Gene Therapy in Heart Failure


Heart failure is a chronic condition leading to debilitating symptoms and reduced life expectancy. Several pharmacological therapies which improve symptoms and mortality have been developed over the past 30 years. These therapies are, however, limited in terms of both efficacy and side‐effect profile. Gene therapy represents a fundamental change in the way treatments are developed with the potential to directly target and correct individual molecular abnormalities. These therapies have the potential to offer long‐term beneficial effects from a single treatment and, with direct targeting, less off‐target effects. As with any new therapy, a number of challenges must be overcome before gene therapy can be considered a realistic option to patients with heart failure.

Key Concepts

  • Gene therapy could allow direct targeting of molecular abnormalities in patients with heart failure.
  • Preclinical data suggests that in animal models of heart failure, SERCA2a gene therapy significantly improves haemodynamic parameters, reduces arrhythmia risk and corrects molecular abnormalities.
  • Initial clinical data in a small number of patients suggested that SERCA2a gene therapy was beneficial to patients with advanced heart failure. However, a recent study in a larger number of patients was disappointingly neutral.
  • A number of molecular abnormalities exist in the failing myocytes, each of which could represent a potential target to treat heart failure.
  • Gene therapy requires a large financial commitment from pharmaceutical companies and cost is a major limitation to the development of gene therapy products.

Keywords: gene therapy; heart failure; novel heart failure treatment; SERCA2a; cellular therapies for heart failure

Figure 1. Schematic of a cardiomyocyte showing normal Ca2+ handling during excitation–contraction coupling. 1. Normal Ca2+ cycling begins with the cardiac action potential depolarising the surface membrane and triggering a small Ca2+ current into the cytoplasm through L‐type Ca2+ channels. 2. This triggers a much larger influx of Ca2+ from the sarcoplasmic reticulum (SR) store through the ryanodine receptor (RyR). 3. This calcium‐induced calcium release triggers contraction through the binding of Ca2+ to the troponin C component of the cardiac myofilaments. 4. During diastole Ca2+ is taken back up into the SR through the action of sarcoplasmic (endoplasmic) reticulum Ca2+ ATPase 2a (SERCA2a) and extruded from the cell by the Na+‐Ca2+ exchange (NCX) (5). SERCA2a function is regulated by phospholamban (PLN). Ca2+/calmodulin‐dependent protein kinase (CaMKII) can modulate excitation–contraction coupling by phosphorylating important regulatory proteins such as RyR, PLN and L‐type Ca2+ channels.
Figure 2. Illustrating the regulation of SERCA2a by phospholamban (PLN). When PLN is unphosphorylated, it acts as an inhibitor to SERCA2a activity (configuration displayed on the left). When PLN is phosphorylated, it forms a pentamer and the inhibition of SERCA2a is relieved. Factors which increase the activity of SERCA2a are displayed. Ca2+, calcium; CaMkII, Ca2+/calmodulin‐dependent kinase II; I‐1, inhibitor 1; PKA, protein kinase A; PP1, protein phosphatase 1.


Carter PJ and Samulski RJ (2000) Adeno‐associated viral vectors as gene delivery vehicles. International Journal of Molecular Medicine 6: 17–27.

Chung ES, Miller L, Patel AN, et al. (2015) 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. European Heart Journal 36: 2228–2238.

Communal C, Singh K, Sawyer DB and Colucci WS (1999) Opposing effects of beta(1)‐ and beta(2)‐adrenergic receptors on cardiac myocyte apoptosis : role of a pertussis toxin‐sensitive G protein. Circulation 100: 2210–2212.

Del Monte F, Dalal R, Tabchy A, et al. (2004) Transcriptional changes following restoration of SERCA2a levels in failing rat hearts. FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology 18: 1474–1476.

Du XJ, Gao XM, Jennings GL, Dart AM and Woodcock EA (2000) Preserved ventricular contractility in infarcted mouse heart overexpressing beta(2)‐adrenergic receptors. American Journal of Physiology. Heart and Circulatory Physiology 279: H2456–H2463.

Du XJ, Cole TJ, Tenis N, et al. (2002) Impaired cardiac contractility response to hemodynamic stress in S100A1‐deficient mice. Molecular and Cellular Biology 22: 2821–2829.

Engelhardt S, Hein L, Dyachenkow V, et al. (2004) Altered calcium handling is critically involved in the cardiotoxic effects of chronic beta‐adrenergic stimulation. Circulation 109: 1154–1160.

Gansbacher B (2002) Policy statement on the social, ethical and public awareness issues in gene therapy. The Journal of Gene Medicine 4: 687–691.

Gwathmey JK, Copelas L, MacKinnon R, et al. (1987) Abnormal intracellular calcium handling in myocardium from patients with end‐stage heart failure. Circulation Research 61: 70–76.

Hadri L, Bobe R, Kawase Y, et al. (2010) SERCA2a gene transfer enhances eNOS expression and activity in endothelial cells. Molecular Therapy: The Journal of the American Society of Gene Therapy 18: 1284–1292.

Haghighi K, Kolokathis F, Pater L, et al. (2003) Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human. The Journal of Clinical Investigation 111: 869–876.

Hajjar RJ, Zsebo K, Deckelbaum L, et al. (2008) Design of a phase 1/2 trial of intracoronary administration of AAV1/SERCA2a in patients with heart failure. Journal of Cardiac Failure 14: 355–367.

Hata JA, Williams ML and Koch WJ (2004) Genetic manipulation of myocardial beta‐adrenergic receptor activation and desensitization. Journal of Molecular and Cellular Cardiology 37: 11–21.

Hayward C, Patel H and Lyon A (2014) Gene therapy in heart failure. SERCA2a as a therapeutic target. Circulation Journal 78: 2577–2587.

Hoshijima M, Ikeda Y, Iwanaga Y, et al. (2002) Chronic suppression of heart‐failure progression by a pseudophosphorylated mutant of phospholamban via in vivo cardiac rAAV gene delivery. Nature Medicine 8: 864–871.

Iwanaga Y, Hoshijima M, Gu Y, et al. (2004) Chronic phospholamban inhibition prevents progressive cardiac dysfunction and pathological remodeling after infarction in rats. The Journal of Clinical Investigation 113: 727–736.

Jaski BE, Jessup ML, Mancini DM, et al. (2009) Calcium upregulation by percutaneous administration of gene therapy in cardiac disease (CUPID Trial), a first‐in‐human phase 1/2 clinical trial. Journal of Cardiac Failure 15: 171–181.

Jessup M, Greenberg B, Mancini D, et al. (2011) 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.

Karakikes I, Hadri L, Rapti K, et al. (2012) Concomitant intravenous nitroglycerin with intracoronary delivery of AAV1.SERCA2a enhances gene transfer in porcine hearts. Molecular Therapy 20: 565–571.

Kho C, Lee A, Jeong D, et al. (2011) SUMO1‐dependent modulation of SERCA2a in heart failure. Nature 477: 601–605.

Lai NC, Roth DM, Gao MH, et al. (2004) Intracoronary adenovirus encoding adenylyl cyclase VI increases left ventricular function in heart failure. Circulation 110: 330–336.

Liggett SB, Tepe NM, Lorenz JN, et al. (2000) Early and delayed consequences of beta(2)‐adrenergic receptor overexpression in mouse hearts: critical role for expression level. Circulation 101: 1707–1714.

Lyon AR, Bannister ML, Collins T, et al. (2011) SERCA2a gene transfer decreases sarcoplasmic reticulum calcium leak and reduces ventricular arrhythmias in a model of chronic heart failure. Circulation. Arrhythmia and Electrophysiology 4: 362–372.

Maurice JP, Hata JA, Shah AS, et al. (1999) Enhancement of cardiac function after adenoviral‐mediated in vivo intracoronary beta2‐adrenergic receptor gene delivery. The Journal of Clinical Investigation 104: 21–29.

Milano CA, Allen LF, Rockman HA, et al. (1994) Enhanced myocardial function in transgenic mice overexpressing the beta 2‐adrenergic receptor. Science 264: 582–586.

Minamisawa S, Hoshijima M, Chu G, et al. (1999) Chronic phospholamban‐sarcoplasmic reticulum calcium ATPase interaction is the critical calcium cycling defect in dilated cardiomyopathy. Cell 99: 313–322.

Miyamoto MI, del Monte F, Schmidt U, et al. (2000) Adenoviral gene transfer of SERCA2a improves left‐ventricular function in aortic‐banded rats in transition to heart failure. Proceedings of the National Academy of Sciences of the United States of America 97: 793–798.

Monahan PE and Samulski RJ (2000) AAV vectors: is clinical success on the horizon? Gene Therapy 7: 24–30.

del Monte F, Harding SE, Schmidt U, et al. (1999) Restoration of contractile function in isolated cardiomyocytes from failing human hearts by gene transfer of SERCA2a. Circulation 100: 2308–2311.

del Monte F, Williams E, Lebeche D, et al. (2001) Improvement in survival and cardiac metabolism after gene transfer of sarcoplasmic reticulum Ca(2+)‐ATPase in a rat model of heart failure. Circulation 104: 1424–1429.

del Monte F, Harding SE, Dec GW, Gwathmey JK and Hajjar RJ (2002) Targeting phospholamban by gene transfer in human heart failure. Circulation 105: 904–907.

Most P, Pleger ST, Volkers M, et al. (2004) Cardiac adenoviral S100A1 gene delivery rescues failing myocardium. The Journal of Clinical Investigation 114: 1550–1563.

Most P, Seifert H, Gao E, et al. (2006) Cardiac S100A1 protein levels determine contractile performance and propensity toward heart failure after myocardial infarction. Circulation 114: 1258–1268.

Most P and Koch WJ (2007) S100A1: a calcium‐modulating inotropic prototype for future clinical heart failure therapy. Future Cardiology 3: 5–11.

Most P, Remppis A, Pleger ST, Katus HA and Koch WJ (2007) S100A1: a novel inotropic regulator of cardiac performance. Transition from molecular physiology to pathophysiological relevance. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology 293: R568–R577.

Nicolaou P, Rodriguez P, Ren X, et al. (2009) Inducible expression of active protein phosphatase‐1 inhibitor‐1 enhances basal cardiac function and protects against ischemia/reperfusion injury. Circulation Research 104: 1012–1020.

Niemeyer GP, Herzog RW, Mount J, et al. (2009) Long‐term correction of inhibitor‐prone hemophilia B dogs treated with liver‐directed AAV2‐mediated factor IX gene therapy. Blood 113: 797–806.

Pathak A, del Monte F, Zhao W, et al. (2005) Enhancement of cardiac function and suppression of heart failure progression by inhibition of protein phosphatase 1. Circulation Research 96: 756–766.

Pattison JS, Waggoner JR, James J, et al. (2008) Phospholamban overexpression in transgenic rabbits. Transgenic Research 17: 157–170.

Penaud‐Budloo M, Le Guiner C, Nowrouzi A, et al. (2008) Adeno‐associated virus vector genomes persist as episomal chromatin in primate muscle. Journal of Virology 82: 7875–7885.

Pleger ST, Most P, Boucher M, et al. (2007) Stable myocardial‐specific AAV6‐S100A1 gene therapy results in chronic functional heart failure rescue. Circulation 115: 2506–2515.

Pleger ST, Shan C, Ksienzyk J, et al. (2011) Cardiac AAV9‐S100A1 gene therapy rescues post‐ischemic heart failure in a preclinical large animal model. Science Translational Medicine 3: 92ra64.

Prunier F, Kawase Y, Gianni D, et al. (2008) Prevention of ventricular arrhythmias with sarcoplasmic reticulum Ca2+ ATPase pump overexpression in a porcine model of ischemia reperfusion. Circulation 118: 614–624.

Raake PW, Vinge LE, Gao E, et al. (2008) G protein‐coupled receptor kinase 2 ablation in cardiac myocytes before or after myocardial infarction prevents heart failure. Circulation Research 103: 413–422.

Raake PW, Schlegel P, Ksienzyk J, et al. (2013) AAV6.betaARKct cardiac gene therapy ameliorates cardiac function and normalizes the catecholaminergic axis in a clinically relevant large animal heart failure model. European Heart Journal 34: 1437–1447.

Roth DM, Gao MH, Lai NC, et al. (1999) Cardiac‐directed adenylyl cyclase expression improves heart function in murine cardiomyopathy. Circulation 99: 3099–3102.

Roth DM, Bayat H, Drumm JD, et al. (2002) Adenylyl cyclase increases survival in cardiomyopathy. Circulation 105: 1989–1994.

Sakata S, Lebeche D, Sakata N, et al. (2007) Restoration of mechanical and energetic function in failing aortic‐banded rat hearts by gene transfer of calcium cycling proteins. Journal of Molecular and Cellular Cardiology 42: 852–861.

Sato Y, Kiriazis H, Yatani A, et al. (2001) Rescue of contractile parameters and myocyte hypertrophy in calsequestrin overexpressing myocardium by phospholamban ablation. The Journal of Biological Chemistry 276: 9392–9399.

Shah AS, Lilly RE, Kypson AP, et al. (2000) Intracoronary adenovirus‐mediated delivery and overexpression of the beta(2)‐adrenergic receptor in the heart : prospects for molecular ventricular assistance. Circulation 101: 408–414.

Shah AS, White DC, Emani S, et al. (2001) In vivo ventricular gene delivery of a beta‐adrenergic receptor kinase inhibitor to the failing heart reverses cardiac dysfunction. Circulation 103: 1311–1316.

Suckau L, Fechner H, Chemaly E, et al. (2009) Long‐term cardiac‐targeted RNA interference for the treatment of heart failure restores cardiac function and reduces pathological hypertrophy. Circulation 119: 1241–1252.

Volkers M, Loughrey CM, Macquaide N, et al. (2007) S100A1 decreases calcium spark frequency and alters their spatial characteristics in permeabilized adult ventricular cardiomyocytes. Cell Calcium 41: 135–143.

Zhu WZ, Zheng M, Koch WJ, et al. (2001) Dual modulation of cell survival and cell death by beta(2)‐adrenergic signaling in adult mouse cardiac myocytes. Proceedings of the National Academy of Sciences of the United States of America 98: 1607–1612.

Zsebo K, Yaroshinsky A, Rudy JJ, et al. (2014) Long‐term effects of AAV1/SERCA2a gene transfer in patients with severe heart failure: analysis of recurrent cardiovascular events and mortality. Circulation Research 114: 101–108.

Further Reading

Pleger ST, Brinks H, Ritterhoff J, et al. (2013) Heart failure gene therapy. Circulation Research 113: 792–809.

Tilemann L, Ishikawa K, Weber T, et al. (2012) Gene therapy for heart failure. Circulation Research 110: 777–793.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Hayward, Carl, Patel, Hitesh C, Welch, Sophie, Patel, Ketna, and Lyon, Alexander R(Jan 2017) Gene Therapy in Heart Failure. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0025274]