AAV gene therapy for homozygous familial hypercholesterolemia: a phase 1 trial.

Homozygous familial hypercholesterolemia (HoFH) is a rare autosomal disease characterized by severely elevated low-density lipoprotein cholesterol (LDL-C) levels and accelerated atherosclerotic cardiovascular disease. More than 80% of patients with HoFH carry low-density lipoprotein receptor (LDLR) mutations. Here we developed an adeno-associated virus gene therapy designed to express LDLR in the liver and evaluated its safety and efficacy in lowering LDL-C levels in experimental animals and in patients with HoFH. NGGT006, a recombinant adeno-associated virus serotype 8-based vector containing a codon-optimized LDLR complementary DNA, lowered LDL-C levels in Ldlr-/- mice and Ldlr-/- hamsters and decreased aortic plaque size in Ldlr-/- mice. In rhesus monkeys, NGGT006 administration led to transient liver enzyme elevations but no severe adverse events. In an open-label, single-arm, dose-escalation trial, three patients with HoFH received doses of NGGT006 of 7.5 × 1012, 1.5 × 1013 and 3 × 1013 vg kg-1. Primary endpoints included safety and LDL-C reduction over a follow-up of 52 weeks. NGGT006 treatment was well tolerated, with no vector-related severe adverse events. All three patients showed elevations of liver enzymes that were resolved after sirolimus and methylprednisolone therapy. The patient who received the highest dose exhibited a sustained reduction in LDL-C from 11 mmol l-1 to <1.8 mmol l-1 starting at 3 weeks after treatment. These results offer initial insights into the safety and therapeutic potential of NGGT006 and warrant future studies of its safety and efficacy. ClinicalTrials.gov: NCT06125847 .