Viral Gene Therapy for Cardiovascular Diseases: Mechanisms, Vectors, Clinical Advances, And Future Directions

References

[1] Bendall, J. K., Douglas, G., McNeill, E., Channon, K. M., & Crabtree, M. J. (2002). Tetrahydrobiopterin in cardiovascular health and disease. Antioxidants & Redox Signaling, 20(18), 3040–3077. https://doi.org/10.1089/ars.2013.5372

[2] Chamberlain, J. R., & Chamberlain, J. S. (2016). Progress toward gene therapy for Duchenne muscular dystrophy. Molecular Therapy, 25(5), 1125–1131. https://doi.org/10.1016/j.ymthe.2016.12.010

[3] Channon, K. M., & Guzik, T. J. (2002). Mechanisms of superoxide production in human blood vessels: Relationship to endothelial dysfunction, clinical and genetic risk factors. Journal of Physiology, 543(3), 681–694. https://doi.org/10.1113/jphysiol.2002.024800

[4] Ginn, S. L., Amaya, A. K., Alexander, I. E., Edelstein, M. L., & Abedi, M. R. (2013). Gene therapy clinical trials worldwide to 2012 – An update. Journal of Gene Medicine, 15(2), 65–77. https://doi.org/10.1002/jgm.2698

[5] Greenberg, B., Butler, J., Felker, G. M., Ponikowski, P., Voors, A. A., Pogoda, J. M., ... & Zsebo, K. M. (2016). Calcium upregulation by percutaneous administration of gene therapy in cardiac disease (CUPID 2): A randomized, multinational, double-blind, placebo-controlled, phase 2b trial. The Lancet, 387(10024), 1178–1186. https://doi.org/10.1016/S0140-6736(16)00082-9

[6] Gholipour, A., Zahedmehr, A., Arabian, M., Shakerian, F., Maleki, M., Oveisee, M., & Malakootian, M. (2025). MiR-6721-5p as a natural regulator of Meta-VCL is upregulated in the serum of patients with coronary artery disease. Non-coding RNA Research, 10, 25-34.

[7] Grisanti, L. A., Evanson, J., Marchese, M. E., & Tilley, D. G. (2014). Pro-inflammatory responses in the heart are controlled by β2-adrenergic receptor stimulation. American Journal of Physiology–Heart and Circulatory Physiology, 307(3), H368–H375. https://doi.org/10.1152/ajpheart.00144.2014

[8] Gutstein, D. E., Morley, G. E., Tamaddon, H., Vaidya, D., Schneider, M. D., Chen, J., ... & Fishman, G. I. (2001). Conduction slowing and sudden arrhythmic death in mice with cardiac-restricted inactivation of connexin43. Circulation Research, 88(3), 333–339. https://doi.org/10.1161/01.RES.88.3.333

[9] Hacein-Bey-Abina, S., Von Kalle, C., Schmidt, M., Le Deist, F., Wulffraat, N., McIntyre, E., ... & Fischer, A. (2003). A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. The New England Journal of Medicine, 348(3), 255–256. https://doi.org/10.1056/NEJM200301163480314

[10] Jaski, B. E., Jessup, M. L., Mancini, D. M., Cappola, T. P., Pauly, D. F., Greenberg, B., ... & Hajjar, R. J. (2009). Calcium upregulation by percutaneous administration of gene therapy in cardiac disease (CUPID): A phase 1/2 clinical trial. Journal of Cardiac Failure, 15(3), 171–181. https://doi.org/10.1016/j.cardfail.2008.10.004

[11] Jessup, M., Greenberg, B., Mancini, D., Cappola, T., Pauly, D. F., Jaski, B., ... & Hajjar, R. J. (2011). Calcium upregulation by percutaneous administration of gene therapy in cardiac disease (CUPID): A phase 2 trial. Lancet, 377(9762), 406–412. https://doi.org/10.1016/S0140-6736(10)61801-5

[12] Beheshtizadeh, N., Amiri, Z., Tabatabaei, S. Z., Seraji, A. A., Gharibshahian, M., Nadi, A., ... & Kolahi Azar, H. (2024). Boosting antitumor efficacy using docetaxel-loaded nanoplatforms: from cancer therapy to regenerative medicine approaches. Journal of Translational Medicine, 22(1), 520.

[13] Kastrup, J., Jørgensen, E., Rück, A., Tägil, K., Glogar, D., Ruzyllo, W., ... & Ravn, H. B. (2005). Direct intramyocardial plasmid vascular endothelial growth factor-A165 gene therapy in patients with stable severe angina pectoris: A randomized double-blind placebo-controlled study. Journal of the American College of Cardiology, 45(7), 982–988. https://doi.org/10.1016/j.jacc.2004.12.063

[14] Kawase, Y., Ly, H. Q., Prunier, F., Lebeche, D., Shi, Y., Jin, H., & Hajjar, R. J. (2011). Reversal of cardiac dysfunction after long-term expression of SERCA2a by gene transfer in a pre-clinical model of heart failure. Journal of the American College of Cardiology, 57(1), 40–48. https://doi.org/10.1016/j.jacc.2010.07.043

[15] Kobayashi, J., Takeuchi, T., Jinnouchi, H., Nishikawa, Y., Tano, K., Koyama, T., & Imanaka, T. (2019). New generation gene therapy for cardiovascular diseases. Circulation Journal, 83(3), 611–617. https://doi.org/10.1253/circj.CJ-18-0922

[16] Kupatt, C., Hinkel, R., & Thierfelder, L. (2010). Gene therapy targets in cardiovascular disease: New therapeutic perspectives. Circulation, 121(15), 1735–1746. https://doi.org/10.1161/CIRCULATIONAHA.109.895508

[17] Beheshtizadeh, N., Mohammadzadeh, M., Mostafavi, M., Seraji, A. A., Ranjbar, F. E., Tabatabaei, S. Z., ... & Lolasi, F. (2024). Improving hemocompatibility in tissue-engineered products employing heparin-loaded nanoplatforms. Pharmacological Research, 107260.

[18] Li, C., Narkbunnam, N., Samulski, R. J., Asokan, A., Hu, G., Jacobson, L. J., ... & Monahan, P. E. (2013). Neutralizing antibodies against adeno-associated virus examined prospectively in pediatric patients with hemophilia. Gene Therapy, 20(2), 271–279. https://doi.org/10.1038/gt.2012.34

[19] Mingozzi, F., & High, K. A. (2011). Immune responses to AAV vectors: Overcoming barriers to successful gene therapy. Blood, 117(3), 533–541. https://doi.org/10.1182/blood-2010-09-300988

[20] Musunuru, K., Sheikh, F., Gupta, R. M., Houser, S. R., Maher, K. O., Milan, D. J., ... & Srivastava, D. (2019). Induced pluripotent stem cells for cardiovascular disease modeling and precision medicine: A scientific statement from the American Heart Association. Circulation, 140(17), e101–e114. https://doi.org/10.1161/CIR.0000000000000707

[21] Penn, M. S., Mendelsohn, F. O., Schaer, G. L., Sherman, W., Mueller, G. P., Kowalczyk, T., ... & Losordo, D. W. (2012). AAV-SDF-1 gene therapy for coronary artery disease: Phase 2 trial results. Molecular Therapy, 20(5), 1026–1032. https://doi.org/10.1038/mt.2011.313

[22] Prondzynski, M., Lemoine, M. D., Zech, A. T. L., Horváth, A., Di Mauro, V., Koivumäki, J. T., ... & Eschenhagen, T. (2019). Disease modeling of a mutation in α-actinin 2 guides correction of impaired Z-disc function in human cardiomyocytes. Nature Communications, 10, Article 614. https://doi.org/10.1038/s41467-019-08534-1

[23] Reddy, G. R., Jeong, E. K., & Ponce, F. A. (2021). Magnetic nanoparticles for biomedical applications. Annual Review of Biomedical Engineering, 23, 125–152. https://doi.org/10.1146/annurev-bioeng-062220-022226

[24] Silvestre, J. S., Smadja, D. M., & Lévy, B. I. (2011). Postischemic revascularization: From cellular and molecular mechanisms to clinical applications. Physiological Reviews, 91(2), 1077–1115. https://doi.org/10.1152/physrev.00032.2009

[25] Sugie, K., Yamamoto, A., Murata, M., & Kondo, T. (2020). Gene therapy in Danon disease: A current update. Frontiers in Cardiovascular Medicine, 7, Article 587152. https://doi.org/10.3389/fcvm.2020.587152

[26] Wang, L., Gao, Q., Zhang, H., & Li, X. (2023). 3D bioprinted cardiac tissues integrated with optogenetic circuits for heart regeneration. Biofabrication, 15(2), Article 025013. https://doi.org/10.1088/1758-5090/aca8e6

[27] World Health Organization. (2023). Cardiovascular diseases (CVDs). https://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds)

[28] Yotti, R., Seidman, C. E., & Seidman, J. G. (2019). Advances in the genetic basis and pathogenesis of sarcomere cardiomyopathies. Annual Review of Genomics and Human Genetics, 20, 129–153. https://doi.org/10.1146/annurev-genom-083118-015306

[29] Zacchigna, S., Zentilin, L., & Giacca, M. (2014). Adeno-associated virus vectors as therapeutic and investigational tools in the cardiovascular system. Circulation Research, 114(11), 1827–1846. https://doi.org/10.1161/CIRCRESAHA.114.302064

[30] Callis, T. E., Pandya, K., Seok, H. Y., Tang, R. H., Tatsuguchi, M., Huang, Z. P., ... & Wang, D. Z. (2009). MicroRNA-208a is a regulator of cardiac hypertrophy and conduction in mice. Journal of Clinical Investigation, 119(9), 2772–2786. https://doi.org/10.1172/JCI36154

@article{1708921,
      author = {Nahal Vahedi, Zeinab Samiee Zafarghandi, Seyedeh Zoha Tabatabaei},
      title = {Viral Gene Therapy for Cardiovascular Diseases: Mechanisms, Vectors, Clinical Advances, And Future Directions},
      journal = {Iconic Research And Engineering Journals},
      year = {2025},
      volume = {8},
      number = {12},
      pages = {3-18},
      issn = {2456-8880},
      url = {https://www.irejournals.com/formatedpaper/1708921.pdf},
      abstract = {Cardiovascular diseases (CVDs) sit atop the list leading to human mortality, thus preventing prompt attention by conventional pharmacologic or surgical treatments. Viral gene therapy has thus unfolded as a promising novel approach to treat the molecular causes of CVD by gene delivery, correction, or modulation in cardiac and vascular tissues. Therapeutic genes may be delivered via viral vectors such as adeno-associated virus (AAV), adenovirus, and lentivirus with great precision to cardiomyocytes, endothelial cells, and smooth muscle cells to treat heart failure, myocardial infarction, arrhythmias, and atherosclerosis, among others. Preclinical and clinical studies have established the efficacy of viral gene therapies in enhancing contractility, vascular regeneration, and the reversal of maladaptive remodeling. Clinical trials with some visibility to the world included those in which SERCA2a was targeted in chronic heart failure and VEGF for ischemic angiogenesis, which were deemed safe and moderately successful, yet the limitations of these studies bar their implementation as medicine. Immunogenicity of vectors, delivery efficacy, tissue specificity, limitations in packaging capacity, and maintenance of dent gene expression are among the major challenges. This article presents a comprehensive review of the mechanism, types of viral vectors, outcomes of clinical trials, targeting strategies, and perspectives for innovations in viral gene therapy for cardiovascular diseases. With continued evolution of gene editing tools and vector engineering, viral gene therapy is destined to emerge as a fundamental candidate in precision cardiology and regenerative cardiovascular medicine.},
      keywords = {Viral gene therapy, Cardiovascular disease, Adeno-associated virus, Lentivirus, SERCA2a, Myocardial infarction, Heart failure, Gene delivery, CRISPR, Vascular targeting},
      month = {June},
  }