingly, one case produced a cryptic splice site with a single nucleotide substitution in the deep intron that led to intronic exonization containing a stop codon; however, the patient showed a clearly milder phenotype for X-linked Alport syndrome in men with a truncating mutation. mRNA extracted from the kidney showed both normal and abnormal transcripts, with the normal transcript resulting in the milder phenotype. This novel mechanism leads to mild clinical characteristics.ConclusionsThis report highlights the importance of analyzing transcripts to enhance the mutation detection rate and provides insight into genotype-phenotype correlations. This approach can clarify the cause of atypically mild phenotypes in X-linked Alport syndrome.

Dataset Information

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

Publications

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

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