Gene Therapy in Heart Failure

Abstract

Heart failure is a chronic condition leading to debilitating symptoms and reduced life expectancy. Several pharmacological therapies which improve symptoms and mortality have been developed over the past 30 years. These therapies are, however, limited in terms of both efficacy and side‐effect profile. Gene therapy represents a fundamental change in the way treatments are developed with the potential to directly target and correct individual molecular abnormalities. These therapies have the potential to offer long‐term beneficial effects from a single treatment and, with direct targeting, less off‐target effects. As with any new therapy, a number of challenges must be overcome before gene therapy can be considered a realistic option to patients with heart failure.

Key Concepts

  • Gene therapy could allow direct targeting of molecular abnormalities in patients with heart failure.
  • Preclinical data suggests that in animal models of heart failure, SERCA2a gene therapy significantly improves haemodynamic parameters, reduces arrhythmia risk and corrects molecular abnormalities.
  • Initial clinical data in a small number of patients suggested that SERCA2a gene therapy was beneficial to patients with advanced heart failure. However, a recent study in a larger number of patients was disappointingly neutral.
  • A number of molecular abnormalities exist in the failing myocytes, each of which could represent a potential target to treat heart failure.
  • Gene therapy requires a large financial commitment from pharmaceutical companies and cost is a major limitation to the development of gene therapy products.

Keywords: gene therapy; heart failure; novel heart failure treatment; SERCA2a; cellular therapies for heart failure

Figure 1. Schematic of a cardiomyocyte showing normal Ca2+ handling during excitation–contraction coupling. 1. Normal Ca2+ cycling begins with the cardiac action potential depolarising the surface membrane and triggering a small Ca2+ current into the cytoplasm through L‐type Ca2+ channels. 2. This triggers a much larger influx of Ca2+ from the sarcoplasmic reticulum (SR) store through the ryanodine receptor (RyR). 3. This calcium‐induced calcium release triggers contraction through the binding of Ca2+ to the troponin C component of the cardiac myofilaments. 4. During diastole Ca2+ is taken back up into the SR through the action of sarcoplasmic (endoplasmic) reticulum Ca2+ ATPase 2a (SERCA2a) and extruded from the cell by the Na+‐Ca2+ exchange (NCX) (5). SERCA2a function is regulated by phospholamban (PLN). Ca2+/calmodulin‐dependent protein kinase (CaMKII) can modulate excitation–contraction coupling by phosphorylating important regulatory proteins such as RyR, PLN and L‐type Ca2+ channels.
Figure 2. Illustrating the regulation of SERCA2a by phospholamban (PLN). When PLN is unphosphorylated, it acts as an inhibitor to SERCA2a activity (configuration displayed on the left). When PLN is phosphorylated, it forms a pentamer and the inhibition of SERCA2a is relieved. Factors which increase the activity of SERCA2a are displayed. Ca2+, calcium; CaMkII, Ca2+/calmodulin‐dependent kinase II; I‐1, inhibitor 1; PKA, protein kinase A; PP1, protein phosphatase 1.
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Further Reading

Pleger ST, Brinks H, Ritterhoff J, et al. (2013) Heart failure gene therapy. Circulation Research 113: 792–809.

Tilemann L, Ishikawa K, Weber T, et al. (2012) Gene therapy for heart failure. Circulation Research 110: 777–793.

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Hayward, Carl, Patel, Hitesh C, Welch, Sophie, Patel, Ketna, and Lyon, Alexander R(Jan 2017) Gene Therapy in Heart Failure. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0025274]