Cardiac gene therapy with SERCA2a: from bench to bedside

Abstract

While progress in conventional treatments is making steady and incremental gains to reduce mortality associated with heart failure, there remains a need to explore potentially new therapeutic approaches. Heart failure induced by different etiologies such as coronary artery disease, hypertension, diabetes, infection, or inflammation results generally in calcium cycling dysregulation at the myocyte level. Recent advances in understanding of the molecular basis of these calcium cycling abnormalities, together with the evolution of increasingly efficient gene transfer technology, have placed heart failure within reach of gene-based therapy. Furthermore, the recent successful completion of a phase 2 trial targeting the sarcoplasmic reticulum calcium pump (SERCA2a) ushers in a new era for gene therapy for the treatment of heart failure. This article is part of a Special Section entitled "Special Section: Cardiovascular Gene Therapy".

Figure 1

Various steps from target validation to clinical trials in gene therapy

Figure 2. Excitation-Contraction Coupling

Solid lines indicate the Ca²⁺ cycling in the cardiomyocyte. Upon a depolarizing signal, extracellular Ca²⁺ enters the cytosol via the LTTC, which triggers induces the release of a greater amount of Ca²⁺ through the RYR2 which initiates contraction at the myofilaments. Removal of Ca²⁺ during diastole is primarily facilitated via SERCA2a and to a lesser extent by the NCX, and PMCA. Increase the cytosolic Ca²⁺ concentration activates CaMKII. CaMKII phosphorylates the LTTC, RyR2, and PLN; Long dash dot lines. Dash lines delineate β-adrenergic stimulation, AC is activated, which leads to production of cAMP and PKA activation. PKA then phosphorylates the RyR2, TnI, and PLN, which augments contractility. Also, PKA phosphorylates I-1, and then I-1 activate PP1, which cause hypophosphorylation of PLN. AC, adenylyl cyclase; β-AR, β-adrenergic receptor; CASQ, calsequestrin; CaMKII, Ca²⁺/calmodulin-denpendent protein kinase; GαS, GTP binding protein; HRC, histidin-rich Ca²⁺ binding protein; I-1, inhibitor-1; LTTC, L-type Ca²⁺ channel; NCX, Na⁺/Ca²⁺ exchanger; PKA, protein kinase A; PLN, phospholamban; PMCA, plasma-membrane Ca²⁺-ATPase; RyR2: ryanodine receptor 2; SERCA2a, SR Ca⁺-ATPase; TnI: troponin I.

Figure 3

Various effects of SERCA2a on the cardiovascular system.

Figure 4

Method of gene transfer using slow infusion into the coronary arteries.