Gene Therapy for Cardiovascular Disorders - Applications of Biotechnology in Cardiovascular Therapeutics - page 241

Exposure of these cells to AdShK, an adenovirus that overexpresses potassium
channels has been shown to reverse the action potential prolongation of the failing
heart. This demonstrates that viral gene transfer can modify the electrical properties
of the heart cells but clinical application of this therapy will require development of
a sensitive mechanism to control the level and distribution of the transgene expres-
sion. In animal studies, localized gene therapy has been successfully investigated
using an ion channel mutation to treat atrial arrhythmias (Fishbein et al. 2005 ).
A novel gene therapy approach for atrial arrhythmias uses a clarithromycin-
responsive ion channel subunit mutation, hMiRP1-Q9E, cloned into an expression
plasmid (Perlstein et al. 2005 ). In a series of pig studies, right atrial myocardium
was injected at one site with hMiRP1-Q9E plasmid DNA; a separate site in the
same right atrium was injected with wild-type plasmid or was sham injected. Two
weeks after, transfection intravenous clarithromycin administration resulted in a
site-specific, dose-dependent prolongation of the repolarization phase of the right
atrial epicardial monophasic action potential (MAP) only at the hMiRPQ9E sites,
but not at sham or wild-type sites. MAP recordings before clarithromycin adminis-
tration did not differ between hMiRP1-Q9E and control sites. These studies show
that regional control of atrial myocardial repolarization by site-specific transfection
with plasmid DNA encoding an antibiotic-responsive ion channel subunit is feasi-
ble and, because hMiRP1-Q9E-transfected sites were affected only if clarithromy-
cin was given, provide proof of concept for a posttranslational, controllable gene
therapy strategy for atrial arrhythmias.
Hyperpolarization-activated and cyclic nucleotide-gated (HCN) ion channels play
a critical role in maintaining a normal, evenly paced heartbeat. These channels
control the flow of sodium and potassium ions in and out of cells that regulate the
electrical impulses of the heart. Overexpression of an engineered HCN construct
via somatic gene transfer offers a flexible approach for fine-tuning cardiac pacing
in vivo. In one study, the researchers used a recombinant adenoviral vector to
deliver the gene encoding a bioengineered cell-surface protein, which mimics the
action of HCN ion channels, to heart-muscle cells of pigs (Tse et al. 2006 ). By get-
ting heart muscle cells to produce bioengineered HCN channels, they were able to
reconstruct the SA node of the heart in pigs with implanted electronic pacemakers.
The catecholamine-responsive in vivo “bioartificial node” exhibited a physiological
heart rate and was capable of reliably pacing the myocardium, substantially reduc-
ing electronic pacing. The study offers positive and direct evidence in living models
that bioengineered cells can replace the electronic pacemaker. HCN gene-based
therapy is feasible for correcting defects in cardiac impulse generation.
Management of Arrhythmias Due to Myoblast Transplantation
Skeletal myoblasts are an attractive cell type for transplantation because they are
autologous and resistant to ischemia. However, clinical trials of myoblast transplan-
tation in heart failure have been plagued by ventricular tachyarrhythmias and sud-
den cardiac death. Previous research from animal transplants showed that heart
tissue regrowth produced a mix of skeletal and heart muscle. The pathogenesis of