Chimeric DNA-RNA hammerhead ribozyme to proliferating cell nuclear antigenreduces stent-induced stenosis in a porcine coronary model

Background-Stent-induced coronary restenosis is a major clinical and public health problem. Proliferating cell nuclear antigen (PCNA) is an important regulator of cell division, and blocking of its expression after angioplast y may limit intimal proliferation. Methods and Results-We cloned the porcine PCNA gene and constructed a chime ric hammerhead ribozyme to a segment of the gene with human homology, In vi tro studies with both cultured porcine and human vascular smooth muscle cel ls demonstrated uptake of ribozyme within the nucleus and significant inhib ition of cellular proliferation. The ribozyme was then delivered locally in to pig coronaries in a stent model. At 30 days, histomorphometric; analysis showed neointimal thickness-of 0.51+/-0.20 mm in the ribozyme group versus 0.71+/-0.27 and 0.66+/-0.25 mm in stent controls and scrambled ribozyme co ntrol, respectively (P=0.002, P=0.03). Quantitative angiographic analysis s howed late loss of 1.4+/-0.5 mm for ribozyme versus 1.9+/-0.4 and 2.0+/-0.4 mm for the controls (P=0.05 and P=0.02). Conclusions-Chimeric hammerhead ribozyme to PCNA inhibits smooth muscle cel l proliferation in vitro and reduces both histomorphometric and angiographi c restenosis in the porcine coronary stent model when delivered locally.