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 hereditary tyrosinaemia type I, hypercholesterolaemia, lipoprotein metabolism disorders and transthyretin amyloidosis, as demonstrated in preclinical studies.
“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]
Following a single i.v. injection of Cas9 mRNA and e-sgRNA targeting Pcsk9 with cKK-E12 LNPs, hepatic PCSK9 protein was reduced by 80% and plasma cholesterol levels were reduced by about 40%.
“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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- 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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