Gene Transfer of the Sarcoplasmic Reticulum Pump in the Treatment of Heart Failure

This editorial refers to ‘Augmentation of left ventricular mechanics by recirculation-mediated AAV2/1-SERCA2a gene delivery in experimental heart failure’ by Justin Mariani et al. published in this issue on page 247–253. Therapy of congestive heart failure was revolutionized more than 20 years ago by the introduction of angiotensin-converting enzyme inhibitors and β-adrenoceptor blocking agents. Both have resulted in the improvement of symptoms and prognosis of patients with chronic heart failure. In the meantime, device-based therapies have been added to the therapeutic armamentarium. However, all attempts to directly address molecular alterations relevant to heart failure pathophysiology as treatment strategies have failed. Because morbidity and mortality of heart failure patients are still unacceptably high, there is an urgent need for new treatment strategies. Alterations of calcium cycling have been identified as a significant contributor to heart failure pathophysiology, and therefore, therapeutic strategies addressing calcium homeostasis seem logical.1 Altered calcium homeostasis may result in disturbed activation of contractile proteins with systolic dysfunction, and disturbed relaxation of contractile proteins with diastolic dysfunction. In addition, altered calcium homoeostasis may trigger arrhythmias, impair energy metabolism, and may play a major role in activation of the pathological gene programme. The major player in calcium homeostasis of the myocyte is the cardiac sarcoplasmic reticulum (SR), controlling activation, and deactivation of the contractile machinery. Trigger calcium, which enters the cell during the action potential, activates the calcium release channels of the SR, termed ryanodine receptors, to release a much larger amount of calcium for activation of contractile proteins. The muscle relaxes when calcium is eliminated from the cytosol, which occurs predominantly by activity of the SR calcium pump (SERCA2a). A minor part of the systolic calcium is eliminated outside the cell through the sodium–calcium exchanger. Disturbed calcium homeostasis in heart failure can be attributed to three major alterations causing impaired calcium accumulation of the SR: (i) leakiness of the SR through disturbed function of the ryanodine receptors, (ii) increased activity of the sodium–calcium exchanger with excessive transport of calcium outside the cell, and (iii) disturbed calcium reuptake into the SR.1 The latter results from decreased expression levels of the SR calcium pump, as well as from disturbed pump function. Accordingly, a logical approach to treat congestive heart failure would include stimulation of SR calcium uptake by influencing the SR calcium pump. The present study by Mariani et al. addresses these pathophysiological considerations by a gene therapy approach with virus-mediated gene transfer of the gene encoding the SR calcium (ATPase) pump.2 Gene therapy of congestive heart failure was seen with great expectations more than a decade ago; however, a significant risk to the patients results from the need to use viruses as vectors to transport the genes into the cells. The development of new virus systems, in particular the adeno-associated viruses (AAV), has only recently provided enough safety to study gene transfer approaches in patients. A number of studies have been performed to evaluate the possibility of SERCA gene transfer and upregulation of SERCA2a, the cardiac isoform of the SR calcium ATPase in different animal models of heart failure, results have shown an improvement in systolic and diastolic function.3,4 A recent paper in a sheep model of myocardial infarction and mitral regurgitation showed that SERCA upregulation improves function and reduces the remodelling process.5 Moreover, the calcium upregulation by percutaneous administration of gene therapy in cardiac disease (CUPID) study that enrolled a total of 39 patients with severe heart failure randomized to AAV transfer of SERCA2a or placebo has recently been presented.6 The CUPID trial suggests adequate safety and potential efficacy warranting further studies to evaluate this new treatment option in heart failure. The study by Mariani et al.2 evaluates the effects of AAV-mediated SERCA2a gene transfer on cardiac mechanics in sheep with tachycardia pacing-induced heart failure. In order to achieve efficient transfection rates and to prevent access of the virus to the peripheral circulation, the authors used a recirculation system. This system includes coronary venous blood drain from the coronary sinus with an occlusive balloon catheter and return of blood from the coronary sinus into the coronary artery via a roller pump. Gene therapy was performed after 4 weeks of tachycardia pacing with a heart rate of 180 b.p.m. resulting in congestive heart failure. The effect of the gene therapy was measured after an additional 4 weeks during which pacing was continued, and gene therapy treatment was compared with a control group. The results show that SERCA2a gene therapy increases fractional shortening significantly. Moreover, gene therapy results in a significant increase in end-systolic pressure volume relationship as a strong surrogate for cardiac contractility. Functional improvement was associated with a decrease in ventricular brain natriuretic peptide mRNA expression without a change in left ventricular dimensions. Accordingly, this large animal study shows that SERCA2a gene therapy increases cardiac contractility in this heart failure model. In addition, the study confirms the safety of this approach. There was no inflammatory or fibrotic response observed in the myocardium of treated animals. In addition, no arrhythmias were associated with gene transfer treatment. This further diminishes concerns that SERCA upregulation by increasing SR calcium content would result in increased arrhythmias.7 Some limitations of the present study have to be addressed: (i) the authors use a replication-deficient AAV2/1 vector, while newer engineered recombinant versions such as AAV8 and AAV9 are now available.8,9 These newer viruses exhibit relative cardiac specificity that allows intracoronary injection without the need for a recirculation system. Nevertheless, the recirculation system described in this manuscript may still offer an interesting option to enhance efficacy of gene transfer; (ii) the experiments were performed only 4 weeks after gene transfer, and therefore no long-term data regarding efficacy or safety are available from the present study; and (iii) the tachycardia pacing-induced heart failure model may not be representative of other heart failure pathophysiologies. In summary, the present study adds new information regarding safety and efficacy of gene transfer of the SR calcium pump as a new therapeutic approach to treat heart failure by correcting disturbed SR calcium handling. Together with the existing clinical safety data, this study creates optimism regarding this new approach. Conflict of interest: G.H. has received research grants and consulting fees from Servier, Orion Pharmaceuticals.