The DOI matches its Crossref record; 48 of the 48 references it cites were found in a registry or an index.
Structure-guided chemical modification of guide RNA enables potent non-viral in vivo genome editing
Open accessAbstract
Efficient genome editing with Cas9-sgRNA in vivo has required the use of viral delivery systems, which have limitations for clinical applications. Translational efforts to develop other RNA therapeutics have shown that judicious chemical modification of RNAs can improve therapeutic efficacy by reducing susceptibility to nuclease degradation. Guided by the structure of the Cas9-sgRNA complex, we identify regions of sgRNA that can be modified while maintaining or enhancing genome-editing activity, and we develop an optimal set of chemical modifications for in vivo applications. Using lipid nanoparticle formulations of these enhanced sgRNAs (e-sgRNA) and mRNA encoding Cas9, we show that a single intravenous injection into mice induces >80% editing of Pcsk9 in the liver. Serum Pcsk9 is reduced to undetectable levels, and cholesterol levels are significantly lowered about 35% to 40% in animals. This strategy may enable non-viral, Cas9-based genome editing in the liver in clinical settings.
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“Gene-editing components can be delivered by lipid nanoparticle–mRNA formulations to treat genetic diseases, including HTI92,238, hypercholesterolaemia81,96,105,239, lipoprotein metabolism disorders85 and transthyretin amyloidosis239,240, which has been demonstrated in preclinical studies.”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [96]
In the citing paper
“Following a single i.v. injection, hepatic PCSK9 protein was reduced by 80% and plasma cholesterol levels were reduced by about 40%.[135]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [135]
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Cites
A Programmable Dual-RNA–Guided DNA Endonuclease in Adaptive Bacterial Immunity
Jinek, M., Chylinski, K., Fonfara, I., Hauer, M., Doudna, J. A., & Charpentier, E. (2012) · Science · doi:10.1126/science.1225829 · Cited by 17,116
Multiplex Genome Engineering Using CRISPR/Cas Systems
Cong, L., Ran, F. A., Cox, D., Lin, S., Barretto, R., Habib, N., Hsu, P. D., Wu, X., Jiang, W., Marraffini, L. A., et al. (2013) · Science · doi:10.1126/science.1231143 · Cited by 15,339
RNA-Guided Human Genome Engineering via Cas9
Mali, P., Yang, L., Esvelt, K. M., Aach, J., Guell, M., DiCarlo, J. E., Norville, J. E., & Church, G. M. (2013) · Science · doi:10.1126/science.1232033 · Cited by 9,210
The new frontier of genome engineering with CRISPR-Cas9
Doudna, J. A., & Charpentier, E. (2014) · Science · doi:10.1126/science.1258096 · Cited by 7,062
Cpf1 Is a Single RNA-Guided Endonuclease of a Class 2 CRISPR-Cas System
Zetsche, B., Gootenberg, J. S., Abudayyeh, O. O., Slaymaker, I. M., Makarova, K. S., Essletzbichler, P., Volz, S. E., Joung, J., van der Oost, J., Regev, A., et al. (2015) · Cell · doi:10.1016/j.cell.2015.09.038 · Cited by 4,761
CRISPR-Mediated Modular RNA-Guided Regulation of Transcription in Eukaryotes
Gilbert, L. A., Larson, M. H., Morsut, L., Liu, Z., Brar, G. A., Torres, S. E., Stern-Ginossar, N., Brandman, O., Whitehead, E. H., Doudna, J. A., et al. (2013) · Cell · doi:10.1016/j.cell.2013.06.044 · Cited by 3,696
High-Frequency off-Target Mutagenesis Induced by CRISPR-Cas Nucleases in Human Cells
Fu, Y., Foden, J. A., Khayter, C., Maeder, M. L., Reyon, D., Joung, J. K., & Sander, J. D. (2013) · Nature Biotechnology · doi:10.1038/nbt.2623 · Cited by 3,292
Non-viral vectors for gene-based therapy
Yin, H., Kanasty, R. L., Eltoukhy, A. A., Vegas, A. J., Dorkin, J. R., & Anderson, D. G. (2014) · Nature Reviews Genetics · doi:10.1038/nrg3763 · Cited by 3,123
Self-citationIn vivo genome editing using Staphylococcus aureus Cas9
Ran, F. A., Cong, L., Yan, W. X., Scott, D. A., Gootenberg, J. S., Kriz, A. J., Zetsche, B., Shalem, O., Wu, X., Makarova, K. S., et al. (2015) · Nature · doi:10.1038/nature14299 · Cited by 2,687
Easy quantitative assessment of genome editing by sequence trace decomposition
Brinkman, E. K., Chen, T., Amendola, M., & van Steensel, B. (2014) · Nucleic Acids Research · doi:10.1093/nar/gku936 · Cited by 2,390
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Zhang, H.-X., Duan, J., Qiubing, C., 林, 磊., Zhang, Y., Duan, M., Chen, D., Liu, X., Wu, L., Wang, G., et al. (2026) · Vita · doi:10.15302/vita.2026.09.0074
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Metadata
- Authors
- Yin, H., Song, C.-Q., Suresh, S., Wu, Q., Walsh, S., Rhym, L. H., Mintzer, E., Bolukbasi, M. F., Zhu, L. J., Kauffman, K., Mou, H., Oberholzer, A., Ding, J., Kwan, S.-Y., Bogorad, R. L., Zatsepin, T., Koteliansky, V., Wolfe, S. A., Xue, W., Langer, R., & Anderson, D. G.
- Affiliations
- Koch Institute for Integrative Cancer Research At MIT (US)
- University of Massachusetts Chan Medical School (US)
- Skolkovo Institute of Science and Technology (RU)
- Harvard–MIT Division of Health Sciences and Technology (US)
- Corresponding author
- Anderson, Daniel G
- ORCID
- Venue
- Nature Biotechnology
- Published
- 2017-11-13
- Volume
- 35
- Issue
- 12
- Pages
- 1179-1187
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- PMC
- PMC5901668
- OpenAlex
- W2770127492
- Cited by
- 499
- References
- 48
- Citations by year
- 2026: 39 · 2025: 31 · 2024: 53 · 2023: 63 · 2022: 75 · 2021: 64 · 2020: 52 · 2019: 51 · 2018: 71
- FWCI
- 19.43
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Biotechnology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- Vedecká Grantová Agentúra MŠVVaŠ SR a SAV
- Skolkovo Institute of Science and Technology
- National Institutes of Health
- National Heart, Lung, and Blood Institute (P01HL131471, DP2HL137167)
- National Cancer Institute (U54CA151884, R00CA169512, P30CA014051)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Keywords
- Cas9, in vivo gene editing, non-viral delivery, lipid nanoparticle delivery, PCSK9, cholesterol lowering, RNA therapeutics, nuclease resistance
- MeSH terms
- Proprotein Convertase 9, Gene Editing, RNA, Guide, CRISPR-Cas Systems, Animals, Liver, Nucleic Acid Conformation, Gene Transfer Techniques, Mice, Nanoparticles, CRISPR-Cas Systems
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