PROSPECTS OF SERCA2A-BASED GENE THERAPY FOR HEART FAILURE

Abstract

Heart failure (HF) remains one of the leading causes of morbidity and mortality worldwide, and despite substantial progress in pharmacological and device-based management, a considerable proportion of patients continue to progress toward refractory disease. At the cellular level, HF of virtually any etiology converges on a common defect: impaired cardiomyocyte calcium handling, of which downregulation of the sarco(endo)plasmic reticulum Ca2+-ATPase 2a (SERCA2a) is a central feature. This has made SERCA2a one of the most extensively pursued molecular targets for gene-based intervention in cardiology. This review summarizes the biology of SERCA2a — its structural family, cardiac localization, and role in excitation–contraction coupling — and evaluates the genetic and pharmacological evidence linking its loss to contractile failure. The core of the review is a critical, trial-by-trial analysis of preclinical and clinical gene therapy programs built around SERCA2a restoration or activation, from the original AAV1.SERCA2a (CUPID) program through its clinical failure in CUPID-2, to second-generation strategies employing AAV9 vectors, indirect SERCA2a activation via phosphatase-1 inhibitor 1c (AB-1002/GenePHIT), and small-molecule, RNA-interference-, and antisense-based modulators of the SERCA2a–phospholamban axis. The advantages and unresolved limitations of this therapeutic direction — vector tropism, transduction efficiency, immunogenicity, and patient selection — are discussed together with emerging strategies intended to overcome them. The overall picture is one of a biologically well-validated target whose clinical translation has been constrained chiefly by delivery technology and trial design rather than by the underlying pathophysiological rationale.