Gene Therapy in Heart Failure

Abstract

Abstract-With increasing knowledge of basic molecular mechanisms governing the development of heart failure (HF), the possibility of specifically targeting key pathological players is evolving. Technology allowing for efficient in vivo transduction of myocardial tissue with long-term expression of a transgene enables translation of basic mechanistic knowledge into potential gene therapy approaches. Gene therapy in HF is in its infancy clinically with the predominant amount of experience being from animal models. Nevertheless, this challenging and promising field is gaining momentum as recent preclinical studies in larger animals have been carried out and, importantly, there are 2 newly initiated phase I clinical trials for HF gene therapy. To put it simply, 2 parameters are needed for achieving success with HF gene therapy: (1) clearly identified detrimental/beneficial molecular targets; and (2) the means to manipulate these targets at a molecular level in a sufficient number of cardiac cells. However, several obstacles do exist on our way to efficient and safe gene transfer to human myocardium. Some of these obstacles are discussed in this review; however, it primarily focuses on the molecular target systems that have been subjected to intense investigation over the last decade in an attempt to make gene therapy for human HF a reality.

Targeting S100A1 in heart failure

“…These studies emphasize the importance of cellular, small and large animal models as well as a broad understanding of cellular and molecular integrity of the target protein to translate novel therapeutic concepts into a clinical setup (for a more detailed summary of additional target for cardiac gene therapy please refer to further article elaborating these points 8,68,69 ).…”

“…Among those, genetically targeted interventions directed at molecular abnormalities within diseased cardiac cells emerged as a promising option to correct key pathologies at the site of origin. 8 The concept of cardiac gene therapy might therefore meet the needs of modern HF therapy and eventually be able to halt and even reverse the disease.…”

Targeting GRK2 by gene therapy for heart failure: benefits above β-blockade

“…24 In consideration of the fact that GRK2 levels often increase before manifested clinical HF, 25 and normalize again with advanced b-adrenergic signaling and ventricular function, 26,27 GRK2 not only represents a potential biomarker of cardiac function, 28 but is also an attractive therapeutic target for HF treatment. 29,30 GRK2 and the adrenal chromaffin cell Beside its essential role in the desensitization process of myocardial GPCRs such as bARs, GRK2 is involved in the regulation of plasma catecholamine release from the adrenal gland and also by extensions of SNS ganglia. Specifically, the physiological function of adrenal a 2c ARs is to inhibit catecholamine release into the synaptic cleft, acting as a negative-feedback loop in this process.…”

“…Gene therapy constitutes a promising potential novel therapeutic strategy for direct manipulation of intracellular mechanisms in cardiac myocytes. 30 Concerning gene therapy, significant efforts have been undertaken to develop molecular tools such as mini-peptides/proteins, which can be used to inhibit protein or enzyme function, or RNA interference (small interfering RNA/microRNA) for downregulation of genes. Alternatively, gene transfer can be used to replace or supplement downregulated proteins or enzyme targets.…”

“…These approaches in combination with modern viral vectors and cardiac-specific promoters are all orchestrated to effectively target intracellular molecular signaling defects and render gene therapy a rather interesting tool in potentially complementing established HF therapies. 30 Of course, cardiac gene therapy is still in its clinical infancy and a lot of effort is put into further optimization, with the ultimate goal of correcting key underlying signaling abnormalities inside the failing cardiac myocyte. Below, we highlight one gene therapeutic strategy, GRK2 inhibition, and how this target may be utilized in established pharmacological approaches (bAR blockade), both aimed at intercepting Cardiac bAR signaling and regulation by GRK2.…”