Catheter-mediated subselective intracoronary gene delivery to the rabbit heart: introduction of a novel method.
BACKGROUND
Recent studies suggest that gene therapy using replication-deficient adenoviruses will benefit treatment of cardiovascular diseases including heart failure. A persistent hurdle is the effective and reproducible delivery of a transgene to the myocardium with minimal iatrogenic morbidity. In this study, we sought to design a relatively non-invasive percutaneous gene delivery system that would maximize cardiac transgene expression and minimize mortality after intracoronary adenovirus injection.


METHODS
Adult rabbits received a left circumflex coronary artery (LCx) infusion of 5x10(11) total viral particles of an adenovirus containing the marker transgene beta-galactosidase (Adeno-betaGal) via either a continuous infusion method utilizing an oxygenated, normothermic, physiologic pH Krebs solution driven by a Langendorff apparatus (n=12) or a timed bolus and set concentration at a constant infusion rate to the LCx (n=12). Six rabbits underwent global transgene delivery via an invasive method involving intraventricular delivery and aortic root cross-clamping. The efficacy of transgene expression via these three distinct delivery methods was determined in the left ventricle at 5 days by histological staining and colorimetric quantification assay.


RESULTS
While the open-chest, aortic cross-clamping method provides the highest level of gene expression throughout the heart, the morbidity of this procedure is clinically prohibitive. Percutaneous LCx delivery of Adeno-betaGal using the Langendorff apparatus was associated with the lowest morbidity and mortality while still supporting significant myocardial gene expression.


CONCLUSIONS
Percutaneous delivery of an adenovirus solution using a continuous infusion of oxygenated Krebs solution via a Langendorff apparatus appears to be a gene delivery modality offering the best compromise of gene expression and clinical utility to maximize any potential therapeutic outcome.
Parsa
Cyrus J
CJ
Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
Reed
Robyn C
RC
Walton
G Brant
GB
Pascal
Laura S
LS
Thompson
Richard B
RB
Petrofski
Jason A
JA
Emani
Sitaram M
SM
Folgar
Francisco
F
Riel
Ryan U
RU
Nicchitta
Christopher V
CV
Koch
Walter J
WJ
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D006328:Cardiac Catheterization; D003331:Coronary Vessels / Q000378:metabolism* / Q000473:pathology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D008297:Male; D009206:Myocardium / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D010100:Oxygen / Q000378:metabolism; D011817:Rabbits; D019076:Transgenes / Q000502:physiology*; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism*
D001616:beta-Galactosidase; D010100:Oxygen