Prevention of restenosis by a herpes simplex virus mutant capable of controlled long-term expression in vascular tissue in vivo.
Neointimal hyperplasia resulting from vascular smooth muscle cell (SMC) proliferation and luminal migration is the major cause of autologous vein graft failure following vascular coronary or peripheral bypass surgery. Strategies to attenuate SMC proliferation by the delivery of oligonucleotides or genes controlling cell division rely on the use of high concentrations of vectors, and require pre-emptive disruption of the endothelial cell layer. We report a genetically engineered herpes simplex virus (HSV-1) mutant that, in an in vivo rabbit model system, infects all vascular layers without prior injury to the endothelium; expresses a reporter gene driven by a viral promoter with high efficiency for at least 4 weeks; exhibits no systemic toxicity; can be eliminated at will by administration of the antiviral drug acyclovir; and significantly reduces SMC proliferation and restenosis in vein grafts in immunocompetent hosts.
Skelly
C L
CL
Section of Vascular Surgery, Department of Surgery, University of Chicago, Chicago, IL 60637, USA.
Curi
M A
MA
Meyerson
S L
SL
Woo
D H
DH
Hari
D
D
Vosicky
J E
JE
Advani
S J
SJ
Mauceri
H J
HJ
Glagov
S
S
Roizman
B
B
Weichselbaum
R R
RR
Schwartz
L B
LB
D000818:Animals; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D006083:Graft Occlusion, Vascular / Q000517:prevention & control*; D018259:Herpesvirus 1, Human / Q000235:genetics*; D006801:Humans; D006965:Hyperplasia / Q000517:prevention & control; D007601:Jugular Veins; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular; D009154:Mutation; D009924:Organ Culture Techniques / Q000379:methods; D011817:Rabbits; D012008:Recurrence; D012501:Saphenous Vein; D014162:Transfection / Q000379:methods; D017539:Tunica Intima / Q000473:pathology*