Engineering adeno-associated virus 2 vectors for targeted gene delivery to atherosclerotic lesions.
Targeted delivery of biological agents to atherosclerotic plaques may provide a novel treatment and/or useful tool for imaging of atherosclerosis in vivo. However, there are no known viral vectors that possess the desired tropism. Two plaque-targeting peptides, CAPGPSKSC (CAP) and CNHRYMQMC (CNH) were inserted into the capsid of adeno-associated virus 2 (AAV2) to assess vector retargeting. AAV2-CNH produced significantly higher levels of transduction than unmodified AAV2 in human, murine and rat endothelial cells, whereas transduction of nontarget HeLa cells was unaltered. Transduction studies and surface plasmon resonance suggest that AAV2-CNH uses membrane type 1 matrix metalloproteinase as a surface receptor. AAV2-CAP only produced higher levels of transduction in rat endothelial cells, possibly because the virus was found to be affected by proteasomal degradation. In vivo substantially higher levels of both peptide-modified AAV2 vectors was detected in the brachiocephalic artery (site of advanced atherosclerotic plaques) and aorta, whereas reduced levels were detected in all other organs examined. These results suggest that in the AAV2 platform the peptides are exposed on the capsid surface in a way that enables efficient receptor binding and so creates effective atherosclerotic plaque targeted vectors.
White
K
K
British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.
Büning
H
H
Kritz
A
A
Janicki
H
H
McVey
J
J
Perabo
L
L
Murphy
G
G
Odenthal
M
M
Work
L M
LM
Hallek
M
M
Nicklin
S A
SA
Baker
A H
AH
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000628:therapy*; D002460:Cell Line; D000229:Dependovirus / Q000235:genetics* / Q000378:metabolism; D018390:Gene Targeting; D005818:Genetic Engineering; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D006493:Heparin / Q000378:metabolism; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000235:genetics; D011485:Protein Binding; D051381:Rats; D020349:Surface Plasmon Resonance; D014161:Transduction, Genetic / Q000379:methods; D019076:Transgenes
D001057:Apolipoproteins E; D010446:Peptide Fragments; D006493:Heparin; D020781:Matrix Metalloproteinase 1