Biomedical Engineering Reference
In-Depth Information
corrective gene is delivered to the heart. Recombinant adeno-associated virus
(rAAV)-mediated gene delivery has emerged as a realistic method for the treatment
of heart disease due to inherited genetic defects. A study monitored by ECG trac-
ings has demonstrated physiological disease correction by AAV9 gene transfer in a
mouse model of Pompe disease, a form of muscular dystrophy that damages the
heart (Pacak et al.
2006
). Intravenous delivery of the AAV9 preferentially trans-
duced cardiac tissue in nonhuman primates and holds promise for long-lasting
treatments of hereditary diseases of the heart. Studies in patients with Pompe
disease are planned.
Molecular Cardiac Surgery with Recirculating Delivery of AAV Vectors
A novel technique termed molecular cardiac surgery with recirculating delivery
(MCARD) enables closed recirculation of vector genomes in the cardiac circulation
using cardiopulmonary bypass (white et al.
2011
). This technique was shown to be
highly efficient in isolating the heart from the systemic circulation in vivo. Using
MCARD, the investigators in this study compared the relative efficacy of single-
stranded (ss) AAV6 (ssAAV9) and self-complimentary (sc)AAV6-encoding
enhanced green fluorescent protein, driven by the constitutive cytomegalovirus
promoter to transduce the ovine myocardium in situ. MCARD enabled delivery of
up to 48 green fluorescent protein genome copies per cell globally in the sheep left
ventricular (LV) myocardium. It was demonstrated that scAAV6-mediated MCARD
delivery results in global, cardiac-specific LV gene expression in the ovine heart
and provides for considerably more robust and cardiac-specific gene delivery than
other available delivery techniques such as intramuscular injection or intracoronary
injection. This technique has the potential for translation into clinical application
for heart failure gene therapy.
Hypoxia-Regulated Gene Therapy for Myocardial Ischemia
Early intervention with a novel gene therapy, combining a therapeutic gene with a
genetic biosensor that recognizes and responds to the oxygen deprivation following
ischemia from coronary artery disease, might effectively prevent the organ damage
commonly suffered by heart attack victims. As soon as the oxygen declines, the
sensor turns on the therapeutic gene, thereby protecting the heart. Application of
this regulatable system using an endogenous physiological stimulus for expression
of a therapeutic gene may be a feasible strategy for protecting tissues at risk of
ischemia/reperfusion injury. In addition to its potential for patients with heart dis-
ease, the strategy might also prove useful for any condition in which tissues are
susceptible to loss of blood supply, including stroke, shock, trauma, and sepsis.
The therapeutic gene construct containing both DNA sequences that can detect
oxygen deficiency and a therapeutic human gene - heme-oxygenase 1 - has been
shown to protect cells. It was inserted into heart, liver, and skeletal muscle of rats
Search WWH ::
Custom Search