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The European Society of Cardiology

The design and preclinical testing of Ad5FGF-4 to treat chronic myocardial ischaemia

G.M Rubanyi*

Gene Therapy Department, Berlex Biosciences, Richmond, CA, USA

* G.M. Rubanyi, Gene Therapy Department, Berlex Biosciences, 2600 Hilltop Dr, Richmond CA 98404, USA. Tel.: +1-510-262-7804; fax: +1-510-669-4750
gabor_rubanyi{at}berlex.com

Abstract

Patients with myocardial ischaemia may experience cardiovascular events, sudden death, or constant pain and limited activity despite maximal medical and surgical therapy. Therapeutic angiogenesis is being developed as a novel treatment strategy for patients with myocardial ischaemia. The goal of therapeutic angiogenesis is to stimulate the formation of collateral coronary arteries around obstructed arteries to restore blood flow to ischaemic regions of the heart. It was hypothesized that local production of an angiogenic growth factor would result in increased collateral formation, myocardial perfusion, and wall motion during contraction. A rational development process resulted in the selection of fibroblast growth factor-4 (FGF-4) as the angiogenic growth factor, adenoviral gene transfer as the delivery mechanism and percutaneous intracoronary infusion as the administration technique. Preclinical studies in pigs with myocardial ischaemia caused by ameroid constriction of the left circumflex coronary artery showed that intracoronary injection of Ad5FGF-4 is well tolerated and effective. Intracoronary infusion of Ad5FGF-4 increased myocardial perfusion to control levels and restored normal heart wall motion, whereas injection of a control vector (Ad5LacZ) or an FGF-2 gene without a signal sequence motif did not. Based on these data, clinical trials in patients with myocardial ischaemia were initiated.

Key Words: Myocardial ischaemia • Collateral coronary arteries • Stable angina • Angiogenesis • Fibroblast growth factor • Adenovirus


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