Recent Progress in Genome Editing Approaches for Inherited Cardiovascular Diseases

  • Balpreet Kaur
  • Isaac Perea-Gil
  • Ioannis Karakikes
Regenerative Medicine (SM Wu, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Regenerative Medicine


Purpose of Review

This review describes the recent progress in nuclease-based therapeutic applications for inherited heart diseases in vitro, highlights the development of the most recent genome editing technologies and discusses the associated challenges for clinical translation.

Recent Findings

Inherited cardiovascular disorders are passed from generation to generation. Over the past decade, considerable progress has been made in understanding the genetic basis of inherited heart diseases. The timely emergence of genome editing technologies using engineered programmable nucleases has revolutionized the basic research of inherited cardiovascular diseases and holds great promise for the development of targeted therapies.


The genome editing toolbox is rapidly expanding, and new tools have been recently added that significantly expand the capabilities of engineered nucleases. Newer classes of versatile engineered nucleases, such as the “base editors,” have been recently developed, offering the potential for efficient and precise therapeutic manipulation of the human genome.


Genome editing Base editing CRISPR/Cas9 Cardiovascular diseases 


Compliance with Ethical Standards

Conflict of Interest

Balpreet Kaur, Isaac Perea Gil, and Ioannis Karakikes declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


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

  1. 1.
    Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, et al. Heart disease and stroke statistics—2015 update: a report from the American Heart Association. Circulation. 2015;131(4):e29–322.Google Scholar
  2. 2.
    Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380(9859):2095–128.Google Scholar
  3. 3.
    Kim YG, Cha J, Chandrasegaran S. Hybrid restriction enzymes: zinc finger fusions to Fok I cleavage domain. Proc Natl Acad Sci U S A. 1996;93(3):1156–60.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Boch J, Scholze H, Schornack S, Landgraf A, Hahn S, Kay S, et al. Breaking the code of DNA binding specificity of TAL-type III effectors. Science. 2009;326(5959):1509–12.Google Scholar
  5. 5.
    Jinek M, Chylinski K, Fonfara I, Hauer M, Doudna JA, Charpentier E. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science. 2012;337(6096):816–21.CrossRefPubMedGoogle Scholar
  6. 6.
    Jasin M, Rothstein R. Repair of strand breaks by homologous recombination. Cold Spring Harb Perspect Biol. 2013;5(11):a012740.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Chiruvella KK, Liang Z, Wilson TE. Repair of double-strand breaks by end joining. Cold Spring Harb Perspect Biol. 2013;5(5):a012757.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Termglinchan V, Karakikes I, Seeger T et al. Current status of genome editing in cardiovascular medicine. In: Turksen K, editor. Genome editing. Cham: Springer International Publishing; 2016. p. 107–26.Google Scholar
  9. 9.
    • Karakikes I, et al. Correction of human phospholamban R14del mutation associated with cardiomyopathy using targeted nucleases and combination therapy. Nat Commun. 2015;6:6955. This proof-of-principle study describes how engineered nucleases can be used to correct a pathogenic mutation associated with dilated cardiomyopathy in vitro. CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Ang YS, et al. Disease model of GATA4 mutation reveals transcription factor cooperativity in human cardiogenesis. Cell. 2016;167(7):1734–1749 e22.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Liang P, Sallam K, Wu H, Li Y, Itzhaki I, Garg P, et al. Patient-specific and genome-edited induced pluripotent stem cell-derived cardiomyocytes elucidate single-cell phenotype of Brugada syndrome. J Am Coll Cardiol. 2016;68(19):2086–96.Google Scholar
  12. 12.
    Karakikes I, Termglinchan V, Cepeda DA, Lee J, Diecke S, Hendel A, et al. A comprehensive TALEN-based knockout library for generating human-induced pluripotent stem cell-based models for cardiovascular diseases. Circ Res. 2017;120(10):1561–71.Google Scholar
  13. 13.
    Cox DB, Platt RJ, Zhang F. Therapeutic genome editing: prospects and challenges. Nat Med. 2015;21(2):121–31.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Pardo B, Gomez-Gonzalez B, Aguilera A. DNA repair in mammalian cells: DNA double-strand break repair: how to fix a broken relationship. Cell Mol Life Sci. 2009;66(6):1039–56.CrossRefPubMedGoogle Scholar
  15. 15.
    Maruyama T, Dougan SK, Truttmann MC, Bilate AM, Ingram JR, Ploegh HL. Increasing the efficiency of precise genome editing with CRISPR-Cas9 by inhibition of nonhomologous end joining. Nat Biotechnol. 2015;33(5):538–42.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Zetsche B, Gootenberg JS, Abudayyeh OO, Slaymaker IM, Makarova KS, Essletzbichler P, et al. Cpf1 is a single RNA-guided endonuclease of a class 2 CRISPR-Cas system. Cell. 2015;163(3):759–71.Google Scholar
  17. 17.
    •• Komor AC, et al. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature, 2016;533(7603):420–4. This study demonstrates that genome editing can be used to make precise changes in DNA without causing double-strand breaks. Google Scholar
  18. 18.
    Yang L, Briggs AW, Chew WL, Mali P, Guell M, Aach J, et al. Engineering and optimising deaminase fusions for genome editing. Nat Commun. 2016;7:13330.Google Scholar
  19. 19.
    Gaudelli NM, Komor AC, Rees HA, Packer MS, Badran AH, Bryson DI, et al. Programmable base editing of A*T to G*C in genomic DNA without DNA cleavage. Nature. 2017;551(7681):464–71.Google Scholar
  20. 20.
    Kleinstiver BP, Pattanayak V, Prew MS, Tsai SQ, Nguyen NT, Zheng Z, et al. High-fidelity CRISPR-Cas9 nucleases with no detectable genome-wide off-target effects. Nature. 2016;529(7587):490–5.Google Scholar
  21. 21.
    Slaymaker IM, Gao L, Zetsche B, Scott DA, Yan WX, Zhang F. Rationally engineered Cas9 nucleases with improved specificity. Science. 2016;351(6268):84–8.CrossRefPubMedGoogle Scholar
  22. 22.
    Chen JS, Dagdas YS, Kleinstiver BP, Welch MM, Sousa AA, Harrington LB, et al. Enhanced proofreading governs CRISPR-Cas9 targeting accuracy. Nature. 2017;550(7676):407–10.Google Scholar
  23. 23.
    Casini A, Olivieri M, Petris G, Montagna C, Reginato G, Maule G, et al. A highly specific SpCas9 variant is identified by in vivo screening in yeast. Nat Biotechnol. 2018;36(3):265–71.Google Scholar
  24. 24.
    Hu JH, Miller SM, Geurts MH, Tang W, Chen L, Sun N, et al. Evolved Cas9 variants with broad PAM compatibility and high DNA specificity. In: Nature, vol. 556; 2018. p. 57–63.Google Scholar
  25. 25.
    Zacchigna S, Zentilin L, Giacca M. Adeno-associated virus vectors as therapeutic and investigational tools in the cardiovascular system. Circ Res. 2014;114(11):1827–46.CrossRefPubMedGoogle Scholar
  26. 26.
    Lau CH, Suh Y. In vivo genome editing in animals using AAV-CRISPR system: applications to translational research of human disease. F1000Res. 2017;6:2153.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    El Refaey M, et al. In vivo genome editing restores dystrophin expression and cardiac function in dystrophic mice. Circ Res. 2017;121(8):923–9.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    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.Google Scholar
  29. 29.
    • Nelson CE, et al. In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophy. Science. 2016;351(6271):403–7. In this study, the gene defect responsible for Duchenne muscular dystrophy was corrected in a mouse model by AAV-mediated genome editing in vivo. CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Balpreet Kaur
    • 1
  • Isaac Perea-Gil
    • 1
    • 2
  • Ioannis Karakikes
    • 1
    • 2
  1. 1.Stanford Cardiovascular InstituteStanford University School of MedicineStanfordUSA
  2. 2.Department of Cardiothoracic SurgeryStanford University School of MedicineStanfordUSA

Personalised recommendations