Reversal of RNA toxicity in myotonic dystrophy via a decoy RNA-binding protein with high affinity for expanded CUG repeats.
Journal
Nature biomedical engineering
ISSN: 2157-846X
Titre abrégé: Nat Biomed Eng
Pays: England
ID NLM: 101696896
Informations de publication
Date de publication:
02 2022
02 2022
Historique:
received:
17
07
2020
accepted:
07
12
2021
pubmed:
12
2
2022
medline:
17
3
2022
entrez:
11
2
2022
Statut:
ppublish
Résumé
Myotonic dystrophy type 1 (DM1) is an RNA-dominant disease whose pathogenesis stems from the functional loss of muscleblind-like RNA-binding proteins (RBPs), which causes the formation of alternative-splicing defects. The loss of functional muscleblind-like protein 1 (MBNL1) results from its nuclear sequestration by mutant transcripts containing pathogenic expanded CUG repeats (CUGexp). Here we show that an RBP engineered to act as a decoy for CUGexp reverses the toxicity of the mutant transcripts. In vitro, the binding of the RBP decoy to CUGexp in immortalized muscle cells derived from a patient with DM1 released sequestered endogenous MBNL1 from nuclear RNA foci, restored MBNL1 activity, and corrected the transcriptomic signature of DM1. In mice with DM1, the local or systemic delivery of the RBP decoy via an adeno-associated virus into the animals' skeletal muscle led to the long-lasting correction of the splicing defects and to ameliorated disease pathology. Our findings support the development of decoy RBPs with high binding affinities for expanded RNA repeats as a therapeutic strategy for myotonic dystrophies.
Identifiants
pubmed: 35145256
doi: 10.1038/s41551-021-00838-2
pii: 10.1038/s41551-021-00838-2
doi:
Substances chimiques
RNA-Binding Proteins
0
RNA
63231-63-0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
207-220Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Nature Limited.
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