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Review Article| Volume 43, ISSUE 4, P591-602, December 2022

Genetics of Cystic Fibrosis

Clinical Implications

      Keywords

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      References

        • De Boeck K.
        • Amaral M.D.
        Progress in therapies for cystic fibrosis.
        Lancet Respir Med. 2016; 4: 662-674
        • Sharma N.
        • Evans T.A.
        • Pellicore M.J.
        • et al.
        Capitalizing on the heterogeneous effects of CFTR nonsense and frameshift variants to inform therapeutic strategy for cystic fibrosis.
        PLoS Genet. 2018; 14: e1007723
        • Fedder J.
        • Jørgensen M.W.
        • Engvad B.
        Prevalence of CBAVD in azoospermic men carrying pathogenic CFTR mutations - evaluated in a cohort of 639 non-vasectomized azoospermic men.
        Andrology. 2021; 9: 588-598
        • Raraigh K.S.
        • Han S.T.
        • Davis E.
        • et al.
        Functional assays are essential for interpretation of missense variants associated with variable expressivity.
        Am J Hum Genet. 2018; 102: 1062-1077
        • Han S.T.
        • Rab A.
        • Pellicore M.J.
        • et al.
        Residual function of cystic fibrosis mutants predicts response to small molecule CFTR modulators.
        JCI Insight. 2018; 3: 121159
        • McCague A.F.
        • Raraigh K.S.
        • Pellicore M.J.
        • et al.
        Correlating cystic fibrosis transmembrane conductance regulator function with clinical features to inform precision treatment of cystic fibrosis.
        Am J Respir Crit Care Med. 2019; 199: 1116-1126
        • Chevalier B.
        • Hinzpeter A.
        The influence of CFTR complex alleles on precision therapy of cystic fibrosis.
        J Cyst Fibros. 2020; 19: S15-S18
        • Aksit M.A.
        • Pace R.G.
        • Vecchio-Pagán B.
        • et al.
        Genetic Modifiers of cystic fibrosis-related diabetes have extensive overlap with type 2 diabetes and related traits.
        J Clin Endocrinol Metab. 2020; 105: dgz102
        • Paranjapye A.
        • Ruffin M.
        • Harris A.
        • et al.
        Genetic variation in CFTR and modifier loci may modulate cystic fibrosis disease severity.
        J Cyst Fibros. 2020; 19: S10-S14
        • Barben J.
        • Castellani C.
        • Munck A.
        • et al.
        Updated guidance on the management of children with cystic fibrosis transmembrane conductance regulator-related metabolic syndrome/cystic fibrosis screen positive, inconclusive diagnosis (CRMS/CFSPID).
        J Cyst Fibros. 2021; 20: 810-819
        • Felício V.
        • Ramalho A.S.
        • Igreja S.
        • et al.
        mRNA-based detection of rare CFTR mutations improves genetic diagnosis of cystic fibrosis in populations with high genetic heterogeneity.
        Clin Genet. 2017; 91: 476-481
        • Middleton P.G.
        • Mall M.A.
        • Dřevínek P.
        • et al.
        Elexacaftor-tezacaftor-ivacaftor for cystic fibrosis with a single Phe508del allele.
        N Engl J Med. 2019; 381: 1809-1819
        • Lopes-Pacheco M.
        • Pedemonte N.
        • Veit G.
        Discovery of CFTR modulators for the treatment of cystic fibrosis.
        Expert Opin Drug Discov. 2021; 16: 897-913
        • Dukovski D.
        • Villella A.
        • Bastos C.
        • et al.
        Amplifiers co-translationally enhance CFTR biosynthesis via PCBP1-mediated regulation of CFTR mRNA.
        J Cyst Fibros. 2020; 19: 733-741
        • Joynt A.T.
        • Evans T.A.
        • Pellicore M.J.
        • et al.
        Evaluation of both exonic and intronic variants for effects on RNA splicing allows for accurate assessment of the effectiveness of precision therapies.
        PLoS Genet. 2020; 16: e1009100
        • Michaels W.E.
        • Bridges R.J.
        • Hastings M.L.
        Antisense oligonucleotide-mediated correction of CFTR splicing improves chloride secretion in cystic fibrosis patient-derived bronchial epithelial cells.
        Nucleic Acids Res. 2020; 48: 7454-7467
        • Oren Y.S.
        • Irony-Tur Sinai M.
        • Golec A.
        • et al.
        Antisense oligonucleotide-based drug development for Cystic Fibrosis patients carrying the 3849+10 kb C-to-T splicing mutation.
        J Cyst Fibros. 2021; 20: 865-875
        • Igreja S.
        • Clarke L.A.
        • Botelho H.M.
        • et al.
        Correction of a cystic fibrosis splicing mutation by antisense oligonucleotides.
        Hum Mutat. 2016; 37: 209-215
        • Donegà S.
        • Rogalska M.E.
        • Pianigiani G.
        • et al.
        Rescue of common exon-skipping mutations in cystic fibrosis with modified U1 snRNAs.
        Hum Mutat. 2020; 41: 2143-2154
        • Gao D.
        • Morini E.
        • Salani M.
        • et al.
        A deep learning approach to identify gene targets of a therapeutic for human splicing disorders.
        Nat Commun. 2021; 12: 3332
        • Shibata S.
        • Ajiro M.
        • Hagiwara M.
        Mechanism-based personalized medicine for cystic fibrosis by suppressing pseudo exon inclusion.
        Cell Chem Biol. 2020; 27: 1472-1482.e6
        • Dyle M.C.
        • Kolakada D.
        • Cortazar M.A.
        • et al.
        How to get away with nonsense: mechanisms and consequences of escape from nonsense-mediated RNA decay.
        Wiley Interdiscip Rev RNA. 2020; 11: e1560
        • Keenan M.M.
        • Huang L.
        • Jordan N.J.
        • et al.
        Nonsense-mediated RNA decay pathway inhibition restores expression and function of W1282X CFTR.
        Am J Respir Cell Mol Biol. 2019; 61: 290-300
        • Aksit M.A.
        • Bowling A.D.
        • Evans T.A.
        • et al.
        Decreased mRNA and protein stability of W1282X limits response to modulator therapy.
        J Cyst Fibros. 2019; 18: 606-613
        • Clarke L.A.
        • Awatade N.T.
        • Felício V.M.
        • et al.
        The effect of premature termination codon mutations on CFTR mRNA abundance in human nasal epithelium and intestinal organoids: a basis for read-through therapies in cystic fibrosis.
        Hum Mutat. 2019; 40: 326-334
        • Wangen J.R.
        • Green R.
        Stop codon context influences genome-wide stimulation of termination codon readthrough by aminoglycosides.
        eLife. 2020; 9: e52611
        • Kerem E.
        • Konstan M.W.
        • De Boeck K.
        • et al.
        Ataluren for the treatment of nonsense-mutation cystic fibrosis: a randomised, double-blind, placebo-controlled phase 3 trial.
        Lancet Respir Med. 2014; 2: 539-547
        • Crawford D.K.
        • Mullenders J.
        • Pott J.
        • et al.
        Targeting G542X CFTR nonsense alleles with ELX-02 restores CFTR function in human-derived intestinal organoids.
        J Cyst Fibros. 2021; 20: 436-442
        • Sharma J.
        • Du M.
        • Wong E.
        • et al.
        A small molecule that induces translational readthrough of CFTR nonsense mutations by eRF1 depletion.
        Nat Commun. 2021; 12: 4358
        • Dietz H.C.
        New therapeutic approaches to mendelian disorders.
        N Engl J Med. 2010; 363: 852-863
        • Adachi H.
        • Yu Y.T.
        Pseudouridine-mediated stop codon readthrough in S. cerevisiae is sequence context–independent.
        RNA. 2020; 26: 1247-1256
        • Porter J.J.
        • Heil C.S.
        • Lueck J.D.
        Therapeutic promise of engineered nonsense suppressor tRNAs.
        Wiley Interdiscip Rev RNA. 2021; 12: e1641
        • Lueck J.D.
        • Yoon J.S.
        • Perales-Puchalt A.
        • et al.
        Engineered transfer RNAs for suppression of premature termination codons.
        Nat Commun. 2019; 10: 822
        • Nickolaus P.
        • Jung B.
        • Sabater J.
        • et al.
        Preclinical evaluation of the epithelial sodium channel inhibitor BI 1265162 for treatment of cystic fibrosis.
        ERJ Open Res. 2020; 6: 00429-02020
        • Danahay H.L.
        • Lilley S.
        • Fox R.
        • et al.
        TMEM16A potentiation: a novel therapeutic approach for the treatment of cystic fibrosis.
        Am J Respir Crit Care Med. 2020; 201: 946-954
        • Cooney A.L.
        • McCray P.B.
        • Sinn P.L.
        Cystic fibrosis gene therapy: looking back, looking forward.
        Genes. 2018; 9: E538
        • Yan Z.
        • Sun X.
        • Feng Z.
        • et al.
        Optimization of recombinant adeno-associated virus-mediated expression for large transgenes, using a synthetic promoter and tandem array enhancers.
        Hum Gene Ther. 2015; 26: 334-346
        • Robinson E.
        • MacDonald K.D.
        • Slaughter K.
        • et al.
        Lipid nanoparticle-delivered chemically modified mRNA restores chloride secretion in cystic fibrosis.
        Mol Ther J Am Soc Gene Ther. 2018; 26: 2034-2046
        • Tang Y.
        • Yan Z.
        • Engelhardt J.F.
        Viral vectors, animal models, and cellular targets for gene therapy of cystic fibrosis lung disease.
        Hum Gene Ther. 2020; 31: 524-537
        • Vaidyanathan S.
        • Baik R.
        • Chen L.
        • et al.
        Targeted replacement of full-length CFTR in human airway stem cells by CRISPR-Cas9 for pan-mutation correction in the endogenous locus.
        Mol Ther J Am Soc Gene Ther. 2021; https://doi.org/10.1016/j.ymthe.2021.03.023
        • Bednarski C.
        • Tomczak K.
        • Vom Hövel B.
        • et al.
        Targeted integration of a super-exon into the CFTR locus leads to functional correction of a cystic fibrosis cell line model.
        PLoS One. 2016; 11: e0161072
        • McNeer N.A.
        • Anandalingam K.
        • Fields R.J.
        • et al.
        Nanoparticles that deliver triplex-forming peptide nucleic acid molecules correct F508del CFTR in airway epithelium.
        Nat Commun. 2015; 6: 6952
        • Maule G.
        • Casini A.
        • Montagna C.
        • et al.
        Allele specific repair of splicing mutations in cystic fibrosis through AsCas12a genome editing.
        Nat Commun. 2019; 10: 3556
        • Sanz D.J.
        • Hollywood J.A.
        • Scallan M.F.
        • et al.
        Cas9/gRNA targeted excision of cystic fibrosis-causing deep-intronic splicing mutations restores normal splicing of CFTR mRNA.
        PLoS One. 2017; 12: e0184009
        • Vaidyanathan S.
        • Salahudeen A.A.
        • Sellers Z.M.
        • et al.
        High-Efficiency, selection-free gene repair in airway stem cells from cystic fibrosis patients rescues CFTR function in differentiated epithelia.
        Cell Stem Cell. 2020; 26: 161-171.e4
        • Santos L.
        • Mention K.
        • Cavusoglu-Doran K.
        • et al.
        Comparison of Cas9 and Cas12a CRISPR editing methods to correct the W1282X-CFTR mutation.
        J Cyst Fibros. 2021; https://doi.org/10.1016/j.jcf.2021.05.014
        • Komor A.C.
        • Kim Y.B.
        • Packer M.S.
        • et al.
        Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage.
        Nature. 2016; 533: 420-424
        • Gaudelli N.M.
        • Komor A.C.
        • Rees H.A.
        • et al.
        Programmable base editing of A•T to G•C in genomic DNA without DNA cleavage.
        Nature. 2017; 551: 464-471
        • Krishnamurthy S.
        • Traore S.
        • Cooney A.L.
        • et al.
        Functional correction of CFTR mutations in human airway epithelial cells using adenine base.
        Nucleic Acids Res. 2021; : gkab788https://doi.org/10.1093/nar/gkab788
        • Geurts M.H.
        • de Poel E.
        • Amatngalim G.D.
        • et al.
        CRISPR-based adenine editors correct nonsense mutations in a cystic fibrosis organoid biobank.
        Cell Stem Cell. 2020; 26: 503-510.e7
        • Jiang T.
        • Henderson J.M.
        • Coote K.
        • et al.
        Chemical modifications of adenine base editor mRNA and guide RNA expand its application scope.
        Nat Commun. 2020; 11: 1979
        • Koblan L.W.
        • Arbab M.
        • Shen M.W.
        • et al.
        Efficient C•G-to-G•C base editors developed using CRISPRi screens, target-library analysis, and machine learning.
        Nat Biotechnol. 2021; https://doi.org/10.1038/s41587-021-00938-z
        • Anzalone A.V.
        • Randolph P.B.
        • Davis J.R.
        • et al.
        Search-and-replace genome editing without double-strand breaks or donor DNA.
        Nature. 2019; 576: 149-157
        • Geurts M.H.
        • de Poel E.
        • Pleguezuelos-Manzano C.
        • et al.
        Evaluating CRISPR-based prime editing for cancer modeling and CFTR repair in organoids.
        Life Sci Alliance. 2021; 4: e202000940https://doi.org/10.26508/lsa.202000940