Percutaneous transendocardial delivery of self-complementary adeno-associated virus 6 achieves global cardiac gene transfer in canines.
Achieving efficient cardiac gene transfer in a large animal model has proven to be technically challenging. Previous strategies have used cardiopulmonary bypass or dual catheterization with the aid of vasodilators to deliver vectors, such as adenovirus, adeno-associated virus (AAV), or plasmid DNA. Although single-stranded AAV (ssAAV) vectors have shown the greatest promise, they suffer from delayed expression, which might be circumvented using self-complementary vectors. We sought to optimize cardiac gene transfer using a percutaneous transendocardial injection catheter to deliver adeno-associated viral vectors to the canine myocardium. Four vectors were evaluated--ssAAV9, self-complementary AAV9 (scAAV9), scAAV8, scAAV6--so that comparison could be made between single-stranded and self-complementary vectors as well as among serotypes 9, 8, and 6. We demonstrate that scAAV is superior to ssAAV and that AAV 6 is superior to the other serotypes evaluated. Biodistribution studies revealed that vector genome copies were 15-4,000 times more abundant in the heart than in any other organ for scAAV6. Percutaneous transendocardial injection of scAAV6 is a safe, effective method to achieve efficient cardiac gene transfer.
Bish
Lawrence T
LT
Department of Physiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA. bish@mail.med.upenn.edu
Sleeper
Meg M
MM
Brainard
Benjamin
B
Cole
Stephen
S
Russell
Nicholas
N
Withnall
Elanor
E
Arndt
Jason
J
Reynolds
Caryn
C
Davison
Ellen
E
Sanmiguel
Julio
J
Wu
Di
D
Gao
Guangping
G
Wilson
James M
JM
Sweeney
H L
HL
D000818:Animals; D000229:Dependovirus / Q000235:genetics*; D004285:Dogs; D004727:Endothelium / Q000378:metabolism; D005822:Genetic Vectors / Q000235:genetics; D006321:Heart; D009206:Myocardium / Q000378:metabolism*; D019076:Transgenes / Q000235:genetics*