IN-VIVO GENE-THERAPY FOR HYPERLIPIDEMIA - PHENOTYPIC CORRECTION IN WATANABE RABBITS BY HEPATIC DELIVERY OF THE RABBIT LDL RECEPTOR GENE

Elevations of plasma total or LDL cholesterol are major risk factors f or cardiovascular disease. Efforts directed at preventing and treating cardiovascular disease have often focused on reducing the levels of t hese substances in the blood. The Watanabe Heritable Hyperlipidemic Ra bbit, which has exceedingly high plasma cholesterol levels resulting f rom an LDL receptor deficiency, provides an excellent animal model for testing new treatments. A recombinant adenoviral vector containing th e rabbit LDL receptor cDNA was administered to Watanabe rabbits. Plasm a total cholesterol levels in the treated animals were reduced from 82 5.5 +/- 69.8 (mean +/- SD) to 247.3 +/- 61.5 mg/dl 6 d after infusion. These animals also demonstrated a 300-400% increase in plasma levels of HDL cholesterol and apo At 10 d after treatment. As a result, the L DL:HDL ratio exhibited a dramatic decrease. Because only the rabbit LD L receptor gene was used for treatment, the results strongly suggest t hat the elevations of plasma HDL cholesterol and apo AI were secondary to a reduction in plasma total cholesterol in the treated animals. Th ese results suggest an inverse relationship between plasma LDL and HDL cholesterol levels and imply that reduction of LDL cholesterol levels may have a beneficial effect on plasma HDL cholesterol.