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Progress in Clinical Gene Therapy for Cardiac Disorders

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A Correction to this article was published on 10 June 2023

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Abstract

Despite significant advances in novel treatments and approaches, cardiovascular disease remains the leading cause of death globally. Gene therapy is a promising option for many diseases, including cardiovascular diseases. In the last 30 years, gene therapy has slowly proceeded towards clinical translation and recently reached US Food and Drug Administration approval for several diseases such as Leber congenital amaurosis and spinal muscular atrophy, among others. Previous attempts at developing gene therapies for cardiovascular diseases have yielded promising results in preclinical studies and early-phase clinical trials. However, larger trials failed to demonstrate consistent benefits in patients with ischemic heart disease and heart failure. In this review, we summarize the history and current status of clinical cardiac gene therapy. Starting with angiogenic gene therapy, we also cover more recent gene therapy trials for heart failure and cardiomyopathies. New programs are actively vying to be the first to get Food and Drug Administration approval for a cardiac gene therapy product by taking advantage of novel techniques.

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References

  1. Narasimhan B, Narasimhan H, Lorente-Ros M, Romeo FJ, Bhatia K, Aronow WS. Therapeutic angiogenesis in coronary artery disease: a review of mechanisms and current approaches. Expert Opin Investig Drugs. 2021;30(9):947–63.

    Article  CAS  PubMed  Google Scholar 

  2. Shweiki D, Itin A, Soffer D, Keshet E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature. 1992;359(6398):843–5.

    Article  CAS  PubMed  Google Scholar 

  3. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285(21):1182–6.

    Article  CAS  PubMed  Google Scholar 

  4. Shing Y, Folkman J, Sullivan R, Butterfield C, Murray J, Klagsbrun M. Heparin affinity: purification of a tumor-derived capillary endothelial cell growth factor. Science. 1984;223(4642):1296–9.

    Article  CAS  PubMed  Google Scholar 

  5. Byrne AM, Bouchier-Hayes DJ, Harmey JH. Angiogenic and cell survival functions of vascular endothelial growth factor (VEGF). J Cell Mol Med. 2005;9(4):777–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Bry M, Kivela R, Holopainen T, Anisimov A, Tammela T, Soronen J, et al. Vascular endothelial growth factor-B acts as a coronary growth factor in transgenic rats without inducing angiogenesis, vascular leak, or inflammation. Circulation. 2010;122(17):1725–33.

    Article  CAS  PubMed  Google Scholar 

  7. Rissanen TT, Markkanen JE, Gruchala M, Heikura T, Puranen A, Kettunen MI, et al. VEGF-D is the strongest angiogenic and lymphangiogenic effector among VEGFs delivered into skeletal muscle via adenoviruses. Circ Res. 2003;92(10):1098–106.

    Article  CAS  PubMed  Google Scholar 

  8. Yun YR, Won JE, Jeon E, Lee S, Kang W, Jo H, et al. Fibroblast growth factors: biology, function, and application for tissue regeneration. J Tissue Eng. 2010;2010: 218142.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Griffioen AW, Molema G. Angiogenesis: potentials for pharmacologic intervention in the treatment of cancer, cardiovascular diseases, and chronic inflammation. Pharmacol Rev. 2000;52(2):237–68.

    CAS  PubMed  Google Scholar 

  10. Rissanen TT, Markkanen JE, Arve K, Rutanen J, Kettunen MI, Vajanto I, et al. Fibroblast growth factor 4 induces vascular permeability, angiogenesis and arteriogenesis in a rabbit hindlimb ischemia model. FASEB J. 2003;17(1):100–2.

    Article  CAS  PubMed  Google Scholar 

  11. Nakamura T, Nishizawa T, Hagiya M, Seki T, Shimonishi M, Sugimura A, et al. Molecular cloning and expression of human hepatocyte growth factor. Nature. 1989;342(6248):440–3.

    Article  CAS  PubMed  Google Scholar 

  12. Min JK, Lee YM, Kim JH, Kim YM, Kim SW, Lee SY, et al. Hepatocyte growth factor suppresses vascular endothelial growth factor-induced expression of endothelial ICAM-1 and VCAM-1 by inhibiting the nuclear factor-kappaB pathway. Circ Res. 2005;96(3):300–7.

    Article  CAS  PubMed  Google Scholar 

  13. Wang LS, Wang H, Zhang QL, Yang ZJ, Kong FX, Wu CT. Hepatocyte growth factor gene therapy for ischemic diseases. Hum Gene Ther. 2018;29(4):413–23.

    Article  CAS  PubMed  Google Scholar 

  14. Kaminsky SM, Rosengart TK, Rosenberg J, Chiuchiolo MJ, Van de Graaf B, Sondhi D, et al. Gene therapy to stimulate angiogenesis to treat diffuse coronary artery disease. Hum Gene Ther. 2013;24(11):948–63.

    Article  CAS  PubMed  Google Scholar 

  15. Lee RJ, Springer ML, Blanco-Bose WE, Shaw R, Ursell PC, Blau HM. VEGF gene delivery to myocardium: deleterious effects of unregulated expression. Circulation. 2000;102(8):898–901.

    Article  CAS  PubMed  Google Scholar 

  16. Wilson JM. Lessons learned from the gene therapy trial for ornithine transcarbamylase deficiency. Mol Genet Metab. 2009;96(4):151–7.

    Article  CAS  PubMed  Google Scholar 

  17. Ishikawa K, Tilemann L, Fish K, Hajjar RJ. Gene delivery methods in cardiac gene therapy. J Gene Med. 2011;13(10):566–72.

    Article  CAS  PubMed  Google Scholar 

  18. Mack CA, Patel SR, Schwarz EA, Zanzonico P, Hahn RT, Ilercil A, et al. Biologic bypass with the use of adenovirus-mediated gene transfer of the complementary deoxyribonucleic acid for vascular endothelial growth factor 121 improves myocardial perfusion and function in the ischemic porcine heart. J Thorac Cardiovasc Surg. 1998;115(1):168–76 (discussion 76–7).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Stewart DJ, Hilton JD, Arnold JM, Gregoire J, Rivard A, Archer SL, et al. Angiogenic gene therapy in patients with nonrevascularizable ischemic heart disease: a phase 2 randomized, controlled trial of AdVEGF(121) (AdVEGF121) versus maximum medical treatment. Gene Ther. 2006;13(21):1503–11.

    Article  CAS  PubMed  Google Scholar 

  20. Bokeriya LA, Golukhova EZ, Eremeeva MV, Aslanidi IP, Merzlyakov VY, Georgiev GP, et al. Use of human VEGF(165) gene for therapeutic angiogenesis in coronary patients: first results. Bull Exp Biol Med. 2005;140(1):106–12.

    Article  CAS  PubMed  Google Scholar 

  21. Grines C, Rubanyi GM, Kleiman NS, Marrott P, Watkins MW. Angiogenic gene therapy with adenovirus 5 fibroblast growth factor-4 (Ad5FGF-4): a new option for the treatment of coronary artery disease. Am J Cardiol. 2003;92(9B):24N-31N.

    Article  CAS  PubMed  Google Scholar 

  22. Sabra M, Karbasiafshar C, Aboulgheit A, Raj S, Abid MR, Sellke FW. Clinical application of novel therapies for coronary angiogenesis: overview, challenges, and prospects. Int J Mol Sci. 2021;22(7):3722.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Simons M, Bonow RO, Chronos NA, Cohen DJ, Giordano FJ, Hammond HK, et al. Clinical trials in coronary angiogenesis: issues, problems, consensus: an expert panel summary. Circulation. 2000;102(11):E73-86.

    Article  CAS  PubMed  Google Scholar 

  24. Symes JF, Losordo DW, Vale PR, Lathi KG, Esakof DD, Mayskiy M, et al. Gene therapy with vascular endothelial growth factor for inoperable coronary artery disease. Ann Thorac Surg. 1999;68(3):830–6 (discussion 6–7).

    Article  CAS  PubMed  Google Scholar 

  25. Losordo DW, Vale PR, Symes JF, Dunnington CH, Esakof DD, Maysky M, et al. Gene therapy for myocardial angiogenesis: initial clinical results with direct myocardial injection of phVEGF165 as sole therapy for myocardial ischemia. Circulation. 1998;98(25):2800–4.

    Article  CAS  PubMed  Google Scholar 

  26. Hedman M, Hartikainen J, Syvanne M, Stjernvall J, Hedman A, Kivela A, et al. Safety and feasibility of catheter-based local intracoronary vascular endothelial growth factor gene transfer in the prevention of postangioplasty and in-stent restenosis and in the treatment of chronic myocardial ischemia: phase II results of the Kuopio Angiogenesis Trial (KAT). Circulation. 2003;107(21):2677–83.

    Article  CAS  PubMed  Google Scholar 

  27. Hedman M, Muona K, Hedman A, Kivela A, Syvanne M, Eranen J, et al. Eight-year safety follow-up of coronary artery disease patients after local intracoronary VEGF gene transfer. Gene Ther. 2009;16(5):629–34.

    Article  CAS  PubMed  Google Scholar 

  28. Hartikainen J, Hassinen I, Hedman A, Kivela A, Saraste A, Knuuti J, et al. Adenoviral intramyocardial VEGF-DDeltaNDeltaC gene transfer increases myocardial perfusion reserve in refractory angina patients: a phase I/IIa study with 1-year follow-up. Eur Heart J. 2017;38(33):2547–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kastrup J, Jorgensen E, Ruck A, Tagil K, Glogar D, Ruzyllo W, et al. Direct intramyocardial plasmid vascular endothelial growth factor-A165 gene therapy in patients with stable severe angina pectoris: a randomized double-blind placebo-controlled study: the Euroinject One trial. J Am Coll Cardiol. 2005;45(7):982–8.

    Article  CAS  PubMed  Google Scholar 

  30. Stewart DJ, Kutryk MJ, Fitchett D, Freeman M, Camack N, Su Y, et al. VEGF gene therapy fails to improve perfusion of ischemic myocardium in patients with advanced coronary disease: results of the NORTHERN trial. Mol Ther. 2009;17(6):1109–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Flynn A, O’Brien T. Alferminogene tadenovec, an angiogenic FGF4 gene therapy for coronary artery disease. IDrugs. 2008;11(4):283–93.

    CAS  PubMed  Google Scholar 

  32. Gao MH, Lai NC, McKirnan MD, Roth DA, Rubanyi GM, Dalton N, et al. Increased regional function and perfusion after intracoronary delivery of adenovirus encoding fibroblast growth factor 4: report of preclinical data. Hum Gene Ther. 2004;15(6):574–87.

    Article  CAS  PubMed  Google Scholar 

  33. Grines CL, Watkins MW, Helmer G, Penny W, Brinker J, Marmur JD, et al. Angiogenic Gene Therapy (AGENT) trial in patients with stable angina pectoris. Circulation. 2002;105(11):1291–7.

    Article  CAS  PubMed  Google Scholar 

  34. Henry TD, Grines CL, Watkins MW, Dib N, Barbeau G, Moreadith R, et al. Effects of Ad5FGF-4 in patients with angina: an analysis of pooled data from the AGENT-3 and AGENT-4 trials. J Am Coll Cardiol. 2007;50(11):1038–46.

    Article  CAS  PubMed  Google Scholar 

  35. 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(12):1749–53.

    Article  CAS  PubMed  Google Scholar 

  36. Yang ZJ, Zhang YR, Chen B, Zhang SL, Jia EZ, Wang LS, et al. Phase I clinical trial on intracoronary administration of Ad-hHGF treating severe coronary artery disease. Mol Biol Rep. 2009;36(6):1323–9.

    Article  CAS  PubMed  Google Scholar 

  37. Kim JS, Hwang HY, Cho KR, Park EA, Lee W, Paeng JC, et al. Intramyocardial transfer of hepatocyte growth factor as an adjunct to CABG: phase I clinical study. Gene Ther. 2013;20(7):717–22.

    Article  CAS  PubMed  Google Scholar 

  38. Povsic TJ, Henry TD, Ohman EM, Pepine CJ, Crystal RG, Rosengart TK, et al. Epicardial delivery of XC001 gene therapy for refractory angina coronary treatment (the EXACT Trial): rationale, design, and clinical considerations. Am Heart J. 2021;241:38–49.

    Article  CAS  PubMed  Google Scholar 

  39. Anttila V, Saraste A, Knuuti J, Jaakkola P, Hedman M, Svedlund S, et al. Synthetic mRNA encoding VEGF-A in patients undergoing coronary artery bypass grafting: design of a phase 2a clinical trial. Mol Ther Methods Clin Dev. 2020;18:464–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Bikou O, Ishikawa K. Gene therapy for heart failure: status quo and quo vadis. Discov Med. 2017;23(129):371–7.

    PubMed  Google Scholar 

  41. Lipskaia L, Chemaly ER, Hadri L, Lompre AM, Hajjar RJ. Sarcoplasmic reticulum Ca(2+) ATPase as a therapeutic target for heart failure. Expert Opin Biol Ther. 2010;10(1):29–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Hajjar RJ, Schmidt U, Matsui T, Guerrero JL, Lee KH, Gwathmey JK, et al. Modulation of ventricular function through gene transfer in vivo. Proc Natl Acad Sci USA. 1998;95(9):5251–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Hajjar RJ, Kang JX, Gwathmey JK, Rosenzweig A. Physiological effects of adenoviral gene transfer of sarcoplasmic reticulum calcium ATPase in isolated rat myocytes. Circulation. 1997;95(2):423–9.

    Article  CAS  PubMed  Google Scholar 

  44. Miyamoto MI, del Monte F, Schmidt U, DiSalvo TS, Kang ZB, Matsui T, et al. Adenoviral gene transfer of SERCA2a improves left-ventricular function in aortic-banded rats in transition to heart failure. Proc Natl Acad Sci USA. 2000;97(2):793–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kawase Y, Ly HQ, Prunier F, Lebeche D, Shi Y, Jin H, et al. Reversal of cardiac dysfunction after long-term expression of SERCA2a by gene transfer in a pre-clinical model of heart failure. J Am Coll Cardiol. 2008;51(11):1112–9.

    Article  CAS  PubMed  Google Scholar 

  46. Jaski BE, Jessup ML, Mancini DM, Cappola TP, Pauly DF, Greenberg B, et al. Calcium upregulation by percutaneous administration of gene therapy in cardiac disease (CUPID Trial), a first-in-human phase 1/2 clinical trial. J Card Fail. 2009;15(3):171–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Jessup M, Greenberg B, Mancini D, Cappola T, Pauly DF, Jaski B, et al. Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID): a phase 2 trial of intracoronary gene therapy of sarcoplasmic reticulum Ca2+-ATPase in patients with advanced heart failure. Circulation. 2011;124(3):304–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Zsebo K, Yaroshinsky A, Rudy JJ, Wagner K, Greenberg B, Jessup M, et al. Long-term effects of AAV1/SERCA2a gene transfer in patients with severe heart failure: analysis of recurrent cardiovascular events and mortality. Circ Res. 2014;114(1):101–8.

    Article  CAS  PubMed  Google Scholar 

  49. Greenberg B, Butler J, Felker GM, Ponikowski P, Voors AA, Desai AS, 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(10024):1178–86.

    Article  CAS  PubMed  Google Scholar 

  50. Hulot JS, Salem JE, Redheuil A, Collet JP, Varnous S, Jourdain P, et al. Effect of intracoronary administration of AAV1/SERCA2a on ventricular remodelling in patients with advanced systolic heart failure: results from the AGENT-HF randomized phase 2 trial. Eur J Heart Fail. 2017;19(11):1534–41.

    Article  CAS  PubMed  Google Scholar 

  51. Lyon AR, Babalis D, Morley-Smith AC, Hedger M, Suarez Barrientos A, Foldes G, et al. Investigation of the safety and feasibility of AAV1/SERCA2a gene transfer in patients with chronic heart failure supported with a left ventricular assist device: the SERCA-LVAD TRIAL. Gene Ther. 2020;27(12):579–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Hulot JS, Ishikawa K, Hajjar RJ. Gene therapy for the treatment of heart failure: promise postponed. Eur Heart J. 2016;37(21):1651–8.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Kamenetsky M, Middelhaufe S, Bank EM, Levin LR, Buck J, Steegborn C. Molecular details of cAMP generation in mammalian cells: a tale of two systems. J Mol Biol. 2006;362(4):623–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Ping P, Anzai T, Gao M, Hammond HK. Adenylyl cyclase and G protein receptor kinase expression during development of heart failure. Am J Physiol. 1997;273(2 Pt 2):H707–17.

    CAS  PubMed  Google Scholar 

  55. Gao M, Ping P, Post S, Insel PA, Tang R, Hammond HK. Increased expression of adenylylcyclase type VI proportionately increases beta-adrenergic receptor-stimulated production of cAMP in neonatal rat cardiac myocytes. Proc Natl Acad Sci USA. 1998;95(3):1038–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Lai NC, Roth DM, Gao MH, Fine S, Head BP, Zhu J, et al. Intracoronary delivery of adenovirus encoding adenylyl cyclase VI increases left ventricular function and cAMP-generating capacity. Circulation. 2000;102(19):2396–401.

    Article  CAS  PubMed  Google Scholar 

  57. Lai NC, Roth DM, Gao MH, Tang T, Dalton N, Lai YY, et al. Intracoronary adenovirus encoding adenylyl cyclase VI increases left ventricular function in heart failure. Circulation. 2004;110(3):330–6.

    Article  CAS  PubMed  Google Scholar 

  58. Hammond HK, Penny WF, Traverse JH, Henry TD, Watkins MW, Yancy CW, et al. Intracoronary gene transfer of adenylyl cyclase 6 in patients with heart failure: a randomized clinical trial. JAMA Cardiol. 2016;1(2):163–71.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Huang C, Gu H, Zhang W, Manukyan MC, Shou W, Wang M. SDF-1/CXCR4 mediates acute protection of cardiac function through myocardial STAT3 signaling following global ischemia/reperfusion injury. Am J Physiol Heart Circ Physiol. 2011;301(4):H1496–505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Hu X, Dai S, Wu WJ, Tan W, Zhu X, Mu J, et al. Stromal cell derived factor-1 alpha confers protection against myocardial ischemia/reperfusion injury: role of the cardiac stromal cell derived factor-1 alpha CXCR4 axis. Circulation. 2007;116(6):654–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Askari AT, Unzek S, Popovic ZB, Goldman CK, Forudi F, Kiedrowski M, et al. Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy. Lancet. 2003;362(9385):697–703.

    Article  CAS  PubMed  Google Scholar 

  62. Penn MS, Pastore J, Miller T, Aras R. SDF-1 in myocardial repair. Gene Ther. 2012;19(6):583–7.

    Article  CAS  PubMed  Google Scholar 

  63. Penn MS, Mendelsohn FO, Schaer GL, Sherman W, Farr M, Pastore J, et al. An open-label dose escalation study to evaluate the safety of administration of nonviral stromal cell-derived factor-1 plasmid to treat symptomatic ischemic heart failure. Circ Res. 2013;112(5):816–25.

    Article  CAS  PubMed  Google Scholar 

  64. Chung ES, Miller L, Patel AN, Anderson RD, Mendelsohn FO, Traverse J, et al. Changes in ventricular remodelling and clinical status during the year following a single administration of stromal cell-derived factor-1 non-viral gene therapy in chronic ischaemic heart failure patients: the STOP-HF randomized phase II trial. Eur Heart J. 2015;36(33):2228–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Lipskaia L, Bobe R, Chen J, Turnbull IC, Lopez JJ, Merlet E, et al. Synergistic role of protein phosphatase inhibitor 1 and sarco/endoplasmic reticulum Ca2+-ATPase in the acquisition of the contractile phenotype of arterial smooth muscle cells. Circulation. 2014;129(7):773–85.

    Article  CAS  PubMed  Google Scholar 

  66. Pathak A, del Monte F, Zhao W, Schultz JE, Lorenz JN, Bodi I, et al. Enhancement of cardiac function and suppression of heart failure progression by inhibition of protein phosphatase 1. Circ Res. 2005;96(7):756–66.

    Article  CAS  PubMed  Google Scholar 

  67. Fish KM, Ladage D, Kawase Y, Karakikes I, Jeong D, Ly H, et al. AAV9.I-1c delivered via direct coronary infusion in a porcine model of heart failure improves contractility and mitigates adverse remodeling. Circ Heart Fail. 2013;6(2):310–7.

    Article  PubMed  Google Scholar 

  68. Ishikawa K, Fish KM, Tilemann L, Rapti K, Aguero J, Santos-Gallego CG, et al. Cardiac I-1c overexpression with reengineered AAV improves cardiac function in swine ischemic heart failure. Mol Ther. 2014;22(12):2038–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Henry T, Chung E, Traverse J et al. A first-in-human phase 1 clinical gene therapy trial for the treatment of heart failure using a novel re-engineered adeno- associated vector. In: American Society of Gene & Cell Therapy 25th Annual Meeting; 16–19 May, 2022; Washington, DC.

  70. Nowak KJ, Davies KE. Duchenne muscular dystrophy and dystrophin: pathogenesis and opportunities for treatment. EMBO Rep. 2004;5(9):872–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Schultz TI, Raucci FJ Jr, Salloum FN. Cardiovascular disease in Duchenne muscular dystrophy: overview and insight into novel therapeutic targets. JACC Basic Transl Sci. 2022;7(6):608–25.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Lai Y, Yue Y, Duan D. Evidence for the failure of adeno-associated virus serotype 5 to package a viral genome ≥8.2 kb. Mol Ther. 2010;18(1):75–9.

    Article  CAS  PubMed  Google Scholar 

  73. Duan D. Duchenne muscular dystrophy gene therapy in the canine model. Hum Gene Ther Clin Dev. 2015;26(1):57–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Duan D. Micro-dystrophin gene therapy goes systemic in Duchenne muscular dystrophy patients. Hum Gene Ther. 2018;29(7):733–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Mendell JR, Sahenk Z, Lehman K, Nease C, Lowes LP, Miller NF, et al. Assessment of systemic delivery of rAAVrh74.MHCK7.micro-dystrophin in children with Duchenne muscular dystrophy: a nonrandomized controlled trial. JAMA Neurol. 2020;77(9):1122–31.

    Article  PubMed  Google Scholar 

  76. Manso AM, Hashem SI, Nelson BC, Gault E, Soto-Hermida A, Villarruel E, et al. Systemic AAV9.LAMP2B injection reverses metabolic and physiologic multiorgan dysfunction in a murine model of Danon disease. Sci Transl Med. 2020;12(535):eaax1744.

    Article  CAS  PubMed  Google Scholar 

  77. Greenberg B, Eshraghian E, Battiprolu P, Ricks D, Yarabe P, Schwartz J, et al. Abstract 10727: results from first-in-human clinical trial of RP-A501 (AAV9:LAMP2B) gene therapy treatment for Danon disease. Circulation. 2021;144(Suppl._1):A10727-A.

    Google Scholar 

  78. Perdomini M, Belbellaa B, Monassier L, Reutenauer L, Messaddeq N, Cartier N, et al. Prevention and reversal of severe mitochondrial cardiomyopathy by gene therapy in a mouse model of Friedreich’s ataxia. Nat Med. 2014;20(5):542–7.

    Article  CAS  PubMed  Google Scholar 

  79. Kukula K, Chojnowska L, Dabrowski M, Witkowski A, Chmielak Z, Skwarek M, et al. Intramyocardial plasmid-encoding human vascular endothelial growth factor A165/basic fibroblast growth factor therapy using percutaneous transcatheter approach in patients with refractory coronary artery disease (VIF-CAD). Am Heart J. 2011;161(3):581–9.

    Article  CAS  PubMed  Google Scholar 

  80. Kastrup J, Jorgensen E, Fuchs S, Nikol S, Botker HE, Gyongyosi M, et al. A randomised, double-blind, placebo-controlled, multicentre study of the safety and efficacy of BIOBYPASS (AdGVVEGF121.10NH) gene therapy in patients with refractory advanced coronary artery disease: the NOVA trial. EuroIntervention. 2011;6(7):813–8.

    Article  PubMed  Google Scholar 

  81. Kilian EG, Sadoni S, Vicol C, Kelly R, van Hulst K, Schwaiger M, et al. Myocardial transfection of hypoxia inducible factor-1alpha via an adenoviral vector during coronary artery bypass grafting: a multicenter phase I and safety study. Circ J. 2010;74(5):916–24.

    Article  PubMed  Google Scholar 

  82. Losordo DW, Vale PR, Hendel RC, Milliken CE, Fortuin FD, Cummings N, et al. Phase 1/2 placebo-controlled, double-blind, dose-escalating trial of myocardial vascular endothelial growth factor 2 gene transfer by catheter delivery in patients with chronic myocardial ischemia. Circulation. 2002;105(17):2012–8.

    Article  CAS  PubMed  Google Scholar 

  83. Hedman M, Hartikainen J, Yla-Herttuala S. Progress and prospects: hurdles to cardiovascular gene therapy clinical trials. Gene Ther. 2011;18(8):743–9.

    Article  CAS  PubMed  Google Scholar 

  84. Cannata A, Ali H, Sinagra G, Giacca M. Gene therapy for the heart: lessons learned and future perspectives. Circ Res. 2020;126(10):1394–414.

    Article  CAS  PubMed  Google Scholar 

  85. Duarte-Costa S, Castro-Ferreira R, Neves JS, Leite-Moreira AF. S100A1: a major player in cardiovascular performance. Physiol Res. 2014;63(6):669–81.

    Article  CAS  PubMed  Google Scholar 

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  1. Icahn School of Medicine at Mount Sinai, Cardiovascular Research Institute, 1 Gustave L. Levy Place, Box 1014, New York, NY, 10029, USA

    Francisco J. Romeo, Spyros A. Mavropoulos & Kiyotake Ishikawa

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Correspondence to Kiyotake Ishikawa.

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This work was supported by National Institutes of Health Grant R01HL139963 to Kiyotake Ishikawa. Spyros A. Mavropoulos was supported by National Institutes of Health Grant T32HL007824-23.

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Francisco J. Romeo, Spyros A. Mavropoulos, and Kiyotake Ishikawa have no conflicts of interest that are directly relevant to the content of this article.

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FJR drafted the manuscript, SAM and KI critically edited the manuscript, and all authors approved the final version of the manuscript.

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The original online version of this article was revised as the Table 2 had several missing rows due to error during typesetting.

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Romeo, F.J., Mavropoulos, S.A. & Ishikawa, K. Progress in Clinical Gene Therapy for Cardiac Disorders. Mol Diagn Ther 27, 179–191 (2023). https://doi.org/10.1007/s40291-022-00632-z

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