Gene-specific nonsense-mediated mRNA decay targeting for cystic fibrosis therapy

Young Jin Kim, Tomoki Nomakuchi, Foteini Papaleonidopoulou, Lucia Yang, Qian Zhang and Adrian R. Krainer ()
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Young Jin Kim: Cold Spring Harbor Laboratory
Tomoki Nomakuchi: Cold Spring Harbor Laboratory
Foteini Papaleonidopoulou: Cold Spring Harbor Laboratory
Lucia Yang: Cold Spring Harbor Laboratory
Qian Zhang: Cold Spring Harbor Laboratory
Adrian R. Krainer: Cold Spring Harbor Laboratory

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-30668-y

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