Base Editing Gene Therapy for Heterozygous Familial Hypercholesterolemia

作者：Ping Wan, Siyuan Tang, Dongni Lin, Yuming Lu, Mei Long, Ling Xiao, Yanhong Jiang, Jiaoyang Liao, Xiaoying Ma, Ying Liu, W. Yu, Zijun Wang, Yuxuan Wu, Taihua Yang, Qiang Xia · 发表于：medRxiv · 年份：2025 · DOI：10.1101/2025.04.17.25325983 · 被引用次数：5 · 研究领域：Biosimilars and Bioanalytical Methods、CAR-T cell therapy research、Biotechnology and Related Fields

ABSTRACT Background Heterozygous 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. Methods This 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. Results Six 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 wee...