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Gene Editing for CF

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Cystic Fibrosis

Part of the book series: Respiratory Medicine ((RM))

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Abstract

Cystic fibrosis therapeutics have advanced steadily over the past half century, increasing life expectancy from pre-school ages into the fourth and fifth decades of life. New, small molecule pharmacologic therapies that modulate CFTR biosynthesis or activity are proving to be quite effective for many CF patients, indicating that intervention at the level of the basic defect is an effective therapeutic strategy. However, there are over 2000 different mutations documented in the CFTR gene of persons with cystic fibrosis. This is a difficult scenario for developing the minimal number of therapeutic approaches that will service the greatest number of affected individuals. Molecular therapies that can alter the genome, repairing or circumventing a CFTR mutation, are becoming more feasible with recent advances in molecular biology along with technologies to deliver these genome editing systems to cells in the body. These new technologies precisely target DNA editing machinery to single sites in the genome and allow one to pursue a variety of strategies. Those that are mutation-specific include homology-dependent repair of DNA breaks, base editing by nucleotide deamination and peptide nucleic acids (PNAs) to actually change a specific mutation. There are also strategies that would circumvent many or all mutations by insertion, such that a complete or partial cDNA is introduced into the CFTR gene at a position that will override mutations. It is unclear which of these or future strategies will prevail, but there is great optimism with such technologies available.

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References

  1. Rommens JM, Iannuzzi MC, Kerem B, Drumm ML, Melmer G, Dean M, Rozmahel R, Cole JL, Kennedy D, Hidaka N, et al. Identification of the cystic fibrosis gene: chromosome walking and jumping. Science. 1989;245:1059–65.

    Article  CAS  Google Scholar 

  2. Rich DP, Anderson MP, Gregory RJ, Cheng SH, Paul S, Jefferson DM, McCann JD, Klinger KW, Smith AE, Welsh MJ. Expression of cystic fibrosis transmembrane conductance regulator corrects defective chloride channel regulation in cystic fibrosis airway epithelial cells. Nature. 1990;347:358–63.

    Article  CAS  Google Scholar 

  3. Drumm ML, Pope HA, Cliff WH, Rommens JM, Marvin SA, Tsui LC, Collins FS, Frizzell RA, Wilson JM. Correction of the cystic fibrosis defect in vitro by retrovirus-mediated gene transfer. Cell. 1990;62:1227–33.

    Article  CAS  Google Scholar 

  4. Alton EW, Boyd AC, Davies JC, Gill DR, Griesenbach U, Harrison PT, Henig N, Higgins T, Hyde SC, Innes JA, et al. Genetic medicines for CF: hype versus reality. Pediatr Pulmonol. 2016;51:S5–S17.

    Article  Google Scholar 

  5. Drumm ML, Wilkinson DJ, Smit LS, Worrell RT, Strong TV, Frizzell RA, Dawson DC, Collins FS. Chloride conductance expressed by delta F508 and other mutant CFTRs in Xenopus oocytes. Science. 1991;254:1797–9.

    Article  CAS  Google Scholar 

  6. Kelley TJ, Al-Nakkash L, Cotton CU, Drumm ML. Activation of endogenous deltaF508 cystic fibrosis transmembrane conductance regulator by phosphodiesterase inhibition. J Clin Invest. 1996;98:513–20.

    Article  CAS  Google Scholar 

  7. Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Drevinek P, Griese M, McKone EF, Wainwright CE, Konstan MW, et al. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011;365:1663–72.

    Article  CAS  Google Scholar 

  8. Kim YG, Cha J, Chandrasegaran S. Hybrid restriction enzymes: zinc finger fusions to Fok I cleavage domain. Proceed Nat Acad Sci United States Am. 1996;93:1156–60.

    Article  CAS  Google Scholar 

  9. Boch J, Scholze H, Schornack S, Landgraf A, Hahn S, Kay S, Lahaye T, Nickstadt A, Bonas U. Breaking the code of DNA binding specificity of TAL-type III effectors. Science. 2009;326:1509–12.

    Article  CAS  Google Scholar 

  10. Boch J. TALEs of genome targeting. Nat Biotechnol. 2011;29:135–6.

    Article  CAS  Google Scholar 

  11. Mali P, Yang L, Esvelt KM, Aach J, Guell M, DiCarlo JE, Norville JE, Church GM. RNA-guided human genome engineering via Cas9. Science. 2013;339:823–6.

    Article  CAS  Google Scholar 

  12. Jinek M, East A, Cheng A, Lin S, Ma E, Doudna J. RNA-programmed genome editing in human cells. elife. 2013;2:e00471.

    Article  Google Scholar 

  13. Gaudelli NM, Komor AC, Rees HA, Packer MS, Badran AH, Bryson DI, Liu DR. Programmable base editing of A∗T to G∗C in genomic DNA without DNA cleavage. Nature. 2017;551:464–71.

    Article  CAS  Google Scholar 

  14. Cheng AW, Wang H, Yang H, Shi L, Katz Y, Theunissen TW, Rangarajan S, Shivalila CS, Dadon DB, Jaenisch R. Multiplexed activation of endogenous genes by CRISPR-on, an RNA-guided transcriptional activator system. Cell Res. 2013;23:1163–71.

    Article  CAS  Google Scholar 

  15. Maeder ML, Linder SJ, Cascio VM, Fu Y, Ho QH, Joung JK. CRISPR RNA-guided activation of endogenous human genes. Nat Methods. 2013;10:977–9.

    Article  CAS  Google Scholar 

  16. Gilbert LA, Larson MH, Morsut L, Liu Z, Brar GA, Torres SE, Stern-Ginossar N, Brandman O, Whitehead EH, Doudna JA, et al. CRISPR-mediated modular RNA-guided regulation of transcription in eukaryotes. Cell. 2013;154:442–51.

    Article  CAS  Google Scholar 

  17. Ran FA, Hsu PD, Lin CY, Gootenberg JS, Konermann S, Trevino AE, Scott DA, Inoue A, Matoba S, Zhang Y, et al. Double nicking by RNA-guided CRISPR Cas9 for enhanced genome editing specificity. Cell. 2013;154:1380–9.

    Article  CAS  Google Scholar 

  18. Huang TP, Zhao KT, Miller SM, Gaudelli NM, Oakes BL, Fellmann C, Savage DF, Liu DR. Circularly permuted and PAM-modified Cas9 variants broaden the targeting scope of base editors. Nat Biotechnol. 2019;37:626–31.

    Article  CAS  Google Scholar 

  19. Ricciardi AS, Quijano E, Putman R, Saltzman WM, Glazer PM. Peptide nucleic acids as a tool for site-specific gene editing. Molecules. 2018;23:632.

    Article  Google Scholar 

  20. McNeer NA, Anandalingam K, Fields RJ, Caputo C, Kopic S, Gupta A, Quijano E, Polikoff L, Kong Y, Bahal R, et al. Nanoparticles that deliver triplex-forming peptide nucleic acid molecules correct F508del CFTR in airway epithelium. Nat Commun. 2015;6:6952.

    Article  CAS  Google Scholar 

  21. Zhou L, Dey CR, Wert SE, DuVall MD, Frizzell RA, Whitsett JA. Correction of lethal intestinal defect in a mouse model of cystic fibrosis by human CFTR. Science. 1994;266:1705–8.

    Article  CAS  Google Scholar 

  22. Hodges CA, Grady BR, Mishra K, Cotton CU, Drumm ML. Cystic fibrosis growth retardation is not correlated with loss of Cftr in the intestinal epithelium. Am J Physiol Gastrointest Liver Physiol. 2011;301:G528–36.

    Article  CAS  Google Scholar 

  23. Plasschaert LW, Zilionis R, Choo-Wing R, Savova V, Knehr J, Roma G, Klein AM, Jaffe AB. A single-cell atlas of the airway epithelium reveals the CFTR-rich pulmonary ionocyte. Nature. 2018;560:377–81.

    Article  CAS  Google Scholar 

  24. Montoro DT, Haber AL, Biton M, Vinarsky V, Lin B, Birket SE, Yuan F, Chen S, Leung HM, Villoria J, et al. A revised airway epithelial hierarchy includes CFTR-expressing ionocytes. Nature. 2018;560:319–24.

    Article  CAS  Google Scholar 

  25. Hawkins FJ, Kotton DN. Pulmonary ionocytes challenge the paradigm in cystic fibrosis. Trends Pharmacol Sci. 2018;39:852–4.

    Article  CAS  Google Scholar 

  26. Bonfield TL, Hodges CA, Cotton CU, Drumm ML. Absence of the cystic fibrosis transmembrane regulator (Cftr) from myeloid-derived cells slows resolution of inflammation and infection. J Leukoc Biol. 2012;92:1111–22.

    Article  CAS  Google Scholar 

  27. Mueller C, Braag SA, Keeler A, Hodges C, Drumm M, Flotte TR. Lack of cystic fibrosis transmembrane conductance regulator in CD3+ lymphocytes leads to aberrant cytokine secretion and hyperinflammatory adaptive immune responses. Am J Respir Cell Mol Biol. 2011;44:922–9.

    Article  CAS  Google Scholar 

  28. Schwank G, Koo BK, Sasselli V, Dekkers JF, Heo I, Demircan T, Sasaki N, Boymans S, Cuppen E, van der Ent CK, et al. Functional repair of CFTR by CRISPR/Cas9 in intestinal stem cell organoids of cystic fibrosis patients. Cell Stem Cell. 2013;13:653–8.

    Article  CAS  Google Scholar 

  29. Ruan J, Hirai H, Yang D, Ma L, Hou X, Jiang H, Wei H, Rajagopalan C, Mou H, Wang G, et al. Efficient gene editing at major CFTR mutation loci. Mol Ther Nucl Acids. 2019;16:73–81.

    Article  CAS  Google Scholar 

  30. Maule G, Casini A, Montagna C, Ramalho AS, De Boeck K, Debyser Z, Carlon MS, Petris G, Cereseto A. Allele specific repair of splicing mutations in cystic fibrosis through AsCas12a genome editing. Nat Commun. 2019;10:3556.

    Article  Google Scholar 

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Author information

Authors and Affiliations

  1. Case Western Reserve University, Department of Genetics and Genome Sciences, Cystic Fibrosis Research Center, Cleveland, OH, USA

    Mitchell L. Drumm

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  1. Mitchell L. Drumm
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Correspondence to Mitchell L. Drumm .

Editor information

Editors and Affiliations

  1. The University of North Carolina at Chapel Hill, Department of Pediatrics, UNC Children’s Hospital, Chapel Hill, NC, USA

    Stephanie Duggins Davis

  2. Department of Pediatrics, University of Washington School of Medicine, Division of Pulmonary and Sleep Medicine, Seattle Children’s Hospital, Seattle, WA, USA

    Margaret Rosenfeld

  3. Department of Pediatrics, Indiana University School of Medicine, Division of Pediatric Pulmonology, Allergy and Sleep Medicine, Riley Hospital for Children at IU Health, Indianapolis, IN, USA

    James Chmiel

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Drumm, M.L. (2020). Gene Editing for CF. In: Davis, S., Rosenfeld, M., Chmiel, J. (eds) Cystic Fibrosis. Respiratory Medicine. Humana, Cham. https://doi.org/10.1007/978-3-030-42382-7_25

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  • DOI: https://doi.org/10.1007/978-3-030-42382-7_25

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  • Publisher Name: Humana, Cham

  • Print ISBN: 978-3-030-42381-0

  • Online ISBN: 978-3-030-42382-7

  • eBook Packages: MedicineMedicine (R0)

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