Autosomal dominant familial hypercholesterolemia (FH) is a monogenic life-threatening disease. We tested the efficacy of lowdensity\nlipoprotein receptor (LDLR) gene therapy using helper-dependent adenoviral vector (HDAd) in a nonhuman primate model\nof FH, comparing intravenous injection versus intrahepatic arterial injection in the presence of balloon catheter-based hepatic\nvenous occlusion. Rhesus monkeys heterozygous for mutant LDLR gene (LDLR+/ ? ) developed hypercholesterolemia while on a\nhigh-cholesterol diet. We treated them with HDAd-LDLR either by intravenous delivery or by catheter-based intrahepatic artery\ninjection. Intravenous injection of ?1.1 Ã?â?? 1012 viral particles (vp) kg? 1 failed to have any effect on plasma cholesterol. Increasing the\ndose to 5 Ã?â?? 1012 vp kg? 1 led to a 59% lowering of the plasma cholesterol that lasted for 30 days before it returned to pre-treatment\nlevels by day 40. A further increase in dose to 8.4 Ã?â?? 1012 vp kg? 1 resulted in severe lethal toxicity. In contrast, direct hepatic artery\ninjection following catheter-based hepatic venous occlusion enabled the use of a reduced HDAd-LDLR dose of 1 Ã?â?? 1012 vp kg? 1 that\nlowered plasma cholesterol within a week, and reached a nadir of 59% pre-treatment level on days 20ââ?¬â??48 after injection. Serum\nalanine aminotransferase remained normal until day 48 when it went up slightly and stayed mildly elevated on day 72 before it\nreturned to normal on day 90. In this monkey, the HDAd-LDLR-induced trough of hypocholesterolemia started trending upward on\nday 72 and returned to pre-treatment levels on day 120. We measured the LDL apolipoprotein B turnover rate at 10 days before,\nand again 79 days after, HDAd-LDLR treatment in two monkeys that exhibited a cholesterol-lowering response. HDAd-LDLR therapy\nincreased the LDL fractional catabolic rate by 78 and 50% in the two monkeys, coincident with an increase in hepatic LDLR mRNA\nexpression. In conclusion, HDAd-mediated LDLR gene delivery to the liver using a balloon catheter occlusion procedure is effective\nin reversing hypercholesterolemia in a nonhuman primate FH model; however, the unsustainability of the hypocholesterolemic\nresponse during 3ââ?¬â??4 months of follow up and heterogeneous response to the treatment remains a challenge.
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