Gene therapy for rhesus monkeys heterozygous for LDL receptor deficiency by balloon catheter hepatic delivery of helper-dependent adenoviral vector

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