In vivo suppression of injury-induced vascular smooth muscle cell accumulation using adenovirus-mediated transfer of the herpes simplex virus thymidine kinase gene.
Restenosis, a process characterized in part by excessive smooth muscle cell (SMC) proliferation in areas of vascular injury, occurs in up to 50% of patients undergoing balloon angioplasty. In an effort to develop a treatment strategy for restenosis, we constructed a replication-deficient recombinant adenovirus (AdMLP.HSTK) containing the herpes simplex virus thymidine kinase gene (HSV tk). This viral gene product phosphorylates the prodrug ganciclovir to form a nucleoside analog that inhibits DNA synthesis. Cultured primary rat SMCs infected with AdMLP.HSTK were completely growth-inhibited by incubation in ganciclovir-containing medium. In addition, when only a portion of the SMC population received the HSV tk transgene, an inhibitory effect on neighboring SMCs was evident. Evaluation of this strategy in vivo using a rat carotid balloon injury model demonstrated that local infection of injured arteries with AdMLP.-HSTK followed by 2 weeks of systemic ganciclovir treatment significantly (P < 0.01) reduced injury-induced SMC accumulation. In contrast, there was no suppression of injury-induced SMC accumulation in animals infected with AdMLP.HSTK but not receiving ganciclovir or in those animals infected with a control adenovirus and either treated or not treated with ganciclovir. These results demonstrate the potential utility of adenovirus-mediated gene transfer for treatment of restenosis after balloon injury.
Guzman
R J
RJ
Cardiology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
Hirschowitz
E A
EA
Brody
S L
SL
Crystal
R G
RG
Epstein
S E
SE
Finkel
T
T
D000256:Adenoviridae / Q000235:genetics / Q000502:physiology; D000800:Angioplasty, Balloon; D000818:Animals; D030801:Animals, Genetically Modified; D001013:Aorta, Thoracic / Q000166:cytology* / Q000187:drug effects; D001483:Base Sequence; D016893:Carotid Stenosis / Q000628:therapy; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003327:Coronary Disease / Q000628:therapy; D017931:DNA Primers; D004279:DNA, Viral / Q000032:analysis; D015774:Ganciclovir / Q000494:pharmacology*; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000293:injuries; D016133:Polymerase Chain Reaction; D051381:Rats; D012008:Recurrence; D018139:Simplexvirus / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D013937:Thymidine Kinase / Q000235:genetics*; D014162:Transfection; D014779:Virus Replication
D017931:DNA Primers; D004279:DNA, Viral; D013937:Thymidine Kinase; D015774:Ganciclovir