气候变化领域集成服务门户(CCPortal): Open reading frame correction using splice-switching antisense oligonucleotides for the treatment of cystic fibrosis

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DOI	10.1073/pnas.2114886119
	Open reading frame correction using splice-switching antisense oligonucleotides for the treatment of cystic fibrosis
	Michaels W.E.; Pena-Rasgado C.; Kotaria R.; Bridges R.J.; Hastings M.L.
发表日期	2022
ISSN	0027-8424
卷号	119 期号:3
英文摘要	CFTR gene mutations that result in the introduction of premature termination codons (PTCs) are common in cystic fibrosis (CF). This mutation type causes a severe form of the disease, likely because of low CFTR messenger RNA (mRNA) expression as a result of nonsense-mediated mRNA decay, as well as the production of a nonfunctional, truncated CFTR protein. Current therapeutics for CF, which target residual protein function, are less effective in patients with these types of mutations due in part to low CFTR protein levels. Splice-switching antisense oligonucleotides (ASOs), designed to induce skipping of exons in order to restore the mRNA open reading frame, have shown therapeutic promise preclinically and clinically for a number of diseases. We hypothesized that ASO-mediated skipping of CFTR exon 23 would recover CFTR activity associated with terminating mutations in the exon, including CFTR p.W1282X, the fifth most common mutation in CF. Here, we show that CFTR lacking the amino acids encoding exon 23 is partially functional and responsive to corrector and modulator drugs currently in clinical use. ASO-induced exon 23 skipping rescued CFTR expression and chloride current in primary human bronchial epithelial cells isolated from a homozygote CFTR-W1282X patient. These results support the use of ASOs in treating CF patients with CFTR class I mutations in exon 23 that result in unstable CFTR mRNA and truncations of the CFTR protein. © This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).
英文关键词	Antisense oligonucleotides; Cystic fibrosis; Human bronchial epithelial cells; Nonsense-mediated decay; Splicing
语种	英语
scopus关键词	amino acid; antisense oligonucleotide; chloride; cystic fibrosis transmembrane conductance regulator; messenger RNA; morpholino oligonucleotide; splice switching antisense oligonucleotide; unclassified drug; Article; chloride current; controlled study; cystic fibrosis; cystic fibrosis transmembrane conductance regulator gene; DNA splicing; exon skipping; gene expression regulation; genetic association; HBEC cell line (bronchial epithelium); homozygote; human; human cell; immortalized cell line; mRNA expression level; mutator gene; nonsense mutation; open reading frame; protein expression; protein targeting
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/250891
作者单位	Center for Genetic Diseases, Chicago Medical School, Rosalind Franklin University of Science and Medicine, North Chicago, IL 60064, United States; School of Graduate and Postdoctoral Studies, Rosalind Franklin University of Science and Medicine, North Chicago, IL 60064, United States
推荐引用方式 GB/T 7714	Michaels W.E.,Pena-Rasgado C.,Kotaria R.,et al. Open reading frame correction using splice-switching antisense oligonucleotides for the treatment of cystic fibrosis[J],2022,119(3).
APA	Michaels W.E.,Pena-Rasgado C.,Kotaria R.,Bridges R.J.,&Hastings M.L..(2022).Open reading frame correction using splice-switching antisense oligonucleotides for the treatment of cystic fibrosis.Proceedings of the National Academy of Sciences of the United States of America,119(3).
MLA	Michaels W.E.,et al."Open reading frame correction using splice-switching antisense oligonucleotides for the treatment of cystic fibrosis".Proceedings of the National Academy of Sciences of the United States of America 119.3(2022).