Biomedical Engineering Reference
In-Depth Information
The most obvious application of gene therapy is to correct monogeneic deficiency
disorders such as hemophilia or adenosine deaminase deficiency. Indeed, the latter is
the only disease to have been cured (in a few infants) by gene therapy [7]. Gene
therapy for cardiovascular disorders, as it is most commonly being developed today,
focuses not on correcting deficiency disorders but rather on attempts to foster
angiogenesis in ischemic myocardium [43, 63], or to suppress vascular stenosis in a
variety of iatrogenic settings [44, 55]. The concept of gene or cell therapy for cardiac
arrhythmias differs conceptually from conventional applications. We seek to achieve
functional re-engineering of cardiac tissue, so as to alter a specific electrical property
of the tissue in a salutary manner. For example, genes or cells are introduced to alter
the velocity of electrical conduction in a defined region of the heart, or to create a
spontaneously active biological pacemaker from normally quiescent myocardium. A
relevant analogy is the use of off-the-shelf or customized parts to improve the
performance of a lackluster automobile engine. Our ''parts'' are wild-type (or mutant)
genes and engineered cells; our engine is the heart.
Here, we will review our progress in the creation of biological pacemakers. We
then conclude by considering future directions of this type of gene therapy.
2 Biological Pacemaker by I
K1
Knockout
The pacemaker of the heart is normally encompassed within a small region known as
the sinoatrial (SA) node. The SA node initiates the heartbeat, sets the rate and rhythm
of cardiac contraction, and thereby sustains the circulation [9]. The working muscle of
the heart (myocardium), comprising the pumping chambers known as the atria and the
ventricles, is normally excited by pacemaker activity originating in the SA node.
However, in the absence of such activity, the rhythmic contraction and relaxation of
myocardium discontinues. Therefore, loss of specialized pacemaker cells in the SA
node, as occurs in a variety of common diseases, results in circulatory collapse,
necessitating the implantation of an electronic pacemaker [39]. To create an
alternative to electronic pacemakers, we sought to render electrically quiescent
myocardium spontaneously active.
Our strategy to effect such a conversion was based upon the premise that
ventricular myocardium contains all it requires to pace, but that pacing is normally
suppressed by an expressed gene. The reasoning is as follows. In the early embryonic
heart, each cell possesses intrinsic pacemaker activity. The mechanism of
spontaneous beating in the early embryo is remarkably simple [78]. The opening of L-
type calcium channels produces depolarization; the subsequent voltage-dependent
opening of transient outward potassium channels leads to repolarization. With further
development, the heart differentiates into specialized functional regions, each with its
own distinctive electrical signature. The atria and ventricles become electrically
quiescent; only a small number of pacemaker cells, within compact ''nodes'', set the
overall rate and rhythm. Nevertheless, there is reason to wonder whether pacemaker
activity may be latent within adult ventricular myocytes and masked by the
differential expression of many other ionic currents. Among these, the inward rectifier
potassium current (
I
K1
) is notable for its intense expression in electrically quiescent
atria and ventricle, but not in nodal pacemaker cells.
I
K1
, encoded by the Kir2 gene
family [38], stabilizes a strongly negative resting potential and thereby would be
