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(Circulation. 1999;99:697-703.)
© 1999 American Heart Association, Inc.

Basic Science Reports

Chimeric DNA-RNA Hammerhead Ribozyme to Proliferating Cell Nuclear Antigen Reduces Stent-Induced Stenosis in a Porcine Coronary Model

Aaron Frimerman, MD; Peter J. Welch, PhD; Xiaomei Jin, MD, PhD; Neal Eigler, MD; Soonpin Yei, PhD; James Forrester, MD; Hidehiko Honda, MD; Raj Makkar, MD; Jack Barber, PhD; Frank Litvack, MD

From the Cardiovascular Intervention Center, Division of Cardiology, Department of Medicine, Cedars-Sinai Medical Center and the UCLA School of Medicine, Los Angeles, Calif (A.F., N.E., J.F., H.H., R.M., F.L.), and Immusol Inc, La Jolla, Calif (P.J.W., X.J., S.Y., J.B.).

Correspondence to Frank Litvack, MD, Cardiovascular Intervention Center, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Suite 6560, Los Angeles, CA 90048.

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 angioplasty may limit intimal proliferation.

Methods and Results—We cloned the porcine PCNA gene and constructed a chimeric hammerhead ribozyme to a segment of the gene with human homology. In vitro studies with both cultured porcine and human vascular smooth muscle cells demonstrated uptake of ribozyme within the nucleus and significant inhibition of cellular proliferation. The ribozyme was then delivered locally into 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 control, respectively (P=0.002, P=0.03). Quantitative angiographic analysis showed 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 cell proliferation in vitro and reduces both histomorphometric and angiographic restenosis in the porcine coronary stent model when delivered locally.

Key Words: restenosis • stents • oligonucleotides • RNA, catalytic

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