02909nam a2200301 4500 ESSALUD 20260817160341.0 ta t pe ||||| |||| 00| 0 spa d BMG eng Vafai, Scott B. Autor 54105 In vivo base editing of PCSK9 with VERVE-102 for hypercholesterolemia páginas: 648-659 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. CARDIOLOGÍA GENERAL 53638 EDICIÓN GENÉTICA 54106 GENÉTICA GENERAL 54107 LÍPIDOS 51326 Täubel, Jörg 54108 Ashdown, Thomas 54109 Patel, Riyaz S. 54110 Diamondali, Sadaf 54111 Cegla, Jaimini 54112 Soran, Handrean 54113 22717 22647 Massachusetts NEJM Group NEJM010 The New England Journal of Medicine ESSALUD 0028-4793 ARTICULOS 2026-08-17 SQB 22825 22825