Systematic screening identifies therapeutic antisense oligonucleotides for Hutchinson-Gilford progeria syndrome.
Journal
Nature medicine
ISSN: 1546-170X
Titre abrégé: Nat Med
Pays: United States
ID NLM: 9502015
Informations de publication
Date de publication:
03 2021
03 2021
Historique:
received:
08
07
2020
accepted:
25
01
2021
pubmed:
13
3
2021
medline:
17
4
2021
entrez:
12
3
2021
Statut:
ppublish
Résumé
Hutchinson-Gilford progeria syndrome (HGPS) is a rare, invariably fatal childhood premature aging disorder caused by a pre-messenger RNA (mRNA) splicing defect in the LMNA gene. We used combined in vitro screening and in vivo validation to systematically explore the effects of target sequence, backbone chemistry and mechanism of action to identify optimized antisense oligonucleotides (ASOs) for therapeutic use in HGPS. In a library of 198 ASOs, the most potent ASOs targeted the LMNA exon 12 junction and acted via non-RNase H-mediated mechanisms. Treatment with an optimized lead candidate resulted in extension of lifespan in a mouse model of HGPS. Progerin mRNA levels were robustly reduced in vivo, but the extent of progerin protein reduction differed between tissues, suggesting a long half-life and tissue-specific turnover of progerin in vivo. These results identify a novel therapeutic agent for HGPS and provide insight into the HGPS disease mechanism.
Identifiants
pubmed: 33707772
doi: 10.1038/s41591-021-01262-4
pii: 10.1038/s41591-021-01262-4
pmc: PMC10167920
mid: NIHMS1883464
doi:
Substances chimiques
LMNA protein, human
0
Lamin Type A
0
Oligonucleotides, Antisense
0
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
526-535Subventions
Organisme : Intramural NIH HHS
ID : ZIA BC010309
Pays : United States
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Type : ErratumIn
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