Calcium upregulation by percutaneous administration of gene therapy in cardiac disease (CUPID Trial), a first-in-human phase 1/2 clinical trial
Jaski BE, Jessup ML, Mancini DM, Cappola TP, Pauly DF, Greenberg B, Borow K, Dittrich H, Zsebo KM, Hajjar RJ; and CUPID Trial Investigators
Journal of Cardiac Failure, March 2009
SERCA2a deficiency is commonly seen in advanced heart failure (HF). This study is designed to investigate safety and biological effects of enzyme replacement using gene transfer in patients with advanced HF. A total of 9 patients with advanced HF (New York Heart Association [NYHA] Class III/IV, ejection fraction [EF] < or = 30%, maximal oxygen uptake [VO2 max] <16 mL.kg.min, with maximal pharmacological and device therapy) received a single intracoronary infusion of AAV1/SERCA2a in the open-label portion of this ongoing study. Doses administered ranged from 1.4 x 10(11) to 3 x 10(12) DNase resistant particles per patient. We present 6- to 12-month follow-up data for these patients.

The cardiac sarcoplasmic/endoplasmic reticulum calcium ATPase: a potent target for cardiovascular diseases
Kawase Y, Hajjar RJ
Nature clinical practice: Cardiovascular medicine, September 2008
The cardiac isoform of the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA2a) is a calcium ion (Ca(2+)) pump powered by ATP hydrolysis. SERCA2a transfers Ca(2+) from the cytosol of the cardiomyocyte to the lumen of the sarcoplasmic reticulum during muscle relaxation. As such, this transporter has a key role in cardiomyocyte Ca(2+) regulation. In both experimental models and human heart failure, SERCA2a expression is significantly decreased, which leads to abnormal Ca(2+) handling and a deficient contractile state. Following a long line of investigations in isolated cardiac myocytes and small and large animal models, a clinical trial is underway that is restoring SERCA2a expression in patients with heart failure by use of adeno-associated virus type 1.

Conditional increase in SERCA2a protein is able to reverse contractile dysfunction and abnormal calcium flux in established diabetic cardiomyopathy
Suarez J, Scott B, Dillmann WH
The American Journal of Physiology - Regulatory, Integrative and Comparative Physiology, September 2008
Diabetic cardiomyopathy is characterized by reduced cardiac contractility independent of vascular disease. A contributor to contractile dysfunction in the diabetic heart is impaired sarcoplasmic reticulum function with reduced sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2a) pump activity, leading to disturbed intracellular calcium handling. It is currently unclear whether increasing SERCA2a activity in hearts with existing diabetic cardiomyopathy could still improve calcium flux and contractile performance. To test this hypothesis, we generated a cardiac-specific tetracycline-inducible double transgenic mouse, which allows for doxycycline (DOX)-based inducible SERCA2a expression in which DOX exposure turns on SERCA2a expression. Isolated cardiomyocytes and Langendorff perfused hearts from streptozotocin-induced diabetic mice were studied.

Design of a phase 1/2 trial of intracoronary administration of AAV1/SERCA2a in patients with heart failure
Hajjar RJ, Zsebo K, Deckelbaum L, Thompson C, Rudy J, Yaroshinsky A, Ly H, Kawase Y, Wagner K, Borow K, Jaski B, London B, Greenberg B, Pauly DF, Patten R, Starling R, Mancini D, Jessup M.
Journal of Cardiac Failure, June 2008
Heart failure (HF) remains a major cause of morbidity and mortality in North America. With an aging population and an unmet clinical need by current pharmacologic and device-related therapeutic strategies, novel treatment options for HF are being explored. One such promising strategy is gene therapy to target underlying molecular anomalies in the dysfunctional cardiomyocyte. Prior animal and human studies have documented decreased expression of SERCA2a, a major cardiac calcium cycling protein, as a major defect found in HF.  We hypothesize that increasing the activity of SERCA2a in patients with moderate to severe HF will improve their cardiac function, disease status, and quality of life.

Intracellular devastation in heart failure
del Monte F, Hajjar R
Heart Failure Review, 2008
Abstract End-stage heart failure is characterized by a number of abnormalities at the cellular level, which include changes in excitation–contraction coupling, alterations in contractile proteins and activation/deactivation of signaling pathways. Even though many of these changes are adaptive to the high workload and stress in heart failure, a significant number of these alterations are deeply deleterious to the cardiac cell. In this article, we will review the changes in calcium cycling that occur in myopathic hearts and how they can be effectively targeted. We will also focus on protein misfolding in the setting of cardiac dysfunction.

Clinical recovery from end-stage heart failure using left-ventricular assist device and pharmacological therapy correlates with increased sarcoplasmic reticulum calcium content but not with regression of cellular hypertrophy
Terracciano CM, Hardy J, Birks EJ, Khaghani A, Banner NR, Yacoub MH
Circulation, May 2004
Left ventricular assist device (LVAD) treatment is known to lead to structural and functional cellular modifications in the heart. The relevance of these changes for clinical recovery is unknown. We compared properties of cardiomyocytes obtained from tissue taken at explantation of the LVAD in patients with clinical recovery with those obtained from hearts of patients who did not show clinical recovery, thus requiring transplantation. Compared with myocytes taken at implantation, both the recovery and nonrecovery groups showed approximately 50% reduction in cell capacitance, an index of cell size. However, action potential duration shortened, L-type Ca2+ current fast inactivation was more rapid, and sarcoplasmic reticulum Ca2+ content was increased in the recovery compared with the nonrecovery group.

Gene Transfer in Cardiac Myocytes
Chaudhri BB, del Monte F, Harding SE, Hajjar RJ
Surgical Clinics of North America, February 2004
Congestive heart failure (CHF) represents an enormous clinical problem and remains a leading cause of death despite advances in treatment. New treatments significantly impact mortality and disease course; they do not cure the underlying pathology. Gene transfer, the ability to genetically reprogram the heart in relevant cardiovascular disease models, allows testing the role of specific molecular pathways in disease pathogenesis. Potential therapeutic intervention targets can be then identified and approached with the full spectrum of therapeutic options, including traditional pharmacology, targeted synthesis of small molecule agonists or antagonists, biological agents (cells, antibodies, genetic material), or gene-based therapy. Lessons gleaned from gene transfer experiments on local modulation of cardiac genetic programs will guide attempts to transform early investigations into established therapy.

Myocardial gene expression in dilated cardiomyopathy treated with beta-blocking agents
Lowes BD, Gilbert EM, Abraham WT, Minobe WA, Larrabee P, Ferguson D, Wolfel EE, Lindenfeld J, Tsvetkova T, Robertson AD, Quaife RA, Bristow MR
New England Journal of Medicine, May 2002
Beta-blocker therapy may improve cardiac function in patients with idiopathic dilated cardiomyopathy. We tested the hypothesis that beta-blocker therapy produces favorable functional effects in dilated cardiomyopathy by altering the expression of myocardial genes that regulate contractility and pathologic hypertrophy. We randomly assigned 53 patients with idiopathic dilated cardiomyopathy to treatment with a beta-adrenergic-receptor blocking agent (metoprolol or carvedilol) or placebo. The amount of messenger RNA (mRNA) for contractility-regulating genes (those encoding beta1- and beta2-adrenergic receptors, calcium ATPase in the sarcoplasmic reticulum, and alpha- and beta-myosin heavy-chain isoforms) and of genes associated with pathologic hypertrophy (beta-myosin heavy chain and atrial natriuretic peptide) was measured with a quantitative reverse-transcription polymerase chain reaction in total RNA extracted from biopsy specimens of the right ventricular septal endomyocardium. Myocardial levels of beta-adrenergic receptors were also measured. Measurements were conducted at base line and after six months of treatment, and changes in gene expression were compared with changes in the left ventricular ejection fraction as measured by radionuclide ventriculography.