Retrovirus-Mediated Herpes Simplex Virus Thymidine Kinase Gene Therapy for the Prevention of Stenosis in Rat Carotid Artery Injury Model

Abstract

Background：Herpes simplex virus thymidine kinase (HSVtk phosphorylates the prodrug ganciclovir to a nucleoside analog that inhibits DNA synthesis, causing cell death. Neighbouring nontransfected cells may be affected through a ‘ bystander effect’ , thereby amplifying the antiproliferative actions. This study was carried out to determine whether retrovirus-mediated HSVtk gene therapy could reduce intimal hyperplasia and prevent stenosis following balloon injury of the rat carotid artery. Methods： A replication-defective recombinant retroviral vector containing HSVtk cDNA (LtkSN was constructed. Cultured primary rat smooth muscle cells (SMCs infected with this vector (SMC / LtkSN were transplanted to the balloon injured rat right carotid artery. One week after transplantation, HSVtk gene therapy group was administered a 2-week treatment of ganciclovir (30 mg / kg / d. Three weeks after balloon injury and SMC/LtkSN transplantation, carotid arteriography was performed and carotid arteries were perfusion-fixed for histologic examination. Results：Carotid arteriographic evaluation comparing with the uninjured left carotid artery showed that the mean luminal diameter of HSVtk gene therapy group (n＝5, 85±3% was significantly larger than that of balloon injury only group (n＝5, 65±5%. The neointimal mass of HSVtk gene therapy group was less than that of balloon injury only group. SMC / LtkSN transplantation without ganciclovir treatment group (n＝3 showed asymmetric intimal proliferation probably because of gravitational pooling of seeding. There were inflammatory cell infiltrations at the gravity dependent portion of HSVtk gene therapy group. Conclusion： Retrovirus-mediated HSVtk gene therapy following balloon injury of the rat carotid artery reduced neointimal expansion and arteriographic stenosis. (Korean Circulation J 1998;28( ( ( (6 :977-989