Bak RO, Gomez-Ospina N, Porteus MH. Gene editing on center stage. Trends Genet. 2018;34:600–11.

CAS  PubMed  Google Scholar 

Broeders M, Herrero-Hernandez P, Ernst MPT, van der Ploeg AT, Pijnappel WWMP. Sharpening the molecular scissors: advances in gene-editing technology. iScience. 2020;23:100789.

Suzuki K, Izpisua-Belmonte JC. In vivo genome editing via the HITI method as a tool for gene therapy. J Hum Genet. 2018;63:157–64.

CAS  PubMed  Google Scholar 

Anzalone AV, Koblan LW, Liu DR. Genome editing with CRISPR–Cas nucleases, base editors, transposases and prime editors. Nat Biotechnol. 2020;38:824–44.

CAS  PubMed  Google Scholar 

Jeong YK, Song B, Bae S. Current status and challenges of DNA base editing tools. Mol Ther. 2020;28:1938–52.

CAS  PubMed  PubMed Central  Google Scholar 

Nuñez JK, Chen J, Pommier GC, Cogan JZ, Replogle JM, Adriaens C, Ramadoss GN, Shi Q, Hung KL, Samelson AJ, et al. Genome-wide programmable transcriptional memory by CRISPR-based epigenome editing. Cell. 2021;184:2503–19.

PubMed  Google Scholar 

Editas Medicine, Inc. Open-Label, Single Ascending Dose Study to Evaluate the Safety, Tolerability, and Efficacy of EDIT-101 in Adult and Pediatric Participants With Leber Congenital Amaurosis Type 10 (LCA10), With Centrosomal Protein 290 (CEP290)-Related Retinal Degeneration Caused by a Compound Heterozygous or Homozygous Mutation Involving c.2991+1655A>G in Intron 26 (IVS26) of the CEP290 Gene (“LCA10-IVS26”) [Internet]. clinicaltrials.gov; 2020 Dec [cited 2021 May 23]. Report No.: NCT03872479. Available from: https://clinicaltrials.gov/ct2/show/NCT03872479

Intellia Therapeutics. Phase 1 Two-Part (Open-label, Single Ascending Dose (Part 1) and Open-label, Single Dose Expansion (Part 2)) Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of NTLA-2001 in Patients With Hereditary Transthyretin Amyloidosis With Polyneuropathy (ATTRv-PN) [Internet]. clinicaltrials.gov; 2020 Dec [cited 2021 May 23]. Report No.: NCT04601051. Available from: https://clinicaltrials.gov/ct2/show/NCT04601051

Vertex Pharmaceuticals Incorporated. A Phase 1/2 Study to Evaluate the Safety and Efficacy of a Single Dose of Autologous CRISPR-Cas9 Modified CD34+ Human Hematopoietic Stem and Progenitor Cells (CTX001) in Subjects With Severe Sickle Cell Disease [Internet]. clinicaltrials.gov; 2021 Jan [cited 2021 May 23]. Report No.: NCT03745287. Available from: https://clinicaltrials.gov/ct2/show/NCT03745287

•• Gillmore JD, Gane E, Taubel J, Kao J, Fontana M, Maitland ML, Seitzer J, O’Connell D, Walsh KR, Wood K, et al. CRISPR-Cas9 in vivo gene editing for transthyretin amyloidosis. N Engl J Med. 2021;385:493–502. Findings from this landmark clinical study using lipid nanoparticle delivery of CRISPR-Cas9 mRNA to knockout TTR in hereditary ATTR amyloidosis demonstrate, for the first time, early efficacy and safety of therapeutic in vivo gene editing in humans.

Riordan JR. CFTR function and prospects for therapy. Annu Rev Biochem. 2008;77:701–26.

CAS  PubMed  Google Scholar 

Pezzulo AA, Tang XX, Hoegger MJ, Abou-Alaiwa MH, Ramachandran S, Moninger TO, Karp PH, Wohlford-Lenane CL, Haagsman HP, van Eijk M, et al. Reduced airway surface pH impairs bacterial killing in the porcine cystic fibrosis lung. Nature. 2012;487:109–13.

CAS  PubMed  PubMed Central  Google Scholar 

Treacy K, Tunney M, Elborn S, Bradley J. Mucociliary clearance in cystic fibrosis: physiology and pharmacological treatments. Paediatr Child Health. 2011;21:425–30.

Google Scholar 

Maule G, Arosio D, Cereseto A. Gene therapy for cystic fibrosis: progress and challenges of genome editing. Int J Mol Sci. 2020;21:3903.

CAS  PubMed Central  Google Scholar 

Graham C, Hart S. CRISPR/Cas9 gene editing therapies for cystic fibrosis. Expert Opin Biol Ther. 2021;21:767–80.

CAS  PubMed  Google Scholar 

Alton EWFW, Armstrong DK, Ashby D, Bayfield KJ, Bilton D, Bloomfield EV, Boyd AC, Brand J, Buchan R, Calcedo R, et al. Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fibrosis: a randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Respir Med. 2015;3:684–91.

CAS  PubMed  PubMed Central  Google Scholar 

Moss RB, Milla C, Colombo J, Accurso F, Zeitlin PL, Clancy JP, Spencer LT, Pilewski J, Waltz DA, Dorkin HL, et al. Repeated aerosolized AAV-CFTR for treatment of cystic fibrosis: a randomized placebo-controlled phase 2B trial. Hum Gene Ther. 2007;18:726–32.

CAS  PubMed  Google Scholar 

Vaidyanathan S, Salahudeen AA, Sellers ZM, Bravo DT, Choi SS, Batish A, Le W, Baik R, de la O S, Kaushik MP, 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;26:161–71.

• Vaidyanathan S, Baik R, Chen L, Bravo DT, Suarez CJ, Abazari SM, Salahudeen AA, Dudek AM, Teran CA, Davis TH, 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. 2021. Findings from this study demonstrate a high level of CRISPR-Cas9-mediated CFTR correction in airway stem cells in vitro illustrating the potential for ex-vivo correction followed by implantation or for a direct in vivo approach.

Gupta A, Zheng SL. Genetic disorders of surfactant protein dysfunction: when to consider and how to investigate. Arch Dis Child. 2017;102:84–90.

PubMed  Google Scholar 

Palomar LM, Nogee LM, Sweet SC, Huddleston CB, Cole FS, Hamvas A. Long-term outcomes after infant lung transplantation for surfactant protein B deficiency related to other causes of respiratory failure. J Pediatr. 2006;149:548–53.

PubMed  Google Scholar 

Kang MH, van Lieshout LP, Xu L, Domm JM, Vadivel A, Renesme L, Mühlfeld C, Hurskainen M, Mižíková I, Pei Y, et al. A lung tropic AAV vector improves survival in a mouse model of surfactant B deficiency. Nat Commun. 2020;11:3929.

CAS  PubMed  PubMed Central  Google Scholar 

• Alapati D, Zacharias WJ, Hartman HA, Rossidis AC, Stratigis JD, Ahn NJ, Coons B, Zhou S, Li H, Singh K, et al. In utero gene editing for monogenic lung disease. Sci Transl Med. 2019;11. Findings from this proof-of-concept mouse study demonstrated the feasibility and potential of in utero CRISPR gene editing to target pulmonary epithelial cells and mitigate the phenotype of a perinatal lethal genetic lung disease.

Bessis N, GarciaCozar FJ. Boissier M-C Immune responses to gene therapy vectors: influence on vector function and effector mechanisms. Gene Ther. 2004;11:S10–7.

CAS  PubMed  Google Scholar 

Shirley JL, de Jong YP, Terhorst C, Herzog RW. Immune responses to viral gene therapy vectors. Mol Ther. 2020;28:709–22.

CAS  PubMed  PubMed Central  Google Scholar 

Greene CM, Marciniak SJ, Teckman J, Ferrarotti I, Brantly ML, Lomas DA, Stoller JK, McElvaney NG. α1-antitrypsin deficiency. Nat Rev Dis Primers. 2016;2:1–17.

Google Scholar 

Quinn M, Ellis P, Pye A, Turner AM. Obstacles to early diagnosis and treatment of alpha-1 antitrypsin deficiency: current perspectives. Ther Clin Risk Manag. 2020;16:1243–55.

CAS  PubMed  PubMed Central  Google Scholar 

Brantly ML, Paul LD, Miller BH, Falk RT, Wu M, Crystal RG. Clinical features and history of the destructive lung disease associated with alpha-1-antitrypsin deficiency of adults with pulmonary symptoms. Am Rev Respir Dis. 1988;138:327–36.

CAS  PubMed  Google Scholar 

Tanash HA, Ekström M, Rönmark E, Lindberg A, Piitulainen E. Survival in individuals with severe alpha 1-antitrypsin deficiency (PiZZ) in comparison to a general population with known smoking habits. Eur Respir J. 2017;50:1700198.

PubMed  Google Scholar 

Tanash HA, Nilsson PM, Nilsson J-Å, Piitulainen E. Survival in severe alpha-1-antitrypsin deficiency (PiZZ). Respir Res. 2010;11:44.

PubMed  PubMed Central  Google Scholar 

Chiuchiolo MJ, Crystal RG. Gene therapy for alpha-1 antitrypsin deficiency lung disease. Ann Am Thorac Soc. 2016;13:S352–69.

PubMed  PubMed Central  Google Scholar 

Chapman KR, Burdon JGW, Piitulainen E, Sandhaus RA, Seersholm N, Stocks JM, Stoel BC, Huang L, Yao Z, Edelman JM, et al. Intravenous augmentation treatment and lung density in severe α1 antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;386:360–8.

CAS  PubMed  PubMed Central  Google Scholar 

Song C, Wang D, Jiang T, O’Connor K, Tang Q, Cai L, Li X, Weng Z, Yin H, Gao G, et al. In vivo genome editing partially restores alpha1-antitrypsin in a murine model of AAT deficiency. Hum Gene Ther. 2018;29:853–60.

CAS  PubMed  PubMed Central  Google Scholar 

Shen S, Sanchez ME, Blomenkamp K, Corcoran EM, Marco E, Yudkoff CJ, Jiang H, Teckman JH, Bumcrot D, Albright CF. Amelioration of alpha-1 antitrypsin deficiency diseases with genome editing in transgenic mice. Hum Gene Ther. 2018;29:861–73.

CAS  PubMed  Google Scholar 

Pickles RJ. Physical and biological barriers to viral vector-mediated delivery of genes to the airway epithelium. Proc Am Thorac Soc. 2004;1:302–8.

CAS  PubMed  Google Scholar 

Sanders N, Rudolph C, Braeckmans K, De Smedt SC, Demeester J. Extracellular barriers in respiratory gene therapy. Adv Drug Deliv Rev. 2009;61:115–27.

CAS  PubMed  Google Scholar 

Barkauskas CE, Cronce MJ, Rackley CR, Bowie EJ, Keene DR, Stripp BR, Randell SH, Noble PW, Hogan BLM. Type 2 alveolar cells are stem cells in adult lung. J Clin Invest. 2013;123:3025–36.

CAS  PubMed  PubMed Central  Google Scholar 

Ferrari S, Griesenbach U, Geddes DM, Alton E. Immunological hurdles to lung gene therapy. Clin Exp Immunol. 2003;132:1–8.

CAS  PubMed  PubMed Central  Google Scholar 

Davey MG, Riley JS, Andrews A, Tyminski A, Limberis M, Pogoriler JE, Partridge E, Olive A, Hedrick HL, Flake AW, et al. Induction of immune tolerance to foreign protein via adeno-associated viral vector gene transfer in mid-gestation fetal sheep. PLoS One. 2017;12:e0171132.

Peranteau WH, Hayashi S, Hsieh M, Shaaban AF, Flake AW. High-level allogeneic chimerism achieved by prenatal tolerance induction and postnatal nonmyeloablative bone marrow transplantation. Blood. 2002;100:2225–34.

CAS  PubMed  Google Scholar 

Riley JS, McClain LE, Stratigis JD, Coons BE, Ahn NJ, Li H, Loukogeorgakis SP, Fachin CG, Dias AIBS, Flake AW, et al. Regulatory T cells promote alloengraftment in a model of late-gestation in utero hematopoietic cell transplantation. Blood Adv. 2020;4:1102–14.

CAS  PubMed  PubMed Central  Google Scholar 

Li A, Tanner MR, Lee CM, Hurley AE, Giorgi MD, Jarrett KE, Davis TH, Doerfler AM, Bao G, Beeton C, et al. AAV-CRISPR gene editing is negated by pre-existing immunity to Cas9. Mol Ther. 2020;28:1432–41.

CAS  PubMed  PubMed Central  Google Scholar 

Charlesworth CT, Deshpande PS, Dever DP, Camarena J, Lemgart VT, Cromer MK, Vakulskas CA, Collingwood MA, Zhang L, Bode NM, et al. Identification of preexisting adaptive immunity to Cas9 proteins in humans. Nat Med. 2019;25:249–54.

CAS  PubMed  PubMed Central  Google Scholar 

Bose SK, White BM, Kashyap MV, Dave A, De Bie FR, Li H, Singh K, Menon P, Wang T, Teerdhala S, et al. In utero adenine base editing corrects multi-organ pathology in a lethal lysosomal storage disease. Nat Commun. 2021;12:4291.

CAS  PubMed  PubMed Central  Google Scholar 

Rossidis AC, Stratigis JD, Chadwick AC, Hartman HA, Ahn NJ, Li H, Singh K, Coons BE, Li L, Lv W, et al. In utero CRISPR-mediated therapeutic editing of metabolic genes. Nat Med. 2018;24:1513–8.

CAS  PubMed  PubMed Central  Google Scholar 

Schene IF, Joore IP, Oka R, Mokry M, van Vugt AHM, van Boxtel R, van der Doef HPJ, van der Laan LJW, Verstegen MMA, van Hasselt PM, et al. Prime editing for functional repair in patient-derived disease models. Nat Commun. 2020;11:5352.

CAS  PubMed  PubMed Central  Google Scholar 

Liu Y, Li X, He S, Huang S, Li C, Chen Y, Liu Z, Huang X, Wang X. Efficient generation of mouse models with the prime editing system. Cell Discov. 2020;6:1–4.

PubMed  PubMed Central  Google Scholar