Molecular Cardiac Surgery
Charles
R. Bridges, MD, ScD was recently awarded
a $3,000,000 R01 grant by the National Heart
Lung and Blood Institute (NHLBI) entitled
“Translational Studies in Heart Failure Gene Therapy.” Dr. Bridges
works closely with Penn Department of Surgery colleague Hansell H. Stedman,
MD, with whom he has several joint U.S. and international issued and pending
patents for platform technologies in the area of highly efficient vector-mediated
gene delivery to cardiac and skeletal muscle.
Prior to the work performed in the combined
laboratories of Drs. Bridges and Stedman, none
of the gene delivery techniques in use were clinically
translatable with high global myocyte transduction
efficiency in both skeletal and cardiac muscle
cells of large animals. The NHLBI grant will
allow the methods developed in the Bridges and
Stedman laboratories to be utilized to deliver
therapeutic transgenes to sheep with heart failure.
Ultimately, successful clinical application of
these methods may lead to new treatments for
selected X-linked and autosomal recessive genetic
cardiomyopathies and for more common forms of
heart failure.
“The
rate-limiter in the quest for clinically
relevant gene therapy for both cardiomyopathy
and skeletal myopathy is the successful
achievement of global vector-mediated
gene delivery to a significant percentage
of cardiac and skeletal myocytes
in situ in a translational animal
model.”
– Charles
R. Bridges, MD, ScD
Chief, Cardiovascular Surgery
Pennsylvania Hospital |
|
On the basis of the work of Drs. Bridges and
Stedman, Penn researchers have developed several
new cardiac surgical procedures (“molecular
cardiac surgery”) that offer exciting solutions
to the previously unsolved cardiac gene delivery
problem. The techniques developed result in efficient
delivery of transgenes to adult, large-animal
cardiac myocytes in situ using cardiopulmonary
bypass with surgical isolation of the heart in
vivo and in situ.
Unlike existing delivery technologies, this
approach allows for limitation of vector delivery
exclusively to cardiac muscle, decreasing the
risk of extracardiac gene expression and providing
an important additional margin of safety over
other methods. The use of this methodology to
deliver novel AAV serotypes encoding therapeutic
transgenes may lead to alternatives to heart
transplantation and permanent mechanical assist
devices in the treatment of end stage heart failure.
Figure 1 illustrates the first demonstration
ever1 of highly efficient marker gene
expression in nearly 100% of the myocytes in
the adult canine limb, using adeno-associated
virus and delivery methods developed by Drs.
Stedman and Bridges at Penn. These researchers
have achieved similar vector-mediated gene delivery
efficiency in the large animal heart in situ.
1 Su LT, Gopal K,
Wang Z, Yin X, Nelson A, Kozyak BW, Burkman,
Mitchell MA, Bridges CR, Stedman HH. Highly
efficient scale-independent vector delivery
to skeletal muscle fibers. Circulation. 2005;
112:1780-1788.
Figure 1
Figure 1 – Illustrates
X-Gal staining of muscle sections
after in situ isolation of the
canine hind limb and retrograde
venous delivery of AAV1.CMV.LacZ,
demonstrating nearly 100% myocyte
transduction. |
|
|
