Vafai, Scott B. creator Autor Täubel, Jörg Ashdown, Thomas Patel, Riyaz S. Diamondali, Sadaf Cegla, Jaimini Soran, Handrean text pe monographic spa eng

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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 EDICIÓN GENÉTICA GENÉTICA GENERAL LÍPIDOS Massachusetts NEJM Group NEJM010 0028-4793 ESSALUD BMG 20260817160341.0 ESSALUD