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<p>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<sup>−1</sup>). 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<sup>−1</sup> cohort (<i>n</i> = 3), demonstrating promise for future clinical development. ClinicalTrials.gov registration: <a href="https://clinicaltrials.gov/ct2/show/NCT06458010">NCT06458010</a>.</p>

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

  • 期刊论文

  • 发表日期：

    2026年3月3日

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  • Ping Wan,
  • Siyuan Tang,
  • Dongni Lin,
  • Yuming Lu,
  • Mei Long,
  • Ling Xiao,
  • Yanhong Jiang,
  • Jiaoyang Liao,
  • Xiaoying Ma,
  • Ying Liu,
  • Wensu Yu,
  • Michael Ott,
  • Zi Jun Wang,
  • Yuxuan Wu,
  • Taihua Yang,
  • Qiang Xia

摘要

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.