SERCA2a Gene Transfer Therapy for Heart Failure

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Heart failure treatments are limited and the prognosis of patients with advanced heart failure is poor. Interventions that reverse contractile deficiency are needed. Heart failure has been elucidated at the level of gene expression in cardiac myocytes, with alterations in expression of calcium-cycling genes one of the best characterized. The sarcoplasmic reticulum (SR) Ca2+ ATPase pump (SERCA2a) is critical in controlling the movement of Ca2+ between the SR and cytoplasm. SERCA2a deficiency is commonly seen in advanced heart failure, driving the systolic and diastolic dysfunction in failing hearts. Replacement of this single enzyme via gene transfer can correct this dysfunction, restore Ca2+ homeostasis, and result in significant improvement in cardiac function. Unlike approved inotropic agents, correcting SERCA2a deficiency via gene transfer improves cardiac contractility, reduces myocardial oxygen consumption, decreases ventricular arrhythmias, and improves survival. A clinical trial has been initiated in heart failure patients targeting replacement of SERCA2a by gene transfer using the recombinant adeno-associated virus rAAV1/SERCA2a.

Disclosure:Krisztina M Zsebo, PhD, is an employee of Celladon Corporation. Brian E Jaski, MD, has no conflicts of interest to declare.



Correspondence Details:Brian E Jaski, MD, San Diego Cardiac Center, 3131 Berger Avenue, STE 200, San Diego, CA 92123. E:

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The copyright in this work belongs to Radcliffe Medical Media. Only articles clearly marked with the CC BY-NC logo are published with the Creative Commons by Attribution Licence. The CC BY-NC option was not available for Radcliffe journals before 1 January 2019. Articles marked ‘Open Access’ but not marked ‘CC BY-NC’ are made freely accessible at the time of publication but are subject to standard copyright law regarding reproduction and distribution. Permission is required for reuse of this content.

Despite important therapeutic improvements in pharmacological and device therapies, the prognosis for patients with advanced cardiovascular disease is poor, even with optimal pharmacological and device management. Heart failure continues to be a major cause of morbidity and mortality in the US. It is the leading medical cause of hospitalization and is expected to result in an estimated direct and indirect cost to the healthcare system in 2009 of $37.2 billion.1

Non-pharmacological therapies (such as heart transplantation and the use of implantable left ventricular assist devices) are considered only in the later stages of the disease, and access to such therapies is restricted to a fraction of patients who could potentially benefit from them. Specifically lacking are interventions that reverse the myocardial contractile deficiency that initially created the heart failure state.2,3

In this context, alternative approaches such as cell and gene therapy have attracted increased attention. Gene therapies have historically been challenged by ethical concerns over potential manipulation of the human genome. However, in the last decade gene transfer agents composed of defined sets of proteins and nucleic acids have become available that are much more amenable to rigorous quality control and potency assessments than their cell therapy counterparts, which presents challenges for consistent manufacturability.

In the US, oversight of the clinical development and ultimate approval of new drugs and biological agents comes under the auspices of the US Food and Drug Administration (FDA). The FDA is familiar with viral-based therapies from the review of vaccine products and has approved a number of agents based on naturally occurring viruses also composed of defined proteins and nucleic acids, as shown in Table 1.

Currently, the most promising of the gene transfer agents is recombinant adeno-associated virus (rAAV). Unlike adenoviral vectors, which were the predominant vectors used in the early days of gene therapy, rAAV vectors are derived from parvoviruses, which have a number of clinically favorable attributes. Foremost, they lack pathogenicity even in their wild-type state, unlike adenovirus vectors or the approved vaccines listed in Table 1. In addition, rAAV vectors have minimal immunogenicity, establish stable long-term transgene expression,4,5 and are non-replicating and non-integrating into the host genome, thereby obviating the issue of insertional mutagenesis that has plagued retroviral-based gene therapies.6

Many factors contribute to the success or failure of gene therapies, such as the complexity of the biological system being modified (e.g. inducing new blood vessel growth for coronary artery disease), the immunogenicity of the vector system used, the efficiency and safety of the delivery device or the system utilized, and appropriate targeting of the diseased organ, along with other biological and technical issues. Given the challenges, it is no wonder that there are no approved ‘gene transfer therapeutics’ in the US. However, the pre-clinical and clinical testing conducted over the last 15 years is finally coming to fruition, and several promising programs are in phase II or III clinical evaluation.7–9 Recently, gene therapy seems to have cured eight of 10 children with adenosine deaminase deficiency (a fatal autosomal recessive form of severe combined immunodeficiency), according to a study that followed their progress for a median of four years (range 1.8–8.0 years) after treatment. The eight patients no longer needed medication for the rare disease, which cripples the body’s defenses against infection.10

The treatment of heart failure with new modalities such as gene therapies has been enabled by increased understanding of the pathogenesis of cardiac hypertrophy and remodeling, which is driven by the response of cardiac myocytes to biomechanical stress. A variety of insults such as pressure or volume load, reactive oxygen species, cytokines, and circulating neurohormones activate a complex network of signaling pathways within cardiac myocytes. These pathways converge to alter cardiac gene expression and induce myocyte hypertrophy and dysfunction, as recently reviewed.11 These changes are similar to those observed during fetal cardiac development, and are co-ordinately regulated. Although many changes occur, among the most well-characterized are alterations in the expression of calcium cycling genes.

Calcium regulation in cardiac myocytes acts as a nodal control point in cardiac electrical activity, excitation–contraction coupling, energetics, and excitation–transcription coupling. In the mammalian heart (see Figure 1), intracellular calcium handling is regulated at various levels within the cell, with the sarcoplasmic reticulum (SR) playing a key role in managing the movement of calcium ions during contraction and relaxation. During relaxation, Ca2+ is reaccumulated back into the SR from the cytoplasm by the SR Ca2+ ATPase pump (SERCA2a). Due to a co-ordinated ‘fetal gene program’ induced in the cardiomyocyte in response to stress, the expression of SERCA2a declines in heart failure, resulting in the contractility and relaxation deficiencies that are a hallmark of this disease. Both SERCA2a enzyme activity and messenger RNA (mRNA) levels are decreased in cardiac tissue isolated from the hearts of patients with heart failure.12–15

The decline in SERCA2a results in abnormal Ca2+ handling, which causes a prolongation of Ca2+ transient, an increase in diastolic intracellular Ca2+, and a reduced SR Ca2+ content. Therefore, abnormal Ca2+ handling due to SERCA2a deficiency drives the systolic and diastolic dysfunction in failing hearts. In studies of human end-stage cardiomyocytes, replacement of this single enzyme via gene transfer can correct the contractile and relaxation deficit and restore Ca2+ homeostasis.12–15

Downstream regulators of the enzyme include phospholamban, a key regulatory protein of SERCA2a activity. Kinases and phosphatases, which regulate phospholamban phosphorylation, also influence SERCA2a activity.17 Unphosphorylated phospholamban inhibits SERCA2a activity, while the phosphorylated protein does not. The regulation of SERCA2a activity via phosphorylation of phospholamban is one of the key pathways responsible for an increase in cardiac performance to beta-adrenergic stimulation. Unfortunately, sustained beta-adrenergic stimulation leads to a profound alteration of the response to circulating catecholamines, including a reduction in SERCA2a that ultimately contributes to the progression of heart failure syndrome.18

Pioneering work by Roger Hajjar, MD, has demonstrated that increasing the level of SERCA2a using gene transfer results in significant improvements in cardiac function in pre-clinical models of heart failure in rodents,19–21 pigs,22 and sheep,23 even when the underlying pathophysiology or insult (e.g. mitral valve rupture or pacing induced heart failure) is not corrected. Since calcium homeostasis has been implicated in ventricular dysrhythmias, restoring Ca2+ homeostasis has potential to correct the contractile and relaxation deficits in patients with heart failure.24 Reduction in ventricular arrhythmias after overexpression of SERCA2a has been demonstrated after ischemia followed by reperfusion in rats21 and pigs.25

The resulting restoration of Ca2+ homeostasis following SERCA2a gene transfer is accompanied by a reversal of the ‘fetal gene program’ induced by heart failure, as studied in a rodent model.26 In this study, 1,300 genes appeared specifically dysregulated after the induction of heart failure, and 251 transcripts were found differentially expressed by at least 1.2-fold during heart failure versus normal. Of these 251 transcripts, 51 returned to normal levels by the restoration of a single enzyme via gene transfer. The normalization of multiple transcriptional elements can potentially be explained by the fact that normalization of SERCA2a activity results in restoration of Ca2+ homeostasis, and that intracellular Ca2+ is the most universal signal used by living organisms to convey information to many different cellular processes. A number of proteins have been identified that sense intracellular Ca2+ and decode the key elements in the nucleus to regulate the activity of various transcriptional networks.27

In addition to correction of contraction and relaxation defects, one of the most important beneficial aspects of restoring SERCA2a levels in heart failure relates to the correction of the abnormal mitochondrial energetics. Cardiac excitation–contraction coupling consumes vast amounts of cellular energy, most of which is produced in mitochondria by oxidative phosphorylation. In order to adapt the constantly varying workload of the heart to energy supply, tight coupling mechanisms are essential to maintain cellular pools of adenosine triphosphate (ATP), phosphocreatine, and nicotinamide adenine dinucleotide, reduced (NADH). The most important regulators of oxidative phosphorylation are adenosine diphosphate (ADP), inorganic phosphates (Pi), and Ca2+. Ca2+ signals in cardiac myocytes have an impact on energy supply and demand matching.28

Defects in excitation–contraction coupling in chronic heart failure may adversely affect mitochondrial Ca2+ uptake and energetics, initiating a vicious cycle of contractile dysfunction and energy depletion. The importance of this process is highlighted by the experience with inotropic agents. The use of inotropic agents has been regarded as a logical approach to treat depressed left-ventricular contractility associated with heart failure. Despite this conceptual framework, inotropic intervention is associated with an increase in the energetic cost of contractility, with consequences including excessive mortality.29 However, unlike inotropic agents, which improve contractile function at the expense of increased mortality and worsening metabolism, gene transfer of SERCA2a improves contractility but, most importantly, also improves survival (see Figure 2) and reduces the oxygen cost of contractility in animal models of heart failure.30,31 Thus, the replacement of SERCA2a by gene transfer may provide a great advantage over many inotropic agents of efficient energy utilization with an equivalent increase in contractility. Based on these pre-clinical results, a gene therapy clinical trial has been initiated in heart failure patients targeting replacement of this key enzyme, SERCA2a, by gene transfer using a rAAV.

The ongoing phase I/II Calcium Up-Regulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) trial16 is investigating the safety and biological activity of SERCA2a enzyme replacement using rAAV-mediated gene transfer in patients with advanced heart failure. Data were recently presented on the initial nine patients dosed in the phase I portion of the trial.32 Patients with class III/IV heart failure (ejection fraction [EF] ≤30%) on maximal medical therapy with baseline AAV1 neutralizing antibody titers of ≤1:2 received a 10-minute percutaneous antegrade intracoronary artery infusion of AAV1/SERCA2a (MYDICAR®) in an open-label dose-escalation manner. All patients in the study have implantable cardiac defibrillators and cardiac resynchronization therapy, if indicated. Safety and efficacy assessments were scheduled at three, six, nine, and 12 months.

The phase I data have shown that MYDICAR results in an acceptable safety profile in patients with advanced heart failure.32 Although the number of patients in each cohort is too small to conduct statistical analyses, quantitative evidence of biological activity could be detected in a number of patients following gene transfer. Of the nine patients treated, several demonstrated improvements from baseline to month six across a number of parameters important in heart failure, including symptomatic (New York Heart Association [NYHA] Classification and Minnesota Living with Heart Failure Questionnaire, five patients), functional (six-minute walk test and maximal oxygen uptake, four patients), biomarker (NT-ProBNP, two patients), and left ventricular function/remodeling (left ventricular ejection fraction and left ventricular end systolic volume, five patients). Of note, two patients who failed to improve had pre-existing anti-AAV1 neutralizing antibodies. These data support the initiation of the ongoing placebo-controlled, randomized phase II trial, with data expected to become available in early 2010.


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