The sustained expression of Cas9 targeting toxic RNAs reverses disease phenotypes in mouse models of myotonic dystrophy type 1.
Journal
Nature biomedical engineering
ISSN: 2157-846X
Titre abrégé: Nat Biomed Eng
Pays: England
ID NLM: 101696896
Informations de publication
Date de publication:
02 2021
02 2021
Historique:
received:
13
05
2019
accepted:
10
08
2020
pubmed:
16
9
2020
medline:
13
3
2021
entrez:
15
9
2020
Statut:
ppublish
Résumé
Myotonic dystrophy type I (DM1) is a multisystemic autosomal-dominant inherited human disorder that is caused by CTG microsatellite repeat expansions (MREs) in the 3' untranslated region of DMPK. Toxic RNAs expressed from such repetitive sequences can be eliminated using CRISPR-mediated RNA targeting, yet evidence of its in vivo efficacy and durability is lacking. Here, using adult and neonatal mouse models of DM1, we show that intramuscular or systemic injections of adeno-associated virus (AAV) vectors encoding nuclease-dead Cas9 and a single-guide RNA targeting CUG repeats results in the expression of the RNA-targeting Cas9 for up to three months, redistribution of the RNA-splicing protein muscleblind-like splicing regulator 1, elimination of foci of toxic RNA, reversal of splicing biomarkers and amelioration of myotonia. The sustained reversal of DM1 phenotypes provides further support that RNA-targeting Cas9 is a viable strategy for treating DM1 and other MRE-associated diseases.
Identifiants
pubmed: 32929188
doi: 10.1038/s41551-020-00607-7
pii: 10.1038/s41551-020-00607-7
pmc: PMC8241012
mid: NIHMS1703760
doi:
Substances chimiques
RNA
63231-63-0
CRISPR-Associated Protein 9
EC 3.1.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
157-168Subventions
Organisme : NINDS NIH HHS
ID : P50 NS048843
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS103172
Pays : United States
Commentaires et corrections
Type : CommentIn
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