Genome Editing for Rare Diseases


Purpose of the Review

Significant numbers of patients worldwide are affected by various rare diseases, but the effective treatment options to these individuals are limited. Rare diseases remain underfunded compared with more common diseases, leading to significant delays in research progress and ultimately, to finding an effective cure. Here, we review the use of genome-editing tools to understand the pathogenesis of rare diseases and develop additional therapeutic approaches with a high degree of precision.

Recent Findings

Several genome-editing approaches, including CRISPR/Cas9, TALEN, and ZFN, have been used to generate animal models of rare diseases, understand the disease pathogenesis, correct pathogenic mutations in patient-derived somatic cells and iPSCs, and develop new therapies for rare diseases. The CRISPR/Cas9 system stands out as the most extensively used method for genome editing due to its relative simplicity and superior efficiency compared with TALEN and ZFN. CRISPR/Cas9 is emerging as a feasible gene-editing option to treat rare monogenic and other genetically defined human diseases.


Less than 5% of ~ 7000 known rare diseases have FDA-approved therapies, providing a compelling need for additional research and clinical trials to identify efficient treatment options for patients with rare diseases. Development of efficient genome-editing tools capable to correct or replace dysfunctional genes will lead to novel therapeutic approaches in these diseases.

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Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.

    Sun W, Zheng W, Simeonov A. Drug discovery and development for rare genetic disorders. Am J Med Genet A. 2017;173(9):2307–22.

    Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Szajner P, Yusufzai T. Introducing rare diseases. Rare Dis. 2013;1:e24735.

    Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Moliner AM, Waligora J. The European Union policy in the field of rare diseases. Adv Exp Med Biol. 2017;1031:561–87.

    Article  PubMed  Google Scholar 

  4. 4.

    •• Papasavva P, Kleanthous M, Lederer CW. Rare opportunities: CRISPR/Cas-based therapy development for rare genetic diseases. Mol Diagn Ther. 2019;23(2):201–22. review about CRISPR/Cas9 technology in rare diseases.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. 5.

    Schieppati A, Henter JI, Daina E, Aperia A. Why rare diseases are an important medical and social issue. Lancet. 2008;371(9629):2039–41.

    Article  PubMed  Google Scholar 

  6. 6.

    Dharmadhikari AV, Szafranski P, Kalinichenko VV, Stankiewicz P. Genomic and epigenetic complexity of the FOXF1 locus in 16q24.1: implications for development and disease. Curr Genom. 2015;16(2):107–16.

    Article  CAS  Google Scholar 

  7. 7.

    •• Pradhan A, Dunn A, Ustiyan V, Bolte C, Wang G, et al. The S52F FOXF1 mutation inhibits STAT3 signaling and causes alveolar capillary dysplasia. Am J Respir Crit Care Med. 2019;200(8):1045–56. of mouse model of ACDMPV using CRISPR/Cas9 approach, and improvement of pulmonary vasculature by nanoparticle-mediated gene delivery.

    Article  PubMed  CAS  Google Scholar 

  8. 8.

    Cuthbert AW. New horizons in the treatment of cystic fibrosis. Br J Pharmacol. 2011;163(1):173–83.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. 9.

    Runz H, Dolle D, Schlitter AM, Zschocke J. NPC-db, a Niemann-Pick type C disease gene variation database. Hum Mutat. 2008;29(3):345–50.

    Article  PubMed  CAS  Google Scholar 

  10. 10.

    Chabannon C, Kuball J, Bondanza A, Dazzi F, Pedrazzoli P, Toubert A, et al. Hematopoietic stem cell transplantation in its 60s: a platform for cellular therapies. Sci Transl Med. 2018;10(436).

  11. 11.

    Bernstein DL, Lobritto S, Iuga A, Remotti H, Schiano T, Fiel MI, et al. Lysosomal acid lipase deficiency allograft recurrence and liver failure- clinical outcomes of 18 liver transplantation patients. Mol Genet Metab. 2018;124(1):11–9.

    Article  PubMed  CAS  Google Scholar 

  12. 12.

    Choi KA, Choi Y, Hong S. Stem cell transplantation for Huntington’s diseases. Methods. 2018;133:104–12.

    Article  PubMed  CAS  Google Scholar 

  13. 13.

    •• Santos R, Amaral O. Advances in sphingolipidoses: CRISPR-Cas9 editing as an option for modelling and therapy. Int J Mol Sci. 2019;20(23):E5897. review about CRISPR/Cas9 technology in generation of animal models of inherited genetic diseases caused by accumulation of glycosphingolipids.

    Article  PubMed  CAS  Google Scholar 

  14. 14.

    Cox DB, Platt RJ, Zhang F. Therapeutic genome editing: prospects and challenges. Nat Med. 2015;21(2):121–31.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. 15.

    •• Doudna JA, Gersbach CA. Genome editing: the end of the beginning. Genome Biol. 2015;16:292. review about genome-editing approaches.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. 16.

    • Kanchiswamy CN, Maffei M, Malnoy M, Velasco R, Kim JS. Fine-tuning next-generation genome editing tools. Trends Biotechnol. 2016;34(7):562–74. review about recent advances of genome-editing tools.

    Article  PubMed  CAS  Google Scholar 

  17. 17.

    Greely HT. Human germline genome editing: an assessment. CRISPR J. 2019;2(5):253–65.

    Article  PubMed  Google Scholar 

  18. 18.

    Doudna JA, Charpentier E. Genome editing. The new frontier of genome engineering with CRISPR-Cas9. Science. 2014;346(6213):1258096.

    Article  PubMed  CAS  Google Scholar 

  19. 19.

    Hsu PD, Lander ES, Zhang F. Development and applications of CRISPR-Cas9 for genome engineering. Cell. 2014;157(6):1262–78.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. 20.

    Barrangou R, Dudley EG. CRISPR-based typing and next-generation tracking technologies. Annu Rev Food Sci Technol. 2016;7:395–411.

    Article  PubMed  CAS  Google Scholar 

  21. 21.

    Kang Y, Chu C, Wang F, Niu Y. CRISPR/Cas9-mediated genome editing in nonhuman primates. Dis Model Mech. 2019;12(10).

  22. 22.

    •• Tseng WC, Loeb HE, Pei W, Tsai-Morris CH, Xu L, Cluzeau CV, et al. Modeling Niemann-Pick disease type C1 in zebrafish: a robust platform for in vivo screening of candidate therapeutic compounds. Dis Model Mech. 2018;11(9). of zebrafish model of NPC1 for screening of therapeutic compounds.

  23. 23.

    Kodama K, Takahashi H, Oiji N, Nakano K, Okamura T, Niimi K, et al. CANT1 deficiency in a mouse model of Desbuquois dysplasia impairs glycosaminoglycan synthesis and chondrocyte differentiation in growth plate cartilage. FEBS Open Bio. 2020;10:1096–103.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. 24.

    Dreano E, Bacchetta M, Simonin J, Galmiche L, Usal C, Slimani L, et al. Characterization of two rat models of cystic fibrosis—KO and F508del CFTR—generated by Crispr-Cas9. Anim Model Exp Med. 2019;2:297–311.

    Article  Google Scholar 

  25. 25.

    • Zabaleta N, Barberia M, Martin-Higueras C, Zapata-Linares N, Betancor I, Rodriguez S, et al. CRISPR/Cas9-mediated glycolate oxidase disruption is an efficacious and safe treatment for primary hyperoxaluria type I. Nat Commun. 2018;9(1):5454. paper demonstrates that CRISPR/Cas9-mediated substrate reduction therapy in Agxt1−/− mice is a promising therapeutic option for primary hyperoxaluria type I.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. 26.

    Schlegel J, Hoffmann J, Röll D, Müller B, Günther S, Zhang W, et al. Toward genome editing in X-linked RP-development of a mouse model with specific treatment relevant features. Transl Res. 2019;203:57–72.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. 27.

    •• Bolte C, Ustiyan V, Ren X, Dunn AW, Pradhan A, Wang G, et al. Nanoparticle delivery of proangiogenic transcription factors into the neonatal circulation inhibits alveolar simplification caused by hyperoxia. Am J Respir Crit Care Med. 2020. paper provides evidence that nanoparticle-mediated delivery of proangiogenic transcription factors stimulates lung angiogenesis and alveolarization during recovery from neonatal hyperoxic injury.

  28. 28.

    Kim YK, Yu JH, Min SH, Park SW. Generation of a GLA knock-out human-induced pluripotent stem cell line, KSBCi002-A-1, using CRISPR/Cas9. Stem Cell Res. 2020;42:101676.

    Article  PubMed  CAS  Google Scholar 

  29. 29.

    Sen P, Dharmadhikari AV, Majewski T, Mohammad MA, Kalin TV, Zabielska J, et al. Comparative analyses of lung transcriptomes in patients with alveolar capillary dysplasia with misalignment of pulmonary veins and in foxf1 heterozygous knockout mice. PLoS One. 2014;9(4):e94390. eCollection 2014.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. 30.

    Bolte C, Whitsett JA, Kalin TV, Kalinichenko VV. Transcription factors regulating embryonic development of pulmonary vasculature. Adv Anat Embryol Cell Biol. 2018;228:1–20.

    Article  PubMed  Google Scholar 

  31. 31.

    Whitsett JA, Kalin TV, Xu Y, Kalinichenko VV. Building and regenerating the lung cell by cell. Physiol Rev. 2019;99(1):513–54.

    Article  PubMed  CAS  Google Scholar 

  32. 32.

    Kim IM, Zhou Y, Ramakrishna S, Hughes DE, Solway J, Costa RH, et al. Functional characterization of evolutionarily conserved DNA regions in forkhead box f1 gene locus. J Biol Chem. 2005;280(45):37908–16.

    Article  PubMed  CAS  Google Scholar 

  33. 33.

    Kalinichenko VV, Gusarova GA, Shin B, Costa RH. The forkhead box F1 transcription factor is expressed in brain and head mesenchyme during mouse embryonic development. Gene Expr Patterns. 2003;3(2):153–8.

    Article  PubMed  CAS  Google Scholar 

  34. 34.

    Hoggatt AM, Kim JR, Ustiyan V, Ren X, Kalin TV, Kalinichenko VV, et al. The transcription factor Foxf1 binds to serum response factor and myocardin to regulate gene transcription in visceral smooth muscle cells. J Biol Chem. 2013;288(40):28477–87.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. 35.

    Bolte C, Ren X, Tomley T, Ustiyan V, Pradhan A, Hoggatt A, et al. Forkhead box F2 regulation of platelet-derived growth factor and myocardin/serum response factor signaling is essential for intestinal development. J Biol Chem. 2015;290(12):7563–75.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. 36.

    Hoffmann AD, Yang XH, Burnicka-Turek O, Bosman JD, Ren X, Steimle JD, et al. Foxf genes integrate tbx5 and hedgehog pathways in the second heart field for cardiac septation. PLoS Genet. 2014;10(10):e1004604. eCollection 2014 Oct.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. 37.

    Xu J, Liu H, Lan Y, Aronow BJ, Kalinichenko VV, Jiang R. A Shh-Foxf-Fgf18-Shh molecular circuit regulating palate development. PLoS Genet. 2016;12(1):e1005769. eCollection 2016 Jan.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. 38.

    Dharmadhikari AV, Sun JJ, Gogolewski K, Carofino BL, Ustiyan V, Hill M, et al. Lethal lung hypoplasia and vascular defects in mice with conditional Foxf1 overexpression. Biol Open. 2016;5(11):1595–606.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. 39.

    Ustiyan V, Bolte C, Zhang Y, Han L, Xu Y, Yutzey KE, et al. FOXF1 transcription factor promotes lung morphogenesis by inducing cellular proliferation in fetal lung mesenchyme. Dev Biol. 2018;443(1):50–63.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. 40.

    Milewski D, Pradhan A, Wang X, Cai Y, Le T, Turpin B, et al. FoxF1 and FoxF2 transcription factors synergistically promote rhabdomyosarcoma carcinogenesis by repressing transcription of p21Cip1 CDK inhibitor. Oncogene. 2017;36(6):850–62.

    Article  PubMed  CAS  Google Scholar 

  41. 41.

    Pradhan A, Ustiyan V, Zhang Y, Kalin TV, Kalinichenko VV. Forkhead transcription factor FoxF1 interacts with fanconi anemia protein complexes to promote DNA damage response. Oncotarget. 2016;7(2):1912–26.

    Article  PubMed  Google Scholar 

  42. 42.

    Flood HM, Bolte C, Dasgupta N, Sharma A, Zhang Y, Gandhi CR, et al. The Forkhead box F1 transcription factor inhibits collagen deposition and accumulation of myofibroblasts during liver fibrosis. Biol Open. 2019;8(2).

  43. 43.

    Bolte C, Kalin TV, Kalinichenko VV. Molecular, cellular, and bioengineering approaches to stimulate lung regeneration after injury. Semin Cell Dev Biol. 2020;100:101–8.

    Article  PubMed  CAS  Google Scholar 

  44. 44.

    Kalinichenko VV, Zhou Y, Shin B, Stolz DB, Watkins SC, Whitsett JA, et al. Wild-type levels of the mouse Forkhead Box f1 gene are essential for lung repair. Am J Physiol Lung Cell Mol Physiol. 2002;282(6):L1253–65.

    Article  PubMed  CAS  Google Scholar 

  45. 45.

    Kalin TV, Meliton L, Meliton AY, Zhu X, Whitsett JA, Kalinichenko VV. Pulmonary mastocytosis and enhanced lung inflammation in mice heterozygous null for the Foxf1 gene. Am J Respir Cell Mol Biol. 2008;39(4):390–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. 46.

    Cai Y, Bolte C, Le T, Goda C, Xu Y, Kalin TV, et al. FOXF1 maintains endothelial barrier function and prevents edema after lung injury. Sci Signal. 2016;9(424):ra40.

    Article  PubMed  CAS  Google Scholar 

  47. 47.

    Black M, Milewski D, Le T, Ren X, Xu Y, Kalinichenko VV, et al. FOXF1 inhibits pulmonary fibrosis by preventing CDH2-CDH11 cadherin switch in myofibroblasts. Cell Rep. 2018;23(2):442–58.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. 48.

    Dunn AW, Kalinichenko VV, Shi D. Highly efficient in vivo targeting of the pulmonary endothelium using novel modifications of polyethylenimine: an importance of charge. Adv Healthc Mater. 2018;7(23):e1800876.

    Article  PubMed  CAS  Google Scholar 

  49. 49.

    Ren X, Ustiyan V, Guo M, Wang G, Bolte C, Zhang Y, et al. Postnatal alveologenesis depends on FOXF1 signaling in c-KIT+ endothelial progenitor cells. Am J Respir Crit Care Med. 2019;200(9):1164–76.

    Article  PubMed  CAS  Google Scholar 

  50. 50.

    Goossens R, van den Boogaard ML, Lemmers RJLF, Balog J, van der Vliet PJ, Willemsen IM, et al. Intronic SMCHD1 variants in FSHD: testing the potential for CRISPR-Cas9 genome editing. J Med Genet. 2019;56(12):828–37.

    Article  PubMed  CAS  Google Scholar 

  51. 51.

    Du X, Lukmantara I, Yang H. CRISPR/Cas9-mediated generation of Niemann-Pick C1 knockout cell line. Methods Mol Biol. 2017;1583:73–83.

    Article  PubMed  CAS  Google Scholar 

  52. 52.

    Lenders M, Stappers F, Niemietz C, Schmitz B, Boutin M, Ballmaier PJ, et al. Mutation-specific Fabry disease patient-derived cell model to evaluate the amenability to chaperone therapy. J Med Genet. 2019;56(8):548–56.

    Article  PubMed  CAS  Google Scholar 

  53. 53.

    •• Song HY, Chien CS, Yarmishyn AA, Chou SJ, Yang YP, Wang ML, et al. Generation of GLA-knockout human embryonic stem cell lines to model autophagic dysfunction and exosome secretion in fabry disease-associated hypertrophic cardiomyopathy. Cells. 2019;8(4). paper provides evidence that GLA−/− human embryonic stem cells (generated using CRISPR/Cas9) can be used as a promising tool to study hypertrophic cardiomyopathy and to develop new therapies for Fabry disease.

  54. 54.

    Song HY, Chiang HC, Tseng WL, Wu P, Chien CS, Leu HB, et al. Using CRISPR/Cas9-mediated GLA gene knockout as an in vitro drug screening model for fabry disease. Int J Mol Sci. 2016;17(12).

  55. 55.

    Park SH, Lee CM, Dever DP, Davis TH, Camarena J, Srifa W, et al. Highly efficient editing of the β-globin gene in patient-derived hematopoietic stem and progenitor cells to treat sickle cell disease. Nucleic Acids Res. 2019;47(15):7955–72.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. 56.

    Kalkan BM, Kala EY, Yuce M, Karadag Alpaslan M, Kocabas F. Development of gene editing strategies for human β-globin (HBB) gene mutations. Gene. 2020;734:144398.

    Article  PubMed  CAS  Google Scholar 

  57. 57.

    Haro-Mora JJ, Uchida N, Demirci S, Wang Q, Zou J, Tisdale JF. Biallelic correction of sickle cell disease-derived iPSCs confirmed at the protein level through serum-free iPS-sac/erythroid differentiation. Stem Cells Transl Med. 2020;9:590–602.

    Article  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Weber L, Frati G, Felix T, Hardouin G, Casini A, Wollenschlaeger C, et al. Editing a γ-globin repressor binding site restores fetal hemoglobin synthesis and corrects the sickle cell disease phenotype. Sci Adv. 2020;6(7):eaay9392. eCollection 2020 Feb.

    Article  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Métais JY, Doerfler PA, Mayuranathan T, Bauer DE, Fowler SC, Hsieh MM, et al. Genome editing of HBG1 and HBG2 to induce fetal hemoglobin. Blood Adv. 2019;3(21):3379–92.

    Article  PubMed  PubMed Central  Google Scholar 

  60. 60.

    •• Sürün D, Schwäble J, Tomasovic A, Ehling R, Stein S, Kurrle N, et al. High efficiency gene correction in hematopoietic cells by donor-template-free CRISPR/Cas9 genome editing. Mol Ther Nucleic Acids. 2018;10:1–8. paper demonstrated the possibility of CRISPR/Cas9-mediated repair of patient-specific point mutations in CYBB gene, whose inactivation causes chronic granulomatous disease (XCGD).

    Article  PubMed  CAS  Google Scholar 

  61. 61.

    Klatt D, Cheng E, Philipp F, Selich A, Dahlke J, Schmidt RE, et al. Targeted repair of p47-CGD in iPSCs by CRISPR/Cas9: functional correction without cleavage in the highly homologous pseudogenes. Stem Cell Rep. 2019;13(4):590–8.

    Article  CAS  Google Scholar 

  62. 62.

    Benati D, Miselli F, Cocchiarella F, Patrizi C, Carretero M, Baldassarri S, et al. CRISPR/Cas9-mediated in situ correction of LAMB3 gene in keratinocytes derived from a junctional epidermolysis bullosa patient. Mol Ther. 2018;26(11):2592–603.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. 63.

    Wang S, Min Z, Ji Q, Geng L, Su Y, Liu Z, et al. Rescue of premature aging defects in Cockayne syndrome stem cells by CRISPR/Cas9-mediated gene correction. Protein Cell. 2020;11(1):1–22.

    Article  PubMed  CAS  Google Scholar 

  64. 64.

    Iyer S, Suresh S, Guo D, Daman K, Chen JCJ, Liu P, et al. Precise therapeutic gene correction by a simple nuclease-induced double-stranded break. Nature. 2019;568(7753):561–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. 65.

    Amoasii L, Li H, Zhang Y, Min YL, Sanchez-Ortiz E, Shelton JM, et al. In vivo non-invasive monitoring of dystrophin correction in a new Duchenne muscular dystrophy reporter mouse. Nat Commun. 2019;10(1):4537.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. 66.

    Min YL, Li H, Rodriguez-Caycedo C, Mireault AA, Huang J, Shelton JM, et al. CRISPR-Cas9 corrects Duchenne muscular dystrophy exon 44 deletion mutations in mice and human cells. Sci Adv. 2019;5(3):eaav4324. eCollection 2019 Mar.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. 67.

    Nelson CE, Hakim CH, Ousterout DG, Thakore PI, Moreb EA, Castellanos Rivera RM, et al. In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophy. Science. 2016;351(6271):403–7.

    Article  PubMed  CAS  Google Scholar 

  68. 68.

    •• Zhang Y, Li H, Min YL, Sanchez-Ortiz E, Huang J, Mireault AA, et al. Enhanced CRISPR-Cas9 correction of Duchenne muscular dystrophy in mice by a self-complementary AAV delivery system. Sci Adv. 2020;6(8):eaay6812. eCollection 2020 Feb. The paper demonstrates that a low dose of scAAV-delivered genome-editing components is sufficient to restore dystrophin protein expression and improve the muscle function in a DMD mouse model.

    Article  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Tropak MB, Yonekawa S, Karumuthil-Melethil S, Thompson P, Wakarchuk W, Gray SJ, et al. Construction of a hybrid β-hexosaminidase subunit capable of forming stable homodimers that hydrolyze GM2 ganglioside in vivo. Mol Ther Methods Clin Dev. 2016;3:15057. eCollection 2016.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. 70.

    Allende ML, Cook EK, Larman BC, Nugent A, Brady JM, Golebiowski D, et al. Cerebral organoids derived from Sandhoff disease-induced pluripotent stem cells exhibit impaired neurodifferentiation. J Lipid Res. 2018;59(3):550–63.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. 71.

    Ou L, Przybilla MJ, Tăbăran AF, Overn P, O’Sullivan MG, Jiang X, et al. A novel gene editing system to treat both Tay-Sachs and Sandhoff diseases. Gene Ther. 2020;27:226–36.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. 72.

    Wang D, Li J, Song CQ, Tran K, Mou H, Wu PH, et al. Cas9-mediated allelic exchange repairs compound heterozygous recessive mutations in mice. Nat Biotechnol. 2018;36(9):839–42.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. 73.

    Hinderer C, Katz N, Louboutin JP, Bell P, Yu H, Nayal M, et al. Delivery of an adeno-associated virus vector into cerebrospinal fluid attenuates central nervous system disease in mucopolysaccharidosis type II mice. Hum Gene Ther. 2016;27(11):906–15.

    Article  PubMed  CAS  Google Scholar 

  74. 74.

    Long C, Amoasii L, Mireault AA, McAnally JR, Li H, Sanchez-Ortiz E, et al. Postnatal genome editing partially restores dystrophin expression in a mouse model of muscular dystrophy. Science. 2016;351(6271):400–3.

    Article  PubMed  CAS  Google Scholar 

  75. 75.

    •• Alapati D, Zacharias WJ, Hartman HA, Rossidis AC, Stratigis JD, Ahn NJ, et al. In utero gene editing for monogenic lung disease. Sci Transl Med. 2019;11(488). utero CRISPR-Cas9-mediated inactivation of the mutant SftpcI73T gene led to improved lung morphology and respiratory function.

  76. 76.

    Ferrari G, Muntoni F, Tedesco FS. Generation of two genomic-integration-free DMD iPSC lines with mutations affecting all dystrophin isoforms and potentially amenable to exon-skipping. Stem Cell Res. 2020;43:101688.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. 77.

    Morisaka H, Yoshimi K, Okuzaki Y, Gee P, Kunihiro Y, Sonpho E, et al. CRISPR-Cas3 induces broad and unidirectional genome editing in human cells. Nat Commun. 2019;10(1):5302.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. 78.

    • Shahryari A, Saghaeian Jazi M, Mohammadi S, Razavi Nikoo H, Nazari Z, Hosseini ES, et al. Development and clinical translation of approved gene therapy products for genetic disorders. Front Genet. 2019;10:868. eCollection 2019. Comprehensive review about gene therapies and cell-based gene therapy products that have been approved for clinical use.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. 79.

    Smith DM, Culme-Seymour EJ, Mason C. Evolving industry partnerships and investments in cell and gene therapies. Cell Stem Cell. 2018;22(5):623–6.

    Article  PubMed  CAS  Google Scholar 

  80. 80.

    Capps B. Can a good tree bring forth evil fruit? The funding of medical research by industry. Br Med Bull. 2016;118(1):5–15.

    Article  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Capps B, Chadwick R, Joly Y, Mulvihill JJ, Lysaght T, Zwart H. Falling giants and the rise of gene editing: ethics, private interests and the public good. Hum Genom. 2017;11(1):20.

    Article  Google Scholar 

  82. 82.

    Riva L, Petrini C. A few ethical issues in translational research for gene and cell therapy. J Transl Med. 2019;17(1):395.

    Article  PubMed  PubMed Central  Google Scholar 

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We thank Anna Kohrs and Erika Smith (Cincinnati Children’s Hospital Medical Center) for the help with the manuscript preparation and Gregory Kalin (Yale University) for the critical comments.


This work was supported by NIH Grants HL84151 (to V.V.K.), HL141174 (to V.V.K.), HL149631 (to V.V.K.), and HL132849 (to T.V.K.).

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Correspondence to Vladimir V. Kalinichenko.

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Arun Pradhan, Tanya V. Kalin, and Vladimir V. Kalinichenko declare that they have no conflict of interest.

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Pradhan, A., Kalin, T.V. & Kalinichenko, V.V. Genome Editing for Rare Diseases. Curr Stem Cell Rep 6, 41–51 (2020).

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  • Genome editing
  • Rare diseases
  • Gene therapy
  • CRISPR/Cas9