Format

Send to

Choose Destination
J Cardiovasc Pharmacol Ther. 2014 Sep;19(5):426-38. doi: 10.1177/1074248414528575. Epub 2014 Apr 17.

Gene therapy for restoring heart rhythm.

Author information

1
Heart Center, Department of Clinical & Experimental Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands Netherlands Heart Institute, ICIN, Utrecht, the Netherlands g.j.boink@amc.nl.
2
Department of Pharmacology, Center for Molecular Therapeutics, Columbia University, New York, NY, USA rbr1@columbia.edu.

Abstract

Efforts to use gene therapy to create a biological pacemaker as an adjunct or replacement of electronic pacemakers have been ongoing for about 15 years. For the past decade, most of these efforts have focused on the hyperpolarization-activated cyclic nucleotide gated-(HCN) gene family of channels alone or in combination with other genes. The HCN gene family is the molecular correlate of the cardiac pacemaker current, If. It is a suitable basis for a biological pacemaker because it generates a depolarizing inward current primarily during diastole and is directly regulated by cyclic adenosine monophosphate (cAMP), thereby incorporating autonomic responsiveness. However, biological pacemakers based either on native HCN channels or on mutated HCN channels designed to optimize biophysical characteristics have failed to attain the desired basal and maximal physiological heart rates in large animals. More recent work has explored dual gene therapy approaches, combining an HCN variant with another gene to reduce outward current, increase an additional inward current, or enhance cAMP synthesis. Several of these dual gene therapy approaches have demonstrated appropriate basal and maximal heart rates with little or no reliance on a backup electronic pacemaker during the period of study. Future research, besides examining the efficacy of other gene combinations, will need to consider the additional issues of safety and persistence of the viral vectors often used to deliver these genes to a specific cardiac region.

KEYWORDS:

cardiac arrhythmias; cardiac electrophysiology; gene therapy; heart disease; ion channels; molecular biology; pacemakers

PMID:
24742766
DOI:
10.1177/1074248414528575
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Atypon
Loading ...
Support Center