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. 2021 May;593(7859):429-434.
doi: 10.1038/s41586-021-03534-y. Epub 2021 May 19.

In vivo CRISPR base editing of PCSK9 durably lowers cholesterol in primates

Kiran Musunuru  1   2   3 , Alexandra C Chadwick  4 , Taiji Mizoguchi  4 , Sara P Garcia  4 , Jamie E DeNizio  4 , Caroline W Reiss  4 , Kui Wang  4 , Sowmya Iyer  4 , Chaitali Dutta  4 , Victoria Clendaniel  4 , Michael Amaonye  4 , Aaron Beach  4 , Kathleen Berth  4 , Souvik Biswas  4 , Maurine C Braun  4 , Huei-Mei Chen  4 , Thomas V Colace  4 , John D Ganey  4 , Soumyashree A Gangopadhyay  4 , Ryan Garrity  4 , Lisa N Kasiewicz  4 , Jennifer Lavoie  4 , James A Madsen  4 , Yuri Matsumoto  4 , Anne Marie Mazzola  4 , Yusuf S Nasrullah  4 , Joseph Nneji  4 , Huilan Ren  4 , Athul Sanjeev  4 , Madeleine Shay  4 , Mary R Stahley  4 , Steven H Y Fan  5 , Ying K Tam  5 , Nicole M Gaudelli  6 , Giuseppe Ciaramella  6 , Leslie E Stolz  4 , Padma Malyala  4 , Christopher J Cheng  4 , Kallanthottathil G Rajeev  4 , Ellen Rohde  4 , Andrew M Bellinger  4 , Sekar Kathiresan  7
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In vivo CRISPR base editing of PCSK9 durably lowers cholesterol in primates

Kiran Musunuru et al. Nature. 2021 May.

Abstract

Gene-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.

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References

    1. Jinek, M. et al. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 337, 816–821 (2012). - PubMed - PMC - DOI
    1. Zetsche, B. et al. Cpf1 is a single RNA-guided endonuclease of a class 2 CRISPR-Cas system. Cell 163, 759–771 (2015). - PubMed - PMC - DOI
    1. Strecker, J. et al. Engineering of CRISPR–Cas12b for human genome editing. Nat. Commun. 10, 212 (2019). - PubMed - PMC - DOI
    1. Komor, A. C., Kim, Y. B., Packer, M. S., Zuris, J. A. & Liu, D. R. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature 533, 420–424 (2016). - PubMed - PMC - DOI
    1. Gaudelli, N. M. et al. Programmable base editing of A•T to G•C in genomic DNA without DNA cleavage. Nature 551, 464–471 (2017). - PubMed - PMC - DOI

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