Lesion-targeted injectable vectors for vascular restenosis.
Pathologic lesions caused by catheter-based revascularization procedures for occlusive artery disease include disruption of the endothelium, exposure of extracellular matrix (ECM) proteins, and proliferation of vascular smooth muscle cells, which lead to neointima formation and restenosis. We have developed matrix-collagen-targeted retroviral vectors that are able to accumulate at sites of vascular injury (Hall et al., Hum. Gene Ther. 1997;8:2183-2192; Hall et al., Hum. Gene Ther. 2000;11:983-993). The primary tissue-targeting motif, adapted from the physiological surveillance sequence found in von Willebrand factor, served to localize and concentrate the vector within vascular lesions. In the present study, we evaluated the efficiency of this vector-targeting system in rats with nonligated balloon-injured carotid arteries. Both intraarterial (by retrograde femoral artery catheterization) and intravenous (via femoral vein) injection of a matrix-targeted vector enhanced transduction of neointimal cells ( approximately 20%) at severely denuded areas when compared with the nontargeted vector (<1%). Further, intraarterial instillation of a matrix-targeted, but not a nontargeted, vector bearing an antisense cyclin G1 construct inhibited neointima lesion formation in the injured carotid arteries. Taken together, these data indicate that strategic targeting of retroviral vectors to vascular lesions would have therapeutic potential in the management of vascular restenosis and many other disorders of uncontrolled proliferation where endothelial disruption, ECM remodeling, and collagen deposition form the nexus for preferential vector localization and concentration in vivo.
Gordon
E M
EM
Gene Therapy Laboratories, Keck School of Medicine of the University of Southern California, 2011 Zonal Avenue, Los Angeles, CA 90033, USA.
Zhu
N L
NL
Forney Prescott
M
M
Chen
Z H
ZH
Anderson
W F
WF
Hall
F L
FL
D016475:3T3 Cells; D000800:Angioplasty, Balloon / Q000009:adverse effects; D000818:Animals; D015153:Blotting, Western; D020212:Carotid Artery Injuries / Q000628:therapy*; D002460:Cell Line; D003094:Collagen / Q000378:metabolism; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D017434:Protein Structure, Tertiary; D051381:Rats; D017208:Rats, Wistar; D012190:Retroviridae / Q000235:genetics; D013997:Time Factors; D014161:Transduction, Genetic; D001616:beta-Galactosidase / Q000378:metabolism
D003094:Collagen; D001616:beta-Galactosidase