# VERVE-102: eenmalige base-editing schakelt PCSK9 blijvend uit (fase 1)

*geplaatst 2026-05-25 · Cholesterol · The New England journal of medicine · doi 10.1056/NEJMoa2601283 · https://hartvaat.nl/2026/05/25/verve-102-eenmalige-base-editing-schakelt-pcsk9-blijvend-uit-fase-1/*

VERVE-102 is een base-editing-therapie die met één infuus het PCSK9-gen in de lever permanent inactiveert — een adenine-base-editor-mRNA plus een gids-RNA, verpakt in een GalNAc-lipidenanopartikel. In deze fase 1-studie bij 35 patiënten met heterozygote familiaire hypercholesterolemie of vroeg coronairlijden daalde het PCSK9-eiwit dosisafhankelijk met 51% tot 88% en het LDL-cholesterol tot 62%, met een blijvend effect na één toediening. Er traden geen dosislimiterende bijwerkingen op; wel milde tot matige infusiereacties en voorbijgaande ALAT-stijgingen (en bij één patiënt met reflux een aspiratiepneumonitis). Daarmee komt een eenmalige, blijvende LDL-verlaging als behandelconcept in beeld.

## English: In Vivo Base Editing of PCSK9 with VERVE-102 for Hypercholesterolemia

VERVE-102 is a base-editing therapy that permanently inactivates the hepatic PCSK9 gene with a single infusion — an adenine base-editor mRNA plus a guide RNA in a GalNAc lipid nanoparticle. In this phase 1 study of 35 patients with heterozygous familial hypercholesterolaemia or premature coronary artery disease, PCSK9 protein fell dose-dependently by 51% to 88% and LDL cholesterol by up to 62%, with a durable effect after one dose. No dose-limiting toxic effects occurred; there were mild-to-moderate infusion reactions and transient ALT elevations (and one aspiration pneumonitis in a patient with reflux). A one-time, durable LDL reduction thus comes into view as a treatment concept.

## Abstract (original, from the publication)

BACKGROUND: Persons carrying loss-of-function variants of proprotein convertase subtilisin-kexin type 9 (PCSK9) have reduced levels of low-density lipoprotein (LDL) cholesterol and fewer atherosclerotic cardiovascular disease events than persons without such variants. VERVE-102 is an investigational base-editing therapy designed to durably inactivate PCSK9 in the liver. METHODS: In this phase 1, open-label, single-ascending-dose study, we administered one intravenous infusion of VERVE-102 at one of six doses (ranging from 0.3 to 1.0 mg of total RNA per kilogram of body weight [mg per kilogram]) to adults with heterozygous familial hypercholesterolemia or premature coronary artery disease. VERVE-102 consists of a messenger RNA encoding an adenine base-editor protein and a guide RNA targeting PCSK9, which are encapsulated in a lipid nanoparticle incorporating N-acetylgalactosamine. The objectives were to assess safety and changes in blood PCSK9 protein and LDL cholesterol levels. RESULTS: A total of 35 participants across the six dose cohorts received VERVE-102 and had at least 28 days of follow-up. No dose-limiting toxic effects occurred. Mild-to-moderate infusion-related reactions and transient elevations in alanine aminotransferase levels were observed. Aspiration pneumonitis occurred in a participant with gastroesophageal reflux disease. Dose-dependent mean reductions in the PCSK9 level ranged from 51% at the 0.3-mg-per-kilogram dose to 88% at the 1.0-mg-per-kilogram dose. Corresponding reductions in the LDL cholesterol level ranged from 9% at the 0.3-mg-per-kilogram dose to 62% at the 1.0-mg-per-kilogram dose, with an absolute reduction of 78 mg per deciliter at the highest dose. Reductions appeared to be durable throughout follow-up, which was at least 1 year in 15 participants. CONCLUSIONS: One dose of VERVE-102 led to dose-dependent, substantial, and sustained reductions in PCSK9 and LDL cholesterol levels. (Funded by Verve Therapeutics; ClinicalTrials.gov number, NCT06164730.).

Auteurs: Scott B Vafai, Jörg Täubel, Thomas Ashdown, Riyaz S Patel, Sadaf Diamondali, Jaimini Cegla, Handrean Soran, Bilal Bashir, Alexander Abitbol, Daniel Gaudet, Alex Lauzière, Liam R Brunham, David E Newby, Stephen J Nicholls, Russell S Scott, Jane Kerr, Jean-Claude Tardif, Catherine Lunken, Steve E Humphries, Verena Karsten, Patrick D Tyler, Xinyan Zhang, Nidal Huniti, Patrick A Flight, Chelsey L Jensen, Rick Falzone, Joseph C Biedenkapp, Troy Lister, Leslie E Stolz, Amit V Khera, Sekar Kathiresan

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Bron: The New England journal of medicine, https://doi.org/10.1056/NEJMoa2601283. Bijgewerkt 2026-07-03T13:31:13Z. 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.