02761nam a2200277   4500001000800000005001700008007000300025008004100028040000800069041000800077100002900085245007400114300002300188520195300211650002602164650002502190650002302215650001402238700002202252700002102274700002102295700002302316700002002339700002102359773010302380ESSALUD20260817160341.0ta      t        pe ||||| |||| 00| 0 spa d  aBMG  aeng  aVafai,  Scott B. eAutor  aIn vivo base editing of PCSK9 with VERVE-102 for hypercholesterolemia  apáginas: 648-659  aBackground: 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.  aCARDIOLOGÍA GENERAL  aEDICIÓN GENÉTICA  aGENÉTICA GENERAL  aLÍPIDOS  aTäubel, Jörg   aAshdown, Thomas   aPatel, Riyaz S.   aDiamondali, Sadaf   aCegla, Jaimini   aSoran, Handrean 0 022717dMassachusetts NEJM GroupoNEJM010tThe New England Journal of Medicine wESSALUDx0028-4793