HEPATIC LIPASE GENE-THERAPY IN HEPATIC LIPASE-DEFICIENT MICE - ADENOVIRUS-MEDIATED REPLACEMENT OF A LIPOLYTIC ENZYME TO THE VASCULAR ENDOTHELIUM

Hepatic lipase (HL) is an endothelial-bound lipolytic enzyme which fun ctions as a phospholipase as well as a triacylglycerol hydrolase and i s necessary for the metabolism of IDL and HDL. To evaluate the feasibi lity of replacing an enzyme whose in vivo physiologic function depends on its localization on the vascular endothelium, we have infused reco mbinant replication-deficient adenovirus vectors expressing either hum an HL (HL-rAdV; n = 7) or luciferase cDNA (Lucif-rAdV; n = 4) into HL- deficient mice with pretreatment plasma cholesterol, phospholipid, and HDL cholesterol values of 176+/-9, 314+/-12, and 129+/-9, respectivel y. After infusion of HL-rAdV. HL could be detected in the post-heparin plasma of HL-deficient mice by and postheparin plasma HL activities w ere 25,700+/-4,810 and 1,510+/-688 nmol/min/ml on days 5 and 15, respe ctively. Unlike the mouse HL, 97% of the newly synthesized human HL wa s heparin releasable, indicating that the human enzyme was virtually t otally bound to the mouse vascular endothelium. Infusion of HL-rAdV in HL-deficient mice was associated with a 50-80% decrease in total chol esterol, tri- glyceride, phospholipids, cholesteryl ester, and HDL cho lesterol (P < 0.001) as well as normalization of the plasma fast prote in liquid chromatography lipoprotein profile by day 8. These studies d emonstrate successful expression and delivery of a lipolytic enzyme to the vascular endothelium for ultimate correction of the HL gene defec t in HL-deficient mice and indicate that recombinant adenovirus vector s may be useful in the replacement of endothelial-bound lipolytic enzy mes in human lipolytic deficiency states.