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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- PMID:34012082
- DOI: 10.1038/s41586-021-03534-y
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In vivo CRISPR base editing of PCSK9 durably lowers cholesterol in primates
Kiran Musunuru et al. Nature.2021 May.
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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.
Comment in
- Pushing the envelope with PCSK9.Kingwell K.Kingwell K.Nat Rev Drug Discov. 2021 Jul;20(7):506. doi: 10.1038/d41573-021-00093-9.Nat Rev Drug Discov. 2021.PMID:34035481No abstract available.
- Base editing takes a shot at disease in non-human primates.Koch L.Koch L.Nat Rev Genet. 2021 Aug;22(8):479. doi: 10.1038/s41576-021-00382-4.Nat Rev Genet. 2021.PMID:34045716No abstract available.
- Three different therapies to target PCSK9.Robson A.Robson A.Nat Rev Cardiol. 2021 Aug;18(8):541. doi: 10.1038/s41569-021-00581-w.Nat Rev Cardiol. 2021.PMID:34089000No abstract available.
- Therapeutic base editing in the adult liver.Paulusma CC, Bosma PJ.Paulusma CC, et al.Nat Rev Gastroenterol Hepatol. 2021 Sep;18(9):597-598. doi: 10.1038/s41575-021-00491-9.Nat Rev Gastroenterol Hepatol. 2021.PMID:34285418No abstract available.
- CRISPR 'cousin' put to the test in landmark heart-disease trial.Ledford H.Ledford H.Nature. 2022 Jul;607(7920):647. doi: 10.1038/d41586-022-01951-1.Nature. 2022.PMID:35840676No abstract available.
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