title: p27-p16 fusion gene inhibits angioplasty-induced neointimal hyperplasia and coronary artery occlusion.
abstract: Inhibition of proliferative neointima formed by vascular smooth muscle cells is a potential target in preventing angioplasty-induced restenosis. We have created a potent antiproliferative by fusing the active regions of the p27 and p16 cell cycle inhibitors. Intravascular delivery of a replication-deficient adenoviral vector (AV) encoding this p27-p16 fusion protein, named W9, inhibited balloon injury-induced neointimal hyperplasia in rabbit carotid arteries. In a therapeutically more relevant model, AV-W9 was delivered to balloon-injured porcine coronary arteries in vivo using an infusion catheter. Of the three coronary arteries, two were injured with a 15-mm balloon catheter and either were left untreated or were treated with 10(12) viral particles of either AV-W9 or a control null virus. AV-W9 treatment significantly inhibited neointimal hyperplasia in this porcine arterial balloon injury model compared with untreated or control virus-treated vessels. The average intimal area of the AV-W9-treated group 10 days after balloon injury and treatment was 0.42+/-0.36 mm(2), whereas the AV-null group demonstrated an intimal area of 0.70+/-0.52 mm(2). At day 10 the average intimal thickness of the AV-W9-treated vessels was 9.1 microm (n=5, x 20 magnification) compared with 21.2 microm (n=5, x 20 magnification) in control virus-treated vessels. This trend was also observed at 28 days after balloon injury and gene transfer during which AV-W9-treated vessels demonstrated an average intimal thickness of 4.7 microm (n=8, x 20 magnification) compared with 13.3 microm (n=3, x 20 magnification) in control virus-treated vessels and 7.3 microm (n=5, x 20 magnification) in the sham-treated vessels. The AV-W9 treatment was safe and well tolerated. These data suggest that AV-W9 gene therapy may be useful in preventing angioplasty-induced intimal hyperplasia in the coronary artery.
authors.affiliation: Cell Genesys Inc., Foster City, CA 94404, USA.
authors.forename: L V
authors.initials: LV
authors.lastname: Tsui
authors.forename: A
authors.initials: A
authors.lastname: Camrud
authors.forename: J
authors.initials: J
authors.lastname: Mondesire
authors.forename: P
authors.initials: P
authors.lastname: Carlson
authors.forename: N
authors.initials: N
authors.lastname: Zayek
authors.forename: L
authors.initials: L
authors.lastname: Camrud
authors.forename: B
authors.initials: B
authors.lastname: Donahue
authors.forename: S
authors.initials: S
authors.lastname: Bauer
authors.forename: A
authors.initials: A
authors.lastname: Lin
authors.forename: D
authors.initials: D
authors.lastname: Frey
authors.forename: M
authors.initials: M
authors.lastname: Rivkin
authors.forename: A
authors.initials: A
authors.lastname: Subramanian
authors.forename: R
authors.initials: R
authors.lastname: Falotico
authors.forename: J
authors.initials: J
authors.lastname: Gyuris
authors.forename: R
authors.initials: R
authors.lastname: Schwartz
authors.forename: J G
authors.initials: JG
authors.lastname: McArthur
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D015906:Angioplasty, Balloon, Coronary / Q000009:adverse effects*; D000818:Animals; D006328:Cardiac Catheterization; D018797:Cell Cycle Proteins / Q000235:genetics*; D002478:Cells, Cultured; D003327:Coronary Disease / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006801:Humans; D006965:Hyperplasia / Q000517:prevention & control*; D007261:Infusions, Intra-Arterial; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011817:Rabbits; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics; D013552:Swine; D014161:Transduction, Genetic / Q000379:methods; D016896:Treatment Outcome; D025521:Tumor Suppressor Proteins; D017539:Tunica Intima / Q000473:pathology
chemical_list: D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D011993:Recombinant Fusion Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases