In vivo CRISPR base editing of PCSK9 durably lowers cholesterol in primates
Abstract
Gene-editing technologies, which include the CRISPR-Cas nucleases 1-3 and CRISPR base editors 4,5, have the potential to permanently modify disease-causing genes in patients 6. 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 worldwide 7), 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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Base editing has been utilized for single point mutations and targeted mutation induction for therapeutic corrections of diseases, mutational screening, and gene knockout.
“It has been utilized for several applications, including single point mutations and targeted mutation induction for therapeutic corrections of diseases (Musunuru et al., 2021), mutational screening, and gene knockout among the genomes (Hanna et al., 2021; Que et al., 2010).”
From Emerging applications of gene editing technologies for the development of climate-resilient crops (2025) · cites this paper as Musunuru et al., 2021
Ionizable lipid nanoparticles (LNPs) are a promising non-viral delivery platform for mRNA nanomedicines and have been used to deliver siRNA and CRISPR-based gene editing therapies to the liver in postnatal mouse, non-human primate, and clinical studies with encouraging results.
“Ionizable lipid nanoparticles (LNPs) are a promising non-viral delivery platform for mRNA nanomedicines (13, 14) that have been used to deliver siRNA and CRISPR-based gene editing therapies to the liver in postnatal mouse, non-human primate, and clinical studies with encouraging results (15–18).”
From Ionizable Lipid Nanoparticles for Therapeutic Base Editing of Congenital Brain Disease (2023) · cites this paper as [16]
An optimal weight ratio of base editor mRNA to sgRNA within the lead LNP formulation (3:1) was identified, differing from previous reports of LNPs co-encapsulating base editor mRNA and sgRNA.
“An optimal weight ratio of base editor mRNA to sgRNA within the lead LNP formulation (3:1) was also identified, differing from previous reports of LNPs co-encapsulating base editor mRNA and sgRNA (16, 40).”
From Ionizable Lipid Nanoparticles for Therapeutic Base Editing of Congenital Brain Disease (2023) · cites this paper as [16]
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- Authors
- Musunuru, K., Chadwick, A. C., Mizoguchi, T., Garcia, S. P., DeNizio, J. E., Reiss, C. W., Wang, K., Iyer, S., Dutta, C., Clendaniel, V., Amaonye, M., Beach, A., Berth, K., Biswas, S., Braun, M. C., Chen, H.-M., Colace, T. V., Ganey, J. D., Gangopadhyay, S. A., Garrity, R., Kasiewicz, L. N., Lavoie, J., Madsen, J. A., Matsumoto, Y., Mazzola, A. M., Nasrullah, Y. S., Nneji, J., Ren, H., Sanjeev, A., Shay, M., Stahley, M. R., Fan, S. H. Y., Tam, Y. K., Gaudelli, N. M., Ciaramella, G., Stolz, L. E., Malyala, P., Cheng, C. J., Rajeev, K. G., Rohde, E., Bellinger, A. M., & Kathiresan, S.
- Affiliations
- University of Pennsylvania (US)
- Verve Therapeutics (United States) (US)
- Acuitas Therapeutics (Canada) (CA)
- Beam Therapeutics (United States) (US)
- Corresponding author
- Kathiresan, Sekar
- ORCID
- Musunuru, Kiran
- Chadwick, Alexandra C.
- Garcia, Sara P.
- Reiss, Caroline W.
- Iyer, Sowmya
- Clendaniel, Victoria
- Amaonye, Michael
- Biswas, Souvik
- Gangopadhyay, Soumyashree A.
- Garrity, Ryan
- Madsen, James A.
- Mazzola, Anne Marie
- Sanjeev, Athul
- Tam, Ying K.
- Gaudelli, Nicole M.
- Ciaramella, Giuseppe
- Cheng, Christopher J.
- Rajeev, Kallanthottathil G.
- Bellinger, Andrew M.
- Kathiresan, Sekar
- Venue
- Nature
- Published
- 2021-05-19
- Volume
- 593
- Issue
- 7859
- Pages
- 429-434
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W3161425918
- Cited by
- 793
- References
- 55
- Citations by year
- 2026: 141 · 2025: 142 · 2024: 143 · 2023: 151 · 2022: 164 · 2021: 52
- FWCI
- 40.14
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- CRISPR base editing, PCSK9, lipid nanoparticles, Macaca fascicularis, LDL cholesterol, hypercholesterolemia, atherosclerotic cardiovascular disease, in vivo gene delivery, single-nucleotide editing
- MeSH terms
- Proprotein Convertase 9, Gene Editing, Loss of Function Mutation, Adenine, Animals, Cells, Cultured, Female, Humans, Cholesterol, LDL, Liver, Macaca fascicularis, Male, Mice, Inbred C57BL, Time Factors, Mutagenesis, Site-Directed, Hepatocytes, Models, Animal, Mice, CRISPR-Cas Systems
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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