Development of an exon skipping therapy for X-linked Alport syndrome with truncating variants in COL4A5.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
02 06 2020
02 06 2020
Historique:
received:
05
05
2019
accepted:
12
05
2020
entrez:
4
6
2020
pubmed:
4
6
2020
medline:
25
8
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32488001
doi: 10.1038/s41467-020-16605-x
pii: 10.1038/s41467-020-16605-x
pmc: PMC7265383
doi:
Substances chimiques
Col4a5 protein, mouse
0
Collagen Type IV
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
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