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(Circulation Research. 2001;89:323.)
© 2001 American Heart Association, Inc.

Molecular Medicine

p27-p16 Fusion Gene Inhibits Angioplasty-Induced Neointimal Hyperplasia and Coronary Artery Occlusion

Lisa V. Tsui, Allan Camrud, Jean Mondesire, Paula Carlson, Nathalie Zayek, LaDonna Camrud, Brian Donahue, Scott Bauer, Andy Lin, David Frey, Marianne Rivkin, Ajit Subramanian, Robert Falotico, Jeno Gyuris, Robert Schwartz, James G. McArthur

From Cell Genesys Inc (L.V.T., J.M., N.Z., B.D., S.B., A.L., D.F., M.R., A.J., J.M.G.), Foster City, Calif; Department of Cardiology (A.C., P.C., L.C., R.S.), Mayo Clinic, Rochester, Minn; Cordis Inc (R.F.), Warren, NJ; and GPC Biotech Inc (J.G.), Cambridge, Mass.

Correspondence to James McArthur, PharmD, PhD, Department of Preclinical Biology and Immunology, Cell Genesys Inc, 342 Lakeside Dr, Foster City, CA 94404. E-mail jamesm{at}cellgenesys.com

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 10¹² 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 mm², whereas the AV-null group demonstrated an intimal area of 0.70±0.52 mm². At day 10 the average intimal thickness of the AV-W9–treated vessels was 9.1 µm (n=5, x20 magnification) compared with 21.2 µm (n=5, x20 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 µm (n=8, x20 magnification) compared with 13.3 µm (n=3, x20 magnification) in control virus–treated vessels and 7.3 µm (n=5, x20 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.

Key Words: p27 • p16 • restenosis • gene therapy

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