Gene Therapy for Coronary Artery Disease

  • Vivekkumar B. Patel
  • Christopher T. Ryan
  • Ronald G. Crystal
  • Todd K. RosengartEmail author


Congestive heart failure is the common end point for advanced coronary artery disease and the leading cause of mortality from heart disease. Stents and surgical bypass can address focal obstruction in larger coronary arteries, but diffuse small vessel disease is not amenable to these interventions. Intrinsic recovery is also limited, as adult cardiac muscle does not effectively regenerate after cardiomyocyte death. Cardiac gene therapy uses growth factors, genes or small molecules to alter gene expression for myocardial regeneration. Genes may be used to induce angiogenesis, reduce pathologic fibrosis, induce replication of endogenous cardiomyocytes, or expand existing cardiac progenitor cells into various cardiac subtypes. Delivery options include plasmids, integrative or non-integrative viruses, micro RNA or small molecules. Administration may be achieved systemically or by intracoronary or local injection, although local administration appears to provide key pharmacokinetic advantages. Initial attempts focused on creating new branches from existing blood vessels, often using vascular endothelial growth factor (VEGF). These demonstrated equivocal clinical results due, in part, to inconsistent study design, controls and clinically relevant endpoints as well as incomplete pharmacokinetics data on required gene “dose” or the ideal methods of gene delivery. Early lessons informed the development of cardiac cellular reprogramming, which transforms cardiac fibroblasts into induced cardiomyocytes using defined reprogramming factor cocktails. This approach has delivered improved post-infarct ejection fraction and reduced fibrosis in preclinical models. Gene therapy in cardiac disease is not yet ready for clinical application, but holds great promise for filling an important therapeutic gap in a growing patient population.


Adeno-associated viruses Angiogenesis Cardiomyocytes Gene therapy Induced cardiomyocytes Induced pluripotent stem cells Vascular endothelial growth factor 



A randomized, controlled, parallel group, multicenter phase 3 study to evaluate the efficacy and safety of Ad5FGF-4 using SPECT myocardIal peRfusion imaging in patients with stable angina pEctoris


Angiogenesis in women with angina pectoris who are not candidates for revascularization


Cardiac Troponin T


Fibroblast growth factor


Gata4, Mef2c and Tbx5 cardiac reprogramming factors


Hepatocyte growth factor (HGH)


Hypoxia-induced factor alpha


Induced cardiomyocytes


Induced pluripotent stem cells


Kuopio Angiogenesis Trial 301


Micro RNA


Short hairpin RNA


Transforming growth factor beta


Vascular endothelial growth factor



The authors would like to thank Scott Holmes, a member of the Michael E. DeBakey Department of Surgery at Baylor College of Medicine, for his assistance with figures during the preparation of this manuscript.


  1. 1.
    Galli A, Lombardi F. Postinfarct left ventricular remodelling: a prevailing cause of heart failure. Cardiol Res Pract. 2016;2016:2579832.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013;128:1810–52.CrossRefGoogle Scholar
  3. 3.
    Baran DA, Jaiswal A. Management of the ACC/AHA Stage D patient: mechanical circulatory support. Cardiol Clin. 2014;32:113–24.PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Kittleson MM, Kobashigawa JA. Management of the ACC/AHA Stage D patient: cardiac transplantation. Cardiol Clin. 2014;32:95–112.PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Hashimoto H, Olson EN, Bassel-duby R. Therapeutic approaches for cardiac regeneration and repair. Nat Rev Cardiol. 2018;15(10):585–600. Scholar
  6. 6.
    Rosengart TK, Fallon E, Crystal RG. Cardiac biointerventions: whatever happened to stem cell and gene therapy? Innovations. 2012;7:173–9.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Segers VF, Lee RT. Stem-cell therapy for cardiac disease. Nature. 2008;451:937–42.PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Fisher SA, Zhang H, Doree C, Mathur A, Martin-Rendon E. Stem cell treatment for acute myocardial infarction. Cochrane Database Syst Rev. 2015;9:CD006536.Google Scholar
  9. 9.
    Nowbar AN, Mielewczik M, Karavassilis M, et al. Discrepancies in autologous bone marrow stem cell trials and enhancement of ejection fraction (DAMASCENE): weighted regression and meta-analysis. BMJ. 2014;348:g2688.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Senyo SE, Lee RT, Kühn B. Cardiac regeneration based on mechanisms of cardiomyocyte proliferation and differentiation. Stem Cell Res. 2014;13:532–41.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663–76.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Ieda M, Fu JD, Delgado-Olguin P, et al. Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell. 2010;3:375–86.CrossRefGoogle Scholar
  13. 13.
    Folkman J. Tumor angiogenesis: therapeutic implications. NEJM. 1971;285:1182–6.PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Gupta R, Tongers J, Losordo DW. Human studies of angiogenic gene therapy. Circ Res. 2009;8:724–36.CrossRefGoogle Scholar
  15. 15.
    Zachary I, Morgan RD. Therapeutic angiogenesis for cardiovascular disease: biological context, challenges, prospects. Heart. 2010;3:181–9.Google Scholar
  16. 16.
    Patel V, Mathison M, Singh VP, Yang J, Rosengart TK. Direct cardiac cellular reprogramming for cardiac regeneration. Curr Treat Options Cardiovasc Med. 2016;18:58.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Patel V, Mathison M, Singh VP, Yang J, Rosengart TK. Cardiac regenerative strategies for advanced heart failure. In: Morgan J, Civitello A, Frazier O, editors. Mechanical circulatory support for advanced heart failure. A Texas Heart Institute/Baylor College of Medicine Approach. Cham: Springer; 2018. p. 221–37.CrossRefGoogle Scholar
  18. 18.
    Srivastava D, Dewitt N. In vivo cellular reprogramming: the next generation. Cell. 2016;166:1386–96.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Naim C, Yerevanian A, Hajjar RJ. Gene therapy for heart failure: where do we stand? Curr Cardiol Rep. 2013;15:333.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Rincon MY, VandenDriessche T, Chuah MK. Gene therapy for cardiovascular disease: advances in vector development, targeting, and delivery for clinical translation. Cardiovasc Res. 2015;108:4–20.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Miyamoto K, Akiyama M, Tamura F, et al. Direct in vivo reprogramming with Sendai virus vectors improves cardiac function after myocardial infarction. Cell Stem Cell. 2018;22:91–103.e105.PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Themis M, May D, Coutelle C, Newbold RF. Mutational effects of retrovirus insertion on the genome of V79 cells by an attenuated retrovirus vector: implications for gene therapy. Gene Ther. 2003;10:1703–11.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Mathison M, Singh VP, Chiuchiolo MJ, et al. In situ reprogramming to transdifferentiate fibroblasts into cardiomyocytes using adenoviral vectors: implications for clinical myocardial regeneration. J Thorac Cardiovasc Surg. 2017;153:329–339.e3.PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Tilemann L, Ishikawa K, Weber T, Hajjar RJ. Gene therapy for heart failure. Circ Res. 2012;110:777–93.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Jayawardena TM, Egemnazarov B, Finch EA, et al. MicroRNA-mediated in vitro and in vivo direct reprogramming of cardiac fibroblasts to cardiomyocytes. Circ Res. 2012;110:1465–73.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Singh VP, Mathison M, Patel V, et al. MiR-590 promotes transdifferentiation of porcine and human fibroblasts toward a cardiomyocyte-like fate by directly repressing specificity protein 1. J Am Heart Assoc. 2016;5(11):e003922.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Muraoka N, Yamakawa H, Miyamoto K, et al. MiR-133 promotes cardiac reprogramming by directly repressing Snai1 and silencing fibroblast signatures. EMBO J. 2014;33:1565–81.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Cao N, Huang Y, Zheng J, et al. Conversion of human fibroblasts into functional cardiomyocytes by small molecules. Science. 2016;352:1216–20.PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Mohamed TM, Stone NR, Berry EC, et al. Chemical enhancement of in vitro and in vivo direct cardiac reprogramming. Circulation. 2017;135:978–95.PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Huang C, Tu W, Fu Y, Wang J, Xie X. Chemical-induced cardiac reprogramming in vivo. Cell Res. 2018;28:686–9.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Greenberg B, Butler J, Felker GM, et al. Calcium upregulation by percutaneous administration of gene therapy in patients with cardiac disease (CUPID 2): a randomised, multinational, double-blind, placebo-controlled, phase 2b trial. Lancet. 2016;387:1178–86.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Yla-Herttuala S. Gene therapy for heart failure: back to the bench. Mol Ther. 2015;23:1551–2.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Lee LY, Patel SR, Hackett NR, et al. Focal angiogen therapy using intramyocardial delivery of an adenovirus vector coding for vascular endothelial growth factor 121. Ann Thorac Surg. 2000;69:14–23.PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    French BA, Mazur W, Geske RS, Bolli R. Direct in vivo gene transfer into porcine myocardium using replication-deficient adenoviral vectors. Circulation. 1994;90:2414–24.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Donahue JK. Cardiac gene therapy: a call for basic methods development. Lancet. 2016;387:1137–9.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Kaminsky SM, Rosengart TK, Rosenberg J, et al. Gene therapy to stimulate angiogenesis to treat diffuse coronary artery disease. Hum Gene Ther. 2013;24:948–63.PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature. 2011;473:298–307.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Ylä-herttuala S, Bridges C, Katz MG, Korpisalo P. Angiogenic gene therapy in cardiovascular diseases: dream or vision? Eur Heart J. 2017;38:1365–71.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Kaski JC, Consuegra-Sanchez L. Evaluation of ASPIRE trial: a Phase III pivotal registration trial, using intracoronary administration of Generx (Ad5FGF4) to treat patients with recurrent angina pectoris. Expert Opin Biol Ther. 2013;13:1749–53.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Qian L, Huang Y, Spencer CI, et al. In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes. Nature. 2012;485:593–8.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Song K, Nam YJ, Luo X, et al. Heart repair by reprogramming non-myocytes with cardiac transcription factors. Nature. 2012;485:599–604.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Inagawa K, Miyamoto K, Yamakawa H, et al. Induction of cardiomyocyte-like cells in infarct hearts by gene transfer of Gata4, Mef2c, and Tbx5. Circ Res. 2012;111:1147–56.PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Mathison M, Singh VP, Gersch RP, et al. “Triplet” polycistronic vectors encoding Gata4, Mef2c, and Tbx5 enhances postinfarct ventricular functional improvement compared with singlet vectors. J Thorac Cardiovasc Surg. 2014;148:1656–1664.e2.PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Ma H, Wang L, Yin C, Liu J, Qian L. In vivo cardiac reprogramming using an optimal single polycistronic construct. Cardiovasc Res. 2015;108:217–9.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Zhao Y, Londono P, Cao Y, et al. High-efficiency reprogramming of fibroblasts into cardiomyocytes requires suppression of pro-fibrotic signalling. Nat Commun. 2015;10:8243.CrossRefGoogle Scholar
  46. 46.
    Ifkovits JL, Addis RC, Epstein JA, Gearhart JD. Inhibition of TGF-beta signaling increases direct conversion of fibroblasts to induced cardiomyocytes. PLoS One. 2014;9:e89678.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Ebrahimi B. Reprogramming barriers and enhancers: strategies to enhance the efficiency and kinetics of induced pluripotency. Cell Regen (Lond). 2015;4:10.PubMedCentralGoogle Scholar
  48. 48.
    Zhou Y, Wang L, Vaseghi HR, et al. Bmi1 is a key epigenetic barrier to direct cardiac reprogramming. Cell Stem Cell. 2016;3:382–95.CrossRefGoogle Scholar
  49. 49.
    Zhou Y, Alimohamadi S, Wang L, et al. A loss of function screen of epigenetic modifiers and splicing factors during early stage of cardiac reprogramming. Stem Cells Int. 2018:3814747. Scholar
  50. 50.
    Wang H, Zhao S, Barton M, Rosengart T, Cooney AJ. Reciprocity of action of increasing Oct4 and repressing p53 in transdifferentiation of mouse embryonic fibroblasts into cardiac myocytes. Cell Reprogram. 2018;20:27–37.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Patel V, Singh VP, Pinnamaneni JP, et al. p63 silencing induces reprogramming of cardiac fibroblasts into cardiomyocyte-like cells. J Thorac Cardiovasc Surg. 2018;156:556–565.e1.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Vivekkumar B. Patel
    • 1
    • 2
  • Christopher T. Ryan
    • 1
    • 2
  • Ronald G. Crystal
    • 1
  • Todd K. Rosengart
    • 1
    • 2
    Email author
  1. 1.Laboratory for Cardiac RegenerationBaylor College of MedicineHoustonUSA
  2. 2.Michael E. DeBakey Department of SurgeryBaylor College of MedicineHoustonUSA

Personalised recommendations