Gene Therapy for Cardiovascular Disorders - Applications of Biotechnology in Cardiovascular Therapeutics - page 238

transfer experiments to rescue heart failure (HF). A study was conducted in HF rats
to evaluate long-term b-ARKct expression with the use of stable myocardial gene
delivery using AAV6 vector (Rengo et al. 2009 ). b-ARKct or green fluorescent pro-
tein as a control was delivered via AAV6-mediated direct intramyocardial injection.
A group was also treated with concurrent administration of the b-blocker meto-
prolol. Robust and long-term transgene expression was found in the left ventricle at
least 12 weeks after delivery. b-ARKct significantly improved cardiac contractility
and reversed left ventricular remodeling, which was accompanied by a normaliza-
tion of the neurohormonal (catecholamines and aldosterone) status of the chronic HF
animals, including normalization of cardiac b-AR signaling. Addition of metoprolol
neither enhanced nor decreased b-ARKct-mediated beneficial effects, although
metoprolol alone prevented further deterioration of the left ventricle in spite of lack
of effect in improving contractility. This study shows that long-term cardiac AAV6-
b-ARKct gene therapy in HF results in sustained improvement of global cardiac
function and reversal of remodeling at least in part as a result of a normalization of
the neurohormonal signaling axis. In addition, b-ARKct alone improves outcomes
more than a b-blocker alone, whereas both treatments are compatible.
GRK2 has now been shown to lead to permanent damage after myocardial infarc-
tion. Overproduction of GRK2 following a heart attack actually stimulates pro-death
pathways in myocyctes outside of the initial zone of damage. There is an inverse link
between GRK2 activity and the production of NO, a molecular messenger that pro-
tects the heart against damage caused by a sudden loss of blood. When there is more
GRK2, there is less NO, and vice versa. GRK2 may be affecting NO production by
inhibiting the prosurvival protein kinase Akt, which itself regulates NO. These con-
clusions are based on a study that used gene therapy to inhibit GRK2, and found
heart muscles cells in mice were substantially protected against destruction that
would otherwise occur after an induced myocardial infarction (Brinks et al. 2010 ).
Conversely, mice engineered to express excess GRK2 had more damage than would
have been expected after myocardial infarction. These findings suggest that humans
experiencing a heart attack might be helped with prompt delivery of a therapeutic
targeting inhibition of GRK2. While it may be years before this concept can be
tested in patients experiencing myocardial infarction, anti-GRK2 gene therapy could
be tested in patients with CHF much sooner. A phase I clinical trial for GRK2-
targeted gene therapy is preparing to be launched, pending FDA approval.
Intracoronary Adenovirus-Mediated Gene Therapy for CHF
The adult ventricular wall cells are usually refractory to conventional procedures
for the introduction of foreign genes but recombinant replication-defective adeno-
viruses can mediate highly efficient gene transfer into adult ventricular myocytes.
Intracoronary adenovirus-mediated Ca 2+ -binding protein S100A1 gene delivery
in vivo to the post-infarcted failing rat heart normalizes myocardial contractile
function (Most et al. 2004 ). Moreover, S100A1 gene transfer restored diminished
intracellular Ca 2+ transients and restored energy supply in failing cardiomyocytes.
This may be a novel therapeutic strategy for the treatment of heart failure.