{"id":"68cc928cf6b4","type":"article","url":"https://hartvaat.nl/2026/03/03/yolt-101-base-editing-schakelt-pcsk9-uit-bij-heterozygote-fh-fase-1/","title":"YOLT-101: base-editing schakelt PCSK9 uit bij heterozygote FH (fase 1)","title_en":"In vivo base editing gene therapy for heterozygous familial hypercholesterolemia: a phase 1 trial.","category":"cholesterol","category_label":"Cholesterol","professions":["apotheker","cardioloog","internist"],"tags":["familiaire-hypercholesterolemie-screening","pcsk9-remmers"],"journal":"Nature medicine","doi":"10.1038/s41591-026-04254-4","source_url":"https://doi.org/10.1038/s41591-026-04254-4","authors":["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"],"significance":8,"published":"2026-03-03","source_date":"2026-03-03","image":"https://hartvaat.nl/global/img/85198a3494d0.webp","kennis":["https://hartvaat.nl/kennis/lipiden/familiaire-hypercholesterolemie/","https://hartvaat.nl/kennis/lipiden/ldl-cholesterol-mechanisme/"],"congress":"","summary_en":"YOLT-101 is an in vivo gene therapy that uses adenine base editing — delivered via GalNAc-modified lipid nanoparticles — to inactivate PCSK9 for durable LDL lowering. In this ongoing phase 1 trial, six adults with heterozygous familial hypercholesterolaemia and uncontrolled LDL received a single ascending dose (0.2–0.6 mg/kg). No grade ≥3 adverse events occurred; transient infusion reactions and liver-enzyme elevations were most common. A single infusion produced dose-dependent, durable reductions: at the highest dose (0.6 mg/kg) PCSK9 and LDL cholesterol fell by 74.4% and 52.3% respectively at 24 weeks. Alongside VERVE-102, this is a second base-editing programme pursuing one-time, durable PCSK9 knockdown.","created":"2026-07-03T10:32:16Z","updated":"2026-07-03T13:31:14Z","licence":"Citeer vrij, met bronvermelding en een link naar hartvaat.nl (de url van het record). Samenvattingen zijn redactioneel werk van HartVaat; de oorspronkelijke publicaties blijven van hun uitgevers (doi). Geen medisch advies.","body_markdown":"YOLT-101 is een in-vivo gentherapie die met adenine-base-editing — afgeleverd via GalNAc-gemodificeerde lipidenanopartikels — het PCSK9-gen inactiveert voor een blijvende LDL-verlaging. In deze lopende fase 1-trial kregen zes volwassenen met heterozygote familiaire hypercholesterolemie en onvoldoende gereguleerd LDL eenmalig een oplopende dosis (0,2–0,6 mg/kg). Er traden geen graad ≥3-bijwerkingen op; voorbijgaande infusiereacties en leverenzymstijgingen waren het meest voorkomend. Eén infuus gaf dosisafhankelijke, blijvende dalingen: in de hoogste dosis (0,6 mg/kg) daalden PCSK9 en LDL-cholesterol na 24 weken met respectievelijk 74,4% en 52,3%. Naast VERVE-102 is dit een tweede base-editing-programma dat de weg naar eenmalige, blijvende PCSK9-uitschakeling verkent.","abstract_original":"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 ."}