https://eutils.ncbi.nlm.nih.gov/entrez/eutils/efetch.fcgi?db=pubmed&id=34012082&retmode=xml&tool=Litmetric&email=readroberts32@gmail.com&api_key=61f08fa0b96a73de8c900d749fcb997acc09 340120822021100120221026
1476-468759378592021MayNatureNatureIn vivo CRISPR base editing of PCSK9 durably lowers cholesterol in primates.429434429-43410.1038/s41586-021-03534-yGene-editing technologies, which include the CRISPR-Cas nucleases1-3 and CRISPR base editors4,5, have the potential to permanently modify disease-causing genes in patients6. The demonstration of durable editing in target organs of nonhuman primates is a key step before in vivo administration of gene editors to patients in clinical trials. Here we demonstrate that CRISPR base editors that are delivered in vivo using lipid nanoparticles can efficiently and precisely modify disease-related genes in living cynomolgus monkeys (Macaca fascicularis). We observed a near-complete knockdown of PCSK9 in the liver after a single infusion of lipid nanoparticles, with concomitant reductions in blood levels of PCSK9 and low-density lipoprotein cholesterol of approximately 90% and about 60%, respectively; all of these changes remained stable for at least 8 months after a single-dose treatment. In addition to supporting a 'once-and-done' approach to the reduction of low-density lipoprotein cholesterol and the treatment of atherosclerotic cardiovascular disease (the leading cause of death worldwide7), our results provide a proof-of-concept for how CRISPR base editors can be productively applied to make precise single-nucleotide changes in therapeutic target genes in the liver, and potentially in other organs.MusunuruKiranK0000-0003-3298-0368Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.Division of Cardiovascular Medicine, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.ChadwickAlexandra CACVerve Therapeutics, Cambridge, MA, USA.MizoguchiTaijiTVerve Therapeutics, Cambridge, MA, USA.GarciaSara PSP0000-0003-3312-6454Verve Therapeutics, Cambridge, MA, USA.DeNizioJamie EJEVerve Therapeutics, Cambridge, MA, USA.ReissCaroline WCW0000-0002-6385-1879Verve Therapeutics, Cambridge, MA, USA.WangKuiKVerve Therapeutics, Cambridge, MA, USA.IyerSowmyaSVerve Therapeutics, Cambridge, MA, USA.DuttaChaitaliCVerve Therapeutics, Cambridge, MA, USA.ClendanielVictoriaV0000-0002-2969-4443Verve Therapeutics, Cambridge, MA, USA.AmaonyeMichaelM0000-0001-6683-2545Verve Therapeutics, Cambridge, MA, USA.BeachAaronAVerve Therapeutics, Cambridge, MA, USA.BerthKathleenKVerve Therapeutics, Cambridge, MA, USA.BiswasSouvikSVerve Therapeutics, Cambridge, MA, USA.BraunMaurine CMCVerve Therapeutics, Cambridge, MA, USA.ChenHuei-MeiHMVerve Therapeutics, Cambridge, MA, USA.ColaceThomas VTVVerve Therapeutics, Cambridge, MA, USA.GaneyJohn DJDVerve Therapeutics, Cambridge, MA, USA.GangopadhyaySoumyashree ASAVerve Therapeutics, Cambridge, MA, USA.GarrityRyanR0000-0002-5015-4505Verve Therapeutics, Cambridge, MA, USA.KasiewiczLisa NLNVerve Therapeutics, Cambridge, MA, USA.LavoieJenniferJVerve Therapeutics, Cambridge, MA, USA.MadsenJames AJAVerve Therapeutics, Cambridge, MA, USA.MatsumotoYuriYVerve Therapeutics, Cambridge, MA, USA.MazzolaAnne MarieAMVerve Therapeutics, Cambridge, MA, USA.NasrullahYusuf SYSVerve Therapeutics, Cambridge, MA, USA.NnejiJosephJVerve Therapeutics, Cambridge, MA, USA.RenHuilanHVerve Therapeutics, Cambridge, MA, USA.SanjeevAthulA0000-0003-4089-5315Verve Therapeutics, Cambridge, MA, USA.ShayMadeleineMVerve Therapeutics, Cambridge, MA, USA.StahleyMary RMRVerve Therapeutics, Cambridge, MA, USA.FanSteven H YSHYAcuitas Therapeutics, Vancouver, British Columbia, Canada.TamYing KYKAcuitas Therapeutics, Vancouver, British Columbia, Canada.GaudelliNicole MNM0000-0001-8608-4855Beam Therapeutics, Cambridge, MA, USA.CiaramellaGiuseppeGBeam Therapeutics, Cambridge, MA, USA.StolzLeslie ELEVerve Therapeutics, Cambridge, MA, USA.MalyalaPadmaPVerve Therapeutics, Cambridge, MA, USA.ChengChristopher JCJVerve Therapeutics, Cambridge, MA, USA.RajeevKallanthottathil GKGVerve Therapeutics, Cambridge, MA, USA.RohdeEllenEVerve Therapeutics, Cambridge, MA, USA.BellingerAndrew MAMVerve Therapeutics, Cambridge, MA, USA.KathiresanSekarS0000-0002-3711-7101Verve Therapeutics, Cambridge, MA, USA. skathiresan@vervetx.com.engJournal ArticleResearch Support, Non-U.S. Gov't20210519
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