In vivo genome editing using Staphylococcus aureus Cas9
Open accessAbstract
The RNA-guided endonuclease Cas9 has emerged as a versatile genome-editing platform. However, the size of the commonly used Cas9 from Streptococcus pyogenes (SpCas9) limits its utility for basic research and therapeutic applications that use the highly versatile adeno-associated virus (AAV) delivery vehicle. Here, we characterize six smaller Cas9 orthologues and show that Cas9 from Staphylococcus aureus (SaCas9) can edit the genome with efficiencies similar to those of SpCas9, while being more than 1 kilobase shorter. We packaged SaCas9 and its single guide RNA expression cassette into a single AAV vector and targeted the cholesterol regulatory gene Pcsk9 in the mouse liver. Within one week of injection, we observed >40% gene modification, accompanied by significant reductions in serum Pcsk9 and total cholesterol levels. We further assess the genome-wide targeting specificity of SaCas9 and SpCas9 using BLESS, and demonstrate that SaCas9-mediated in vivo genome editing has the potential to be efficient and specific.
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The requirement of a specific PAM sequence for targeted genome editing is crucial, and even though it reduces off-target activity, it often results in suboptimal DNA cleavage and editing efficiencies and restricts the scope of targeted editing.
“Also, the requirement of a specific PAM Sequence for targeted genome editing is crucial, and even though it reduces off-target activity, it often results in suboptimal DNA cleavage, editing efficiencies (Ran et al., 2015; Edraki et al., 2019) and restricting the scope of targeted edition.”
From Emerging applications of gene editing technologies for the development of climate-resilient crops (2025) · cites this paper as Ran et al., 2015
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredCas9 genomic localization is delimited by the PAM, which is NGG for SpCas9 while evolved variants of SpCas9 tolerate a broader range of PAM sequences.
“Cas9 genomic localization is delimited by the protospacer adjacent motif (PAM), which is NGG for SpCas9 while evolved variants of SpCas9 tolerate a broader range of PAM sequences17–21.”
From One-step generation of tumor models by base editor multiplexing in adult stem cell-derived organoids (2023) · cites this paper as [20]
The Introduction’s “SaCas9 sgRNA design and PAM discovery” section reports NGG PAMs adjacent to dSpCas9 binding sites, supporting the SpCas9 portion of the claim. Our copy does not report that evolved SpCas9 variants tolerate a broader range of PAM sequences; its discussion of additional PAMs concerns SaCas9. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSaCas9 has been extensively characterized as a highly efficient and significantly smaller alternative to SpCas9.
“The SpCas9 homolog derived from Staphylococcus aureus (SaCas9) has been extensively characterized as a highly efficient and significantly smaller alternative to SpCas9.”
From One-step generation of tumor models by base editor multiplexing in adult stem cell-derived organoids (2023) · cites this paper as [20]
SaCas9 recognizes an NNGRRT PAM (where R = A or G).
“It recognizes an NNGRRT PAM (where R = A or G)20.”
From One-step generation of tumor models by base editor multiplexing in adult stem cell-derived organoids (2023) · cites this paper as [20]
Artificial Cas9 variants with relaxed PAM specificities improve efficiency but are associated with an increase in off-target effects and a decrease in target specificity.
“Recent advancements in gene-editing technologies have led to the development of artificial Cas9 variants with relaxed PAM specificities, which improve efficiency but are associated with an increase in off-target effects and a decrease in target specificity (Ran et al., 2015).”
From Emerging applications of gene editing technologies for the development of climate-resilient crops (2025) · cites this paper as Ran et al., 2015
The SaCas9 sgRNA design and PAM discovery section reports that natural SaCas9 can cleave several PAM sequences and says these should be considered in off-target evaluations. The in vivo genome editing section reports very low off-target signals for the guides tested. Neither passage addresses whether artificial Cas9 variants with relaxed PAM requirements improve efficiency while increasing off-target effects and reducing specificity; searches for relaxed PAM and engineered variants found no such comparison in our copy. (LLM, conf=0.72)
Experimental — accuracy not yet measured
A smaller form of Cas9 was developed and shown capable of packing and delivery with sgRNA by AAV in vivo.
“Recently, a smaller form of Cas9 was developed, and shown capable of packing and delivery with sgRNA by AAV in vivo12.”
From Therapeutic genome editing by combined viral and non-viral delivery of CRISPR system components in vivo (2016) · cites this paper as [12]
Adenovirus or AAV-mediated CRISPR-Cas9 delivery has been successfully applied to knockout genes in the mouse brain and liver.
“Adenovirus or adeno-associated virus (AAV)-mediated CRISPR-Cas9 delivery has been successfully applied to knockout genes in the mouse brain and liver12,13.”
From Therapeutic genome editing by combined viral and non-viral delivery of CRISPR system components in vivo (2016) · cites this paper as [12]
A smaller form of Cas9 (S. aureus Cas9) fits into AAV vectors and has been used to knockout genes by NHEJ in the mouse liver, with more than 40% indel formations in the Pcsk9 locus reported.
“A smaller form of Cas9 (Staphylococcus aureus Cas9), which fits into AAV vectors, has been recently used to knockout genes by NHEJ in the mouse liver. More than 40% indel formations in Pcsk9 locus was reported12.”
From Therapeutic genome editing by combined viral and non-viral delivery of CRISPR system components in vivo (2016) · cites this paper as [12]
Less than 10% indels at the Apob locus in the mouse liver was reported in the same study.
“For example, less than 10% indels at the Apob locus in the mouse liver was reported in the same study12.”
From Therapeutic genome editing by combined viral and non-viral delivery of CRISPR system components in vivo (2016) · cites this paper as [12]
The large genetic size of Cas9 (~4.5 kb) and the total plasmid size (>7 kb) significantly increase the difficulty of delivery and expression of CRISPR/Cas9 systems.
“However, the large genetic size of Cas9 (~ 4.5 kb) and the total plasmid size (> 7 kb) significantly increase the difficulty of delivery and expression of CRISPR/Cas9 systems [94].”
From Non-viral delivery systems for CRISPR/Cas9-based genome editing: challenges and opportunities (2018) · cites this paper as [94]
SaCas9 is about 1 kb shorter than SpCas9, but overall genetic size is still too large for application.
“Although the newly discovered Cas9 form from Staphylococcus aureus strain (SaCas9) is about 1 kb shorter than SpCas9, the overall genetic size is still too large for application [94, 140].”
From Non-viral delivery systems for CRISPR/Cas9-based genome editing: challenges and opportunities (2018) · cites this paper as [94]
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- Authors
- 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., Koonin, E. V., Sharp, P. A., & Zhang, F.
- Affiliations
- Broad Institute (US)
- Massachusetts Institute of Technology (US)
- Koch Institute for Integrative Cancer Research At MIT (US)
- National Institutes of Health (US)
- Corresponding author
- Zhang, Feng
- ORCID
- Venue
- Nature
- Published
- 2015-04
- Volume
- 520
- Issue
- 7546
- Pages
- 186-191
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4393360
- OpenAlex
- W2070614858
- Cited by
- 2,687
- References
- 51
- Citations by year
- 2026: 126 · 2025: 167 · 2024: 180 · 2023: 199 · 2022: 285 · 2021: 263 · 2020: 274 · 2019: 261 · 2018: 264 · 2017: 288 · 2016: 264 · 2015: 113 · 2014: 1 · 2013: 1
- FWCI
- 134.53
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- PMC
- Funders
- Howard Hughes Medical Institute
- National Institute of Mental Health (DP1MH100706)
- National Eye Institute (R01EY024259, P30EY012196)
- National Cancer Institute (R01CA133404, P01CA042063, P30CA014051, P30-CA-14051, P01 CA 42063)
- National Institute of General Medical Sciences (R01GM034277, T32GM008313, R01 GM34277, T32GM007753)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK097768)
- National Center for Chronic Disease Prevention and Health Promotion (5DP1-MH100706)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- SaCas9, SpCas9, CRISPR/Cas9, in vivo gene editing, adeno-associated virus delivery, PCSK9, cholesterol regulation, targeting specificity, single guide RNA
- MeSH terms
- Proprotein Convertase 9, Animals, Base Sequence, Cholesterol, Genetic Engineering, Liver, Male, Mice, Inbred C57BL, Serine Endopeptidases, Staphylococcus aureus, Substrate Specificity, Genome, Gene Targeting, Proprotein Convertases, Mice, CRISPR-Associated Proteins
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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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