Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Gene therapy to treat cardiac arrhythmias

Nature Reviews Cardiology volume 12, pages 531–546 (2015)Cite this article

Subjects

Key Points

  • Clinical trials to test the clinical efficacy of gene therapy in humans are rapidly increasing in number, and confidence about advancing gene therapy to the clinical arena is growing

  • Gene therapy for cardiac diseases is less advanced than in some other clinical fields, and the therapeutic utility of gene therapy in the heart is only now being explored

  • Availability of novel viral vectors, such as the adeno-associated viruses, with an improved safety profile, long-term efficacy, and tissue selectivity has greatly contributed to advancements of cardiac gene therapy

  • Inherited and acquired arrhythmias might be suitable targets for gene therapy because of the lack of highly effective pharmacological treatments and the adverse effects of device therapies

  • The greatest challenge in gene therapy for the treatment of arrhythmias is the possibility that transduction of only a small number of cells might trigger proarrhythmic events

  • In a mouse model of recessive catecholaminergic polymorphic ventricular tachycardia, transduction of 40–50% of cardiomyocytes prevented the development of adrenergically-induced life-threatening arrhythmias

Abstract

Gene therapy to treat electrical dysfunction of the heart is an appealing strategy because of the limited therapeutic options available to manage the most-severe cardiac arrhythmias, such as ventricular tachycardia, ventricular fibrillation, and asystole. However, cardiac genetic manipulation is challenging, given the complex mechanisms underlying arrhythmias. Nevertheless, the growing understanding of the molecular basis of these diseases, and the development of sophisticated vectors and delivery strategies, are providing researchers with adequate means to target specific genes and pathways involved in disorders of heart rhythm. Data from preclinical studies have demonstrated that gene therapy can be successfully used to modify the arrhythmogenic substrate and prevent life-threatening arrhythmias. Therefore, gene therapy might plausibly become a treatment option for patients with difficult-to-manage acquired arrhythmias and for those with inherited arrhythmias. In this Review, we summarize the preclinical studies into gene therapy for acquired and inherited arrhythmias of the atria or ventricles. We also provide an overview of the technical advances in the design of constructs and viral vectors to increase the efficiency and safety of gene therapy and to improve selective delivery to target organs.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Mechanism of gene transfer.
Figure 2: Mechanism of gene silencing.
Figure 3: Mechanism of gene editing.
Figure 4: Mechanisms of arrhythmogenesis.
Figure 5: Schematic representation of the mechanisms of arrhythmogenesis in catecholaminergic polymorphic ventricular tachycardia.

Similar content being viewed by others

References

  1. Donahue, J. K. et al. Focal modification of electrical conduction in the heart by viral gene transfer. Nat. Med. 6, 1395–1398 (2000).

    Article  CAS  PubMed  Google Scholar 

  2. Priori, S. G. & Napolitano, C. From catheters to vectors: the dawn of molecular electrophysiology. Nat. Med. 6, 1316–1318 (2000).

    Article  CAS  PubMed  Google Scholar 

  3. Edelberg, J. M., Aird, W. C. & Rosenberg, R. D. Enhancement of murine cardiac chronotropy by the molecular transfer of the human beta2 adrenergic receptor cDNA. J. Clin. Invest. 101, 337–343 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Meister, G. & Tuschl, T. Mechanisms of gene silencing by double-stranded RNA. Nature 431, 343–349 (2004).

    Article  CAS  PubMed  Google Scholar 

  5. Grimm, D. et al. Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways. Nature 441, 537–541 (2006).

    Article  CAS  PubMed  Google Scholar 

  6. McBride, J. L. et al. Artificial miRNAs mitigate shRNA-mediated toxicity in the brain: implications for the therapeutic development of RNAi. Proc. Natl Acad. Sci. USA 105, 5868–5873 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Boudreau, R. L., Martins, I. & Davidson, B. L. Artificial microRNAs as siRNA shuttles: improved safety as compared to shRNAs in vitro and in vivo. Mol. Ther. 17, 169–175 (2009).

    Article  CAS  PubMed  Google Scholar 

  8. Hohjoh, H. Disease-causing allele-specific silencing by RNA interference. Pharmaceuticals (Basel) 6, 522–535 (2013).

    Article  CAS  Google Scholar 

  9. Mueller, C. et al. Sustained miRNA-mediated knockdown of mutant AAT with simultaneous augmentation of wild-type AAT has minimal effect on global liver miRNA profiles. Mol. Ther. 20, 590–600 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Urnov, F. D., Rebar, E. J., Holmes, M. C., Zhang, H. S. & Gregory, P. D. Genome editing with engineered zinc finger nucleases. Nat. Rev. Genet. 11, 636–646 (2010).

    Article  CAS  PubMed  Google Scholar 

  11. Joung, J. K. & Sander, J. D. TALENs: a widely applicable technology for targeted genome editing. Nat. Rev. Mol. Cell Biol. 14, 49–55 (2013).

    Article  CAS  PubMed  Google Scholar 

  12. Lombardo, A. et al. Site-specific integration and tailoring of cassette design for sustainable gene transfer. Nat. Methods 8, 861–869 (2011).

    Article  CAS  PubMed  Google Scholar 

  13. Lombardo, A. et al. Gene editing in human stem cells using zinc finger nucleases and integrase-defective lentiviral vector delivery. Nat. Biotechnol. 25, 1298–1306 (2007).

    Article  CAS  PubMed  Google Scholar 

  14. Lovric, J. et al. Terminal differentiation of cardiac and skeletal myocytes induces permissivity to AAV transduction by relieving inhibition imposed by DNA damage response proteins. Mol. Ther. 20, 2087–2097 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Chan, F., Hauswirth, W. W., Wensel, T. G. & Wilson, J. H. Efficient mutagenesis of the rhodopsin gene in rod photoreceptor neurons in mice. Nucleic Acids Res. 39, 5955–5966 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Mali, P. et al. RNA-guided human genome engineering via Cas9. Science 339, 823–826 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Long, C. et al. Prevention of muscular dystrophy in mice by CRISPR/Cas9-mediated editing of germline DNA. Science 345, 1184–1188 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lin, H., Parmacek, M. S., Morle, G., Bolling, S. & Leiden, J. M. Expression of recombinant genes in myocardium in vivo after direct injection of DNA. Circulation 82, 2217–2221 (1990).

    Article  CAS  PubMed  Google Scholar 

  19. Buttrick, P. M., Kass, A., Kitsis, R. N., Kaplan, M. L. & Leinwand, L. A. Behavior of genes directly injected into the rat heart in vivo. Circ. Res. 70, 193–198 (1992).

    Article  CAS  PubMed  Google Scholar 

  20. Penn, M. S. 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. 112, 816–825 (2013).

    Article  CAS  PubMed  Google Scholar 

  21. Zangi, L. et al. Modified mRNA directs the fate of heart progenitor cells and induces vascular regeneration after myocardial infarction. Nat. Biotechnol. 31, 898–907 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Naldini, L. et al. In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science 272, 263–267 (1996).

    Article  CAS  PubMed  Google Scholar 

  23. Zhao, J. et al. Lentiviral vectors for delivery of genes into neonatal and adult ventricular cardiac myocytes in vitro and in vivo. Basic Res. Cardiol. 97, 348–358 (2002).

    Article  CAS  PubMed  Google Scholar 

  24. Fleury, S. et al. Multiply attenuated, self-inactivating lentiviral vectors efficiently deliver and express genes for extended periods of time in adult rat cardiomyocytes in vivo. Circulation 107, 2375–2382 (2003).

    Article  CAS  PubMed  Google Scholar 

  25. Niwano, K. et al. Lentiviral vector-mediated SERCA2 gene transfer protects against heart failure and left ventricular remodeling after myocardial infarction in rats. Mol. Ther. 16, 1026–1032 (2008).

    Article  CAS  PubMed  Google Scholar 

  26. Di Pasquale, E., Latronico, M. V., Jotti, G. S. & Condorelli, G. Lentiviral vectors and cardiovascular diseases: a genetic tool for manipulating cardiomyocyte differentiation and function. Gene Ther. 19, 642–648 (2012).

    Article  CAS  PubMed  Google Scholar 

  27. Hacein-Bey-Abina, S. et al. A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N. Engl. J. Med. 348, 255–256 (2003).

    Article  PubMed  Google Scholar 

  28. Hockemeyer, D. et al. Efficient targeting of expressed and silent genes in human ESCs and iPSCs using zinc-finger nucleases. Nat. Biotechnol. 27, 851–857 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Biffi, A. et al. Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science 341, 1233158 (2013).

    Article  CAS  PubMed  Google Scholar 

  30. Aiuti, A. et al. Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome. Science 341, 1233151 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Palfi, S. et al. Long-term safety and tolerability of ProSavin, a lentiviral vector-based gene therapy for Parkinson's disease: a dose escalation, open-label, phase 1/2 trial. Lancet 383, 1138–1146 (2014).

    Article  CAS  PubMed  Google Scholar 

  32. Flight, M. H. Trial watch: Clinical trial boost for lentiviral gene therapy. Nat. Rev. Drug Discov. 12, 654 (2013).

    Article  CAS  PubMed  Google Scholar 

  33. Brunner, M. et al. In vivo gene transfer of Kv1.5 normalizes action potential duration and shortens QT interval in mice with long QT phenotype. Am. J. Physiol. Heart Circ. Physiol. 285, H194–H203 (2003).

    Article  CAS  PubMed  Google Scholar 

  34. Amit, G. et al. Selective molecular potassium channel blockade prevents atrial fibrillation. Circulation 121, 2263–2270 (2010).

    Article  CAS  PubMed  Google Scholar 

  35. Rosengart, T. K. et al. Angiogenesis gene therapy: phase I assessment of direct intramyocardial administration of an adenovirus vector expressing VEGF121 cDNA to individuals with clinically significant severe coronary artery disease. Circulation 100, 468–474 (1999).

    Article  CAS  PubMed  Google Scholar 

  36. French, B. A., Mazur, W., Geske, R. S. & Bolli, R. Direct in vivo gene transfer into porcine myocardium using replication-deficient adenoviral vectors. Circulation 90, 2414–2424 (1994).

    Article  CAS  PubMed  Google Scholar 

  37. Giraud, C., Winocour, E. & Berns, K. I. Site-specific integration by adeno-associated virus is directed by a cellular DNA sequence. Proc. Natl Acad. Sci. USA 91, 10039–10043 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Flotte, T. R. & Berns, K. I. Adeno-associated virus: a ubiquitous commensal of mammals. Hum. Gene Ther. 16, 401–407 (2005).

    Article  CAS  PubMed  Google Scholar 

  39. Wu, Z., Asokan, A. & Samulski, R. J. Adeno-associated virus serotypes: vector toolkit for human gene therapy. Mol. Ther. 14, 316–327 (2006).

    Article  CAS  PubMed  Google Scholar 

  40. Gao, G. et al. Transendocardial delivery of AAV6 results in highly efficient and global cardiac gene transfer in rhesus macaques. Hum. Gene Ther. 22, 979–984 (2011).

    Article  CAS  PubMed  Google Scholar 

  41. Asokan, A., Schaffer, D. V. & Samulski, R. J. The AAV vector toolkit: poised at the clinical crossroads. Mol. Ther. 20, 699–708 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Grieger, J. C. & Samulski, R. J. Packaging capacity of adeno-associated virus serotypes: impact of larger genomes on infectivity and postentry steps. J. Virol. 79, 9933–9944 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. England, S. B. et al. Very mild muscular dystrophy associated with the deletion of 46% of dystrophin. Nature 343, 180–182 (1990).

    Article  CAS  PubMed  Google Scholar 

  44. Chamberlain, J. S. Gene therapy of muscular dystrophy. Hum. Mol. Genet. 11, 2355–2362 (2002).

    Article  CAS  PubMed  Google Scholar 

  45. Liu, M. et al. Adeno-associated virus-mediated microdystrophin expression protects young mdx muscle from contraction-induced injury. Mol. Ther. 11, 245–256 (2005).

    Article  CAS  PubMed  Google Scholar 

  46. Ghosh, A. & Duan, D. Expanding adeno-associated viral vector capacity: a tale of two vectors. Biotechnol. Genet. Eng. Rev. 24, 165–177 (2007).

    Article  CAS  PubMed  Google Scholar 

  47. Ghosh, A., Yue, Y., Lai, Y. & Duan, D. A hybrid vector system expands adeno-associated viral vector packaging capacity in a transgene-independent manner. Mol. Ther. 16, 124–130 (2008).

    Article  CAS  PubMed  Google Scholar 

  48. Lai, Y., Yue, Y., Liu, M. & Duan, D. Synthetic intron improves transduction efficiency of trans-splicing adeno-associated viral vectors. Hum. Gene Ther. 17, 1036–1042 (2006).

    Article  CAS  PubMed  Google Scholar 

  49. Koo, T., Popplewell, L., Athanasopoulos, T. & Dickson, G. Triple trans-splicing adeno-associated virus vectors capable of transferring the coding sequence for full-length dystrophin protein into dystrophic mice. Hum. Gene Ther. 25, 98–108 (2014).

    Article  CAS  PubMed  Google Scholar 

  50. Nayak, S. & Herzog, R. W. Progress and prospects: immune responses to viral vectors. Gene Ther. 17, 295–304 (2010).

    Article  CAS  PubMed  Google Scholar 

  51. Mingozzi, F. & High, K. A. Immune responses to AAV vectors: overcoming barriers to successful gene therapy. Blood 122, 23–36 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Tan, A., Rajadas, J. & Seifalian, A. M. Exosomes as nano-theranostic delivery platforms for gene therapy. Adv. Drug Deliv. Rev. 65, 357–367 (2013).

    Article  CAS  PubMed  Google Scholar 

  53. Ailawadi, S., Wang, X., Gu, H. & Fan, G. C. Pathologic function and therapeutic potential of exosomes in cardiovascular disease. Biochim. Biophys. Acta 1852, 1–11 (2015).

    Article  CAS  PubMed  Google Scholar 

  54. Salva, M. Z. et al. Design of tissue-specific regulatory cassettes for high-level rAAV-mediated expression in skeletal and cardiac muscle. Mol. Ther. 15, 320–329 (2007).

    Article  CAS  PubMed  Google Scholar 

  55. Gerolami, R. et al. Gene transfer to hepatocellular carcinoma: transduction efficacy and transgene expression kinetics by using retroviral and lentiviral vectors. Cancer Gene Ther. 7, 1286–1292 (2000).

    Article  CAS  PubMed  Google Scholar 

  56. Denegri, M. et al. Viral gene transfer rescues arrhythmogenic phenotype and ultrastructural abnormalities in adult calsequestrin-null mice with inherited arrhythmias. Circ. Res. 110, 663–668 (2012).

    Article  CAS  PubMed  Google Scholar 

  57. Denegri, M. et al. Single delivery of an adeno-associated viral construct to transfer the CASQ2 gene to knock-in mice affected by catecholaminergic polymorphic ventricular tachycardia is able to cure the disease from birth to advanced age. Circulation 129, 2673–2681 (2014).

    Article  CAS  PubMed  Google Scholar 

  58. Liu, N. et al. Abnormal propagation of calcium waves and ultrastructural remodeling in recessive catecholaminergic polymorphic ventricular tachycardia. Circ. Res. 113, 142–152 (2013).

    Article  CAS  PubMed  Google Scholar 

  59. Geisler, A. et al. microRNA122-regulated transgene expression increases specificity of cardiac gene transfer upon intravenous delivery of AAV9 vectors. Gene Ther. 18, 199–209 (2011).

    Article  CAS  PubMed  Google Scholar 

  60. Yang, L. et al. A myocardium tropic adeno-associated virus (AAV) evolved by DNA shuffling and in vivo selection. Proc. Natl Acad. Sci. USA 106, 3946–3951 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Asokan, A. et al. Reengineering a receptor footprint of adeno-associated virus enables selective and systemic gene transfer to muscle. Nat. Biotechnol. 28, 79–82 (2010).

    Article  CAS  PubMed  Google Scholar 

  62. Pulicherla, N. et al. Engineering liver-detargeted AAV9 vectors for cardiac and musculoskeletal gene transfer. Mol. Ther. 19, 1070–1078 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Gossen, M. et al. Transcriptional activation by tetracyclines in mammalian cells. Science 268, 1766–1769 (1995).

    Article  CAS  PubMed  Google Scholar 

  64. Tafuro, S. et al. Inducible adeno-associated virus vectors promote functional angiogenesis in adult organisms via regulated vascular endothelial growth factor expression. Cardiovasc. Res. 83, 663–671 (2009).

    Article  CAS  PubMed  Google Scholar 

  65. Jaski, B. E. 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. 15, 171–181 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Jessup, M. 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 124, 304–313 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Katz, M. G., Fargnoli, A. S., Pritchette, L. A. & Bridges, C. R. Gene delivery technologies for cardiac applications. Gene Ther. 19, 659–669 (2012).

    CAS  Google Scholar 

  68. Fargnoli, A. S. et al. Cardiac surgical delivery of the sarcoplasmic reticulum calcium ATPase rescues myocytes in ischemic heart failure. Ann. Thorac. Surg. 96, 586–595 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  69. Igarashi, T. et al. Connexin gene transfer preserves conduction velocity and prevents atrial fibrillation. Circulation 125, 216–225 (2012).

    Article  CAS  PubMed  Google Scholar 

  70. Andrade, J., Khairy, P., Dobrev, D. & Nattel, S. The clinical profile and pathophysiology of atrial fibrillation: relationships among clinical features, epidemiology, and mechanisms. Circ. Res. 114, 1453–1468 (2014).

    Article  CAS  PubMed  Google Scholar 

  71. Bauer, A. et al. Inhibitory G protein overexpression provides physiologically relevant heart rate control in persistent atrial fibrillation. Circulation 110, 3115–3120 (2004).

    Article  CAS  PubMed  Google Scholar 

  72. Lugenbiel, P. et al. Genetic suppression of Gαs protein provides rate control in atrial fibrillation. Basic Res. Cardiol. 107, 265 (2012).

    Article  CAS  PubMed  Google Scholar 

  73. Murata, M., Cingolani, E., McDonald, A. D., Donahue, J. K. & Marbán, E. Creation of a genetic calcium channel blocker by targeted gem gene transfer in the heart. Circ. Res. 95, 398–405 (2004).

    Article  CAS  PubMed  Google Scholar 

  74. Stump, M. R., Gong, Q. & Zhou, Z. Isoform-specific dominant-negative effects associated with hERG1 G628S mutation in long QT syndrome. PLoS ONE 7, e42552 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Soucek, R. et al. Genetic suppression of atrial fibrillation using a dominant-negative ether-a-go-go-related gene mutant. Heart Rhythm 9, 265–272 (2012).

    Article  PubMed  Google Scholar 

  76. Bikou, O. et al. Connexin 43 gene therapy prevents persistent atrial fibrillation in a porcine model. Cardiovasc. Res. 92, 218–225 (2011).

    Article  CAS  PubMed  Google Scholar 

  77. Nattel, S., Maguy, A., Le Bouter, S. & Yeh, Y. H. Arrhythmogenic ion-channel remodeling in the heart: heart failure, myocardial infarction, and atrial fibrillation. Physiol. Rev. 87, 425–456 (2007).

    Article  CAS  PubMed  Google Scholar 

  78. Firouzi, M. et al. Association of human connexin 40 gene polymorphisms with atrial vulnerability as a risk factor for idiopathic atrial fibrillation. Circ. Res. 95, e29–33 (2004).

    Article  CAS  PubMed  Google Scholar 

  79. Thibodeau, I. L. et al. Paradigm of genetic mosaicism and lone atrial fibrillation: physiological characterization of a connexin 43-deletion mutant identified from atrial tissue. Circulation 122, 236–244 (2010).

    Article  CAS  PubMed  Google Scholar 

  80. Trappe, K. et al. Suppression of persistent atrial fibrillation by genetic knockdown of caspase 3: a pre-clinical pilot study. Eur. Heart J. 34, 147–157 (2013).

    Article  CAS  PubMed  Google Scholar 

  81. Lau, D. H. et al. Epicardial border zone overexpression of skeletal muscle sodium channel SkM1 normalizes activation, preserves conduction, and suppresses ventricular arrhythmia: an in silico, in vivo, in vitro study. Circulation 119, 19–27 (2009).

    Article  CAS  PubMed  Google Scholar 

  82. Sasano, T., Kelemen, K., Greener, I. D. & Donahue, J. K. Ventricular tachycardia from the healed myocardial infarction scar: validation of an animal model and utility of gene therapy. Heart Rhythm 6 (Suppl.), S91–S97 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  83. Lyon, A. R. et al. SERCA2a gene transfer decreases sarcoplasmic reticulum calcium leak and reduces ventricular arrhythmias in a model of chronic heart failure. Circ. Arrhythm. Electrophysiol. 4, 362–372 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Plotnikov, A. N. et al. Biological pacemaker implanted in canine left bundle branch provides ventricular escape rhythms that have physiologically acceptable rates. Circulation 109, 506–512 (2004).

    Article  PubMed  Google Scholar 

  85. Bucchi, A. et al. Wild-type and mutant HCN channels in a tandem biological-electronic cardiac pacemaker. Circulation 114, 992–999 (2006).

    Article  PubMed  Google Scholar 

  86. Boink, G. J. et al. HCN2/SkM1 gene transfer into canine left bundle branch induces stable, autonomically responsive biological pacing at physiological heart rates. J. Am. Coll. Cardiol. 61, 1192–1201 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Miake, J., Marbán, E. & Nuss, H. B. Biological pacemaker created by gene transfer. Nature 419, 132–133 (2002).

    Article  CAS  PubMed  Google Scholar 

  88. Nattel, S. Inward rectifier-funny current balance and spontaneous automaticity: cautionary notes for biologic pacemaker development. Heart Rhythm 5, 1318–1319 (2008).

    Article  PubMed  Google Scholar 

  89. Valiunas, V. et al. Human mesenchymal stem cells make cardiac connexins and form functional gap junctions. J. Physiol. 555, 617–626 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Cho, H. C., Kashiwakura, Y. & Marbán, E. Creation of a biological pacemaker by cell fusion. Circ. Res. 100, 1112–1115 (2007).

    Article  CAS  PubMed  Google Scholar 

  91. Kapoor, N., Liang, W., Marbán, E. & Cho, H. C. Direct conversion of quiescent cardiomyocytes to pacemaker cells by expression of Tbx18. Nat. Biotechnol. 31, 54–62 (2013).

    Article  CAS  PubMed  Google Scholar 

  92. Hu, Y. F., Dawkins, J. F., Cho, H. C., Marbán, E. & Cingolani, E. Biological pacemaker created by minimally invasive somatic reprogramming in pigs with complete heart block. Sci. Transl. Med. 6, 245ra94 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. International Human Genome Sequencing Consortium. Finishing the euchromatic sequence of the human genome. Nature 431, 931–945 (2004).

  94. Priori, S. G. et al. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm 10, 1932–1963 (2013).

    Article  PubMed  Google Scholar 

  95. London, B. et al. Long QT and ventricular arrhythmias in transgenic mice expressing the N terminus and first transmembrane segment of a voltage-gated potassium channel. Proc. Natl Acad. Sci. USA 95, 2926–2931 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Kodirov, S. A., Brunner, M., Busconi, L. & Koren, G. Long-term restitution of 4-aminopyridine-sensitive currents in Kv1DN ventricular myocytes using adeno-associated virus-mediated delivery of Kv1.5. FEBS Lett. 550, 74–78 (2003).

    Article  CAS  PubMed  Google Scholar 

  97. Valle, G. et al. Catecholaminergic polymorphic ventricular tachycardia-related mutations R33Q and L167H alter calcium sensitivity of human cardiac calsequestrin. Biochem. J. 413, 291–303 (2008).

    Article  CAS  PubMed  Google Scholar 

  98. Rizzi, N. et al. Unexpected structural and functional consequences of the R33Q homozygous mutation in cardiac calsequestrin: a complex arrhythmogenic cascade in a knock in mouse model. Circ. Res. 103, 298–306 (2008).

    Article  CAS  PubMed  Google Scholar 

  99. Lompré, A. M. et al. Ca2+ cycling and new therapeutic approaches for heart failure. Circulation 121, 822–830 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Cutler, M. J., Wan, X., Laurita, K. R., Hajjar, R. J. & Rosenbaum, D. S. Targeted SERCA2a gene expression identifies molecular mechanism and therapeutic target for arrhythmogenic cardiac alternans. Circ. Arrhythm. Electrophysiol. 2, 686–694 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Zsebo, K. 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. 114, 101–108 (2014).

    Article  CAS  PubMed  Google Scholar 

  102. Greenberg, B. et al. Design of a phase 2b trial of intracoronary administration of AAV1/SERCA2a in patients with advanced heart failure: the CUPID 2 trial (Calcium Up-regulation by Percutaneous Administration of Gene Therapy in Cardiac Disease phase 2b). JACC Heart Fail. 2, 84–92 (2014).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

S.G.P. is also affiliated with the Department of Molecular Medicine, University of Pavia, Pavia, Italy.

Author information

Authors and Affiliations

  1. Division of Cardiology and Molecular Cardiology, Fondazione Salvatore Maugeri, Via Maugeri 10/10°, 27100, Pavia, Italy

    Rossana Bongianino & Silvia G. Priori

Authors
  1. Rossana Bongianino
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Silvia G. Priori
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Both authors researched data for the article, discussed its content, wrote the manuscript, and reviewed/edited it before submission.

Corresponding author

Correspondence to Silvia G. Priori.

Ethics declarations

Competing interests

S.G.P. declares that she is a member of the board of directors of Cardiogene Sciences. R.B. declares no competing interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bongianino, R., Priori, S. Gene therapy to treat cardiac arrhythmias. Nat Rev Cardiol 12, 531–546 (2015). https://doi.org/10.1038/nrcardio.2015.61

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrcardio.2015.61

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research