Gene-Specific Nonsense-Mediated mRNA Decay Targeting for Cystic Fibrosis Therapy

Kim, Young Jin, Nomakuchi, Tomoki, Papaleonidopoulou, Foteini, Krainer, Adrian (July 2021) Gene-Specific Nonsense-Mediated mRNA Decay Targeting for Cystic Fibrosis Therapy. BioRxiv. (Unpublished)

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DOI: 10.1101/2021.07.13.452144


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 developed a cocktail of three ASOs that specifically increases the expression of CFTR W1282X mRNA and CFTR protein in ASO-transfected human bronchial epithelial cells. This treatment increased 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.

Item Type: Paper
Subjects: diseases & disorders > congenital hereditary genetic diseases > cystic fibrosis
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > mRNA
CSHL Authors:
Communities: CSHL labs > Krainer lab
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 18 July 2021
Date Deposited: 26 May 2022 17:35
Last Modified: 26 May 2022 17:35

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