ArticleMolecular therapy : the journal of the American Society of Gene Therapy2022
Versatile and efficient in vivo genome editing with compact Streptococcus pasteurianus Cas9.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 27 citations in OpenAlex.
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- Gene editing therapy as a therapeutic approach for cardiovascular diseases in animal models: A scoping review.PloS one · 2025Article
- All-in-one AAV-mediated Nrl gene inactivation rescues retinal degeneration in Pde6a mice.JCI insight · 2024Article
- Gene editing therapy for cardiovascular diseases.MedComm · 2024Review
- Engineering of a compact, high-fidelity EbCas12a variant that can be packaged with its crRNA into an all-in-one AAV vector delivery system.PLoS biology · 2024Article
- Precise large-fragment deletions in mammalian cells and mice generated by dCas9-controlled CRISPR/Cas3.Science advances · 2024Article
- Targeted mutagenesis in mice via an engineered AsCas12f1 system.Cellular and molecular life sciences : CMLS · 2024Article
- Advances in Recombinant Adeno-Associated Virus Vectors for Neurodegenerative Diseases.Biomedicines · 2023Review
- A strategy for Cas13 miniaturization based on the structure and AlphaFold.Nature communications · 2023Article
- Massively parallel evaluation and computational prediction of the activities and specificities of 17 small Cas9s.Nature methods · 2023Article
- Characterization of CoCas9 nuclease fromRNA biology · 2023Article
- Versatile and efficient genome editing with Neisseria cinerea Cas9.Communications biology · 2022Article
- Contribution of CRISPRable DNA to human complex traits.Communications biology · 2022Review
- CRISPR Modeling and Correction of Cardiovascular Disease.Circulation research · 2022Review
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Compact CRISPR-Cas9 systems that can be packaged into an adeno-associated virus (AAV) show promise for gene therapy. However, the requirement of protospacer adjacent motifs (PAMs) restricts the target scope. To expand this repertoire, we revisited and optimized a small Cas9 ortholog derived from Streptococcus pasteurianus (SpaCas9) for efficient genome editing in vivo. We found that SpaCas9 enables potent targeting of 5'-NNGYRA-3' PAMs, which are distinct from those recognized by currently used small Cas9s; the Spa-cytosine base editor (CBE) and Spa-adenine base editor (ABE) systems efficiently generated robust C-to-T and A-to-G conversions both in vitro and in vivo. In addition, by exploiting natural variation in the PAM-interacting domain, we engineered three SpaCas9 variants to further expand the targeting scope of compact Cas9 systems. Moreover, mutant mice with efficient disruption of the Tyr gene were successfully generated by microinjection of SpaCas9 mRNA and the corresponding single guide RNA (sgRNA) into zygotes. Notably, all-in-one AAV delivery of SpaCas9 targeting the Pcsk9 gene in adult mouse liver produced efficient genome-editing events and reduced its serum cholesterol. Thus, with distinct PAMs and a small size, SpaCas9 will broaden the CRISPR-Cas9 toolsets for efficient gene modifications and therapeutic applications.
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