Gene-specific nonsense-mediated mRNA decay targeting for cystic fibrosis therapy.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
27 05 2022
27 05 2022
Historique:
received:
20
07
2021
accepted:
06
05
2022
entrez:
27
5
2022
pubmed:
28
5
2022
medline:
1
6
2022
Statut:
epublish
Résumé
Low CFTR mRNA expression due to nonsense-mediated mRNA decay (NMD) is a major hurdle in developing a therapy for cystic fibrosis (CF) caused by the W1282X mutation in the CFTR gene. CFTR-W1282X truncated protein retains partial function, so increasing its levels by inhibiting NMD of its mRNA will likely be beneficial. Because NMD regulates the normal expression of many genes, gene-specific stabilization of CFTR-W1282X mRNA expression is more desirable than general NMD inhibition. Synthetic antisense oligonucleotides (ASOs) designed to prevent binding of exon junction complexes (EJC) downstream of premature termination codons (PTCs) attenuate NMD in a gene-specific manner. We describe cocktails of three ASOs that specifically increase the expression of CFTR-W1282X mRNA and CFTR protein upon delivery into human bronchial epithelial cells. This treatment increases the CFTR-mediated chloride current. These results set the stage for clinical development of an allele-specific therapy for CF caused by the W1282X mutation.
Identifiants
pubmed: 35624092
doi: 10.1038/s41467-022-30668-y
pii: 10.1038/s41467-022-30668-y
pmc: PMC9142507
doi:
Substances chimiques
Codon, Nonsense
0
Oligonucleotides, Antisense
0
RNA, Messenger
0
Cystic Fibrosis Transmembrane Conductance Regulator
126880-72-6
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
2978Subventions
Organisme : NIGMS NIH HHS
ID : R37 GM042699
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM008444
Pays : United States
Organisme : NHLBI NIH HHS
ID : F30 HL137326
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA045508
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM042699
Pays : United States
Informations de copyright
© 2022. The Author(s).
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