Percutaneous cardiac recirculation-mediated gene transfer of an inhibitory phospholamban peptide reverses advanced heart failure in large animals.
OBJECTIVE
The purpose of this study was to develop a clinically applicable high-efficiency percutaneous means of therapeutic gene delivery to the failing heart.


BACKGROUND
Substantial advances in the understanding of the cellular and molecular basis of heart failure (HF) have recently fostered interest in the potential utility of gene and cell therapy as novel therapeutic approaches. However, successful clinical translation is currently limited by the lack of safe, efficient, and selective delivery systems.


METHODS
We developed a novel percutaneous closed-loop recirculatory system that provides homogeneous myocardial delivery for gene transfer in the failing large animal heart. After 4 weeks' rapid pacing in adult sheep to induce HF, the animals were randomly allocated to receive either adenovirus expressing a pseudophosphorylated mutant (AdS16E) of phospholamban (PLN) or Ad-beta-galactosidase (AdLacZ).


RESULTS
Two weeks after gene delivery, in the presence of continued pacing, left ventricular (LV) ejection fraction had significantly improved in the AdS16E-treated animals (27 +/- 3% to 50 +/- 4%; p < 0.001), whereas a further decline occurred in the AdLacZ group (34 +/- 4% to 27 +/- 3%; p < 0.05). In conjunction, AdS16E delivery resulted in significant reductions in LV filling pressures and end-diastolic diameter (both p < 0.05). In conjunction, AdS16E-treated animals showed significant improvement in the expression of PLN and Ca2+-adenosine triphosphatase activity. In separate animals, recirculating AdLacZ delivery was shown to achieve superior myocardial gene expression in contrast to intracoronary delivery and was associated with lower systemic expression.


CONCLUSIONS
We report the development of a novel closed-loop system for cardiac gene therapy. Using this approach delivery of AdS16E reversed HF progression in a large animal HF model.
Kaye
David M
DM
Baker Heart Research Institute, Melbourne, Australia. david.kaye@baker.edu.au
Preovolos
Arthur
A
Marshall
Tanneale
T
Byrne
Melissa
M
Hoshijima
Masahiko
M
Hajjar
Roger
R
Mariani
Justin A
JA
Pepe
Salvatore
S
Chien
Kenneth R
KR
Power
John M
JM
D000818:Animals; D002135:Calcium-Binding Proteins / Q000494:pharmacology*; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006333:Heart Failure / Q000503:physiopathology / Q000628:therapy*; D009204:Myocardial Revascularization / Q000379:methods*; D011336:Probability; D011897:Random Allocation; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D012756:Sheep; D018709:Statistics, Nonparametric; D000099211:Phospholamban
D002135:Calcium-Binding Proteins; D000099211:Phospholamban