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Cell-Selective Regulation of CFTR Gene Expression: Relevance to Gene Editing Therapeutics
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Gene and Base Editing as a Therapeutic Option for Cystic Fibrosis—Learning from Other Diseases

by Karen Mention 1,†, Lúcia Santos 1,2,† and Patrick T. Harrison 1,*
1
Department of Physiology, University College Cork, Cork T12 K8AF, Ireland
2
University of Lisboa Faculty of Sciences, BioISI—Biosystems & Integrative Sciences Institute, 1749-016 Lisboa, Portugal
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Genes 2019, 10(5), 387; https://doi.org/10.3390/genes10050387
Received: 15 April 2019 / Revised: 11 May 2019 / Accepted: 15 May 2019 / Published: 21 May 2019
(This article belongs to the Special Issue Cystic Fibrosis: Therapy and Genetics)
Cystic fibrosis (CF) is a monogenic autosomal recessive disorder caused by mutations in the CFTR gene. There are at least 346 disease-causing variants in the CFTR gene, but effective small-molecule therapies exist for only ~10% of them. One option to treat all mutations is CFTR cDNA-based therapy, but clinical trials to date have only been able to stabilise rather than improve lung function disease in patients. While cDNA-based therapy is already a clinical reality for a number of diseases, some animal studies have clearly established that precision genome editing can be significantly more effective than cDNA addition. These observations have led to a number of gene-editing clinical trials for a small number of such genetic disorders. To date, gene-editing strategies to correct CFTR mutations have been conducted exclusively in cell models, with no in vivo gene-editing studies yet described. Here, we highlight some of the key breakthroughs in in vivo and ex vivo gene and base editing in animal models for other diseases and discuss what might be learned from these studies in the development of editing strategies that may be applied to cystic fibrosis as a potential therapeutic approach. There are many hurdles that need to be overcome, including the in vivo delivery of editing machinery or successful engraftment of ex vivo-edited cells, as well as minimising potential off-target effects. However, a successful proof-of-concept study for gene or base editing in one or more of the available CF animal models could pave the way towards a long-term therapeutic strategy for this disease. View Full-Text
Keywords: gene editing; base editing; cystic fibrosis; AAV; ribonucleotide particle; guideRNA; CRISPR; Cas9 gene editing; base editing; cystic fibrosis; AAV; ribonucleotide particle; guideRNA; CRISPR; Cas9
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Mention, K.; Santos, L.; Harrison, P.T. Gene and Base Editing as a Therapeutic Option for Cystic Fibrosis—Learning from Other Diseases. Genes 2019, 10, 387.

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