In vivo base editing gene therapy for heterozygous familial hypercholesterolemia: a phase 1 trial.

Heterozygous familial hypercholesterolemia is a common genetic disorder characterized by lifelong elevation of serum low-density lipoprotein cholesterol (LDL-C) and premature atherosclerotic cardiovascular disease. YOLT-101 is an investigational in vivo gene therapy that uses adenine base-editing technology, delivered via GalNAc-modified lipid nanoparticles to inactivate PCSK9 and achieve sustained LDL-C reduction. Here we report interim results from an ongoing clinical trial evaluating primary (safety and tolerability) and secondary (lowering of PCSK9 and LDL-C levels) outcomes of a single intravenous dose of YOLT-101 in adults with heterozygous familial hypercholesterolemia and uncontrolled LDL-C. Six participants (three men and three women) received escalating doses of YOLT-101 (0.2, 0.4 or 0.6 mg kg-1). No grade ≥3 adverse events occurred. Transient and self-limited infusion-related reactions and elevations in liver enzymes were the most common adverse events. A single infusion of YOLT-101 induced dose-dependent and durable reductions in circulating PCSK9 and LDL-C, with sustained reductions of 74.4% and 52.3%, respectively, at 24 weeks in the 0.6 mg kg-1 cohort (n = 3), demonstrating promise for future clinical development. ClinicalTrials.gov registration: NCT06458010 .