Base Editing Gene Therapy for Heterozygous Familial Hypercholesterolemia

BackgroundHeterozygous familial hypercholesterolemia (HeFH) is a genetic disorder characterized by persistently elevated low-density lipoprotein cholesterol (LDL-C) levels, leading to an increased risk of early-onset atherosclerosis cardiovascular diseases (ASCVD). YOLT-101, an in vivo base-editing therapeutic agent delivered via GalNAc-modified lipid nanoparticles, is designed to achieve permanent inactivation of proprotein convertase subtilisin/kexin type 9 (PCSK9), enabling sustained LDL-C reduction. MethodsThis trial enrolled participants with heterozygous genetic mutations in the low-density lipoprotein receptor (LDLR), and LDL-C levels of [≥]2.6 mmol/L (without ASCVD) or [≥]1.8 mmol/L (with ASCVD) despite receiving moderate- or high-intensity statin therapy. Eligible patients received a single intravenous infusion of YOLT-101 at ascending doses (0.2, 0.4, and 0.6 mg/kg). We report interim results from an ongoing clinical trial evaluating the safety, tolerability, pharmacodynamics, and efficacy of YOLT-101. ResultsSix participants were enrolled (median age, 48 years, range, 34-62) in the study. The most common adverse events (AEs) were transient infusion-related reactions (83.3%) and elevations in alanine/aspartate aminotransferase (50%). No study withdrawals or AEs of grade 3 or higher occurred. PCSK9 and LDL-C levels decreased in a dose-dependent manner following YOLT-101 administration. In the 0.6mg/kg group (n=3), mean PCSK9 levels decreased by 55.9% at week 1 and by 75.8% and 72.5% after 1 and 4 months, respectively; corresponding LDL-C reductions were 33.2%, 48.9%, and 50.4%, respectively. ConclusionsA single infusion of YOLT-101 at 0.6 mg/kg was well tolerated and led to sustained PCSK9 and LDL-C reduction, demonstrating promise for future clinical development. (Funded by YolTech Therapeutics; Registration Number: NCT06458010)