p27-p16 chimera: A superior antiproliferative for the prevention of neointimal hyperplasia

Cyclin-dependent kinase inhibitors (CDKi's) may be useful to treat hyperpro liferative vascular disorders, such as restenosis induced following angiopl asty or vein engraftment. We have shown that a novel fusion protein of the CDKi's p27 and p16, named W9, significantly reduces proliferation of human coronary smooth muscle cells in vitro, by blocking cell proliferation witho ut inducing apoptosis. We have now evaluated the efficacy of adenovirus-med iated gene transfer of W9 (AV-W9) in a balloon-injury model, in the carotid arteries of cholesterol-fed rabbits. We observed that intravascular delive ry of 2 x 10(11) viral particles of AV-W9 3 days following balloon injury i nhibited intimal hyperplasia by 60% compared to a control virus (P > 0.001) . PCNA expression in the AV-W9-treated vessels, a marker of injury-induced cell proliferation, was also reduced compared to the control virus-treated vessels. Direct comparison of the efficacy of AV-W9 and AV-p16 and AV-p27 i n this model indicated that delivery of either of the parental genes was si gnificantly less effective in inhibiting intimal thickening compared to the AV-W9 treatment. We conclude that combining the activities of multiple cel l cycle regulatory proteins greatly increases the potency of cytostatic gen e therapy in the treatment of balloon injury-induced intimal hyperplasia an d represents a promising potential approach to preventing postangioplasty r estenosis.