Tissue-restricted genome editing in vivo specified by microRNA-repressible anti-CRISPR proteins
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Abstract
CRISPR-Cas systems are bacterial adaptive immune pathways that have revolutionized biotechnology and biomedical applications. Despite the potential for human therapeutic development, there are many hurdles that must be overcome before its use in clinical settings. Some clinical safety concerns arise from editing activity in unintended cell types or tissues upon in vivo delivery (e.g., by adeno-associated virus (AAV) vectors). Although tissue-specific promoters and serotypes with tissue tropisms can be used, suitably compact promoters are not always available for desired cell types, and AAV tissue tropism specificities are not absolute. To reinforce tissue-specific editing, we exploited anti-CRISPR proteins (Acrs) that have evolved as natural countermeasures against CRISPR immunity. To inhibit Cas9 in all ancillary tissues without compromising editing in the target tissue, we established a flexible platform in which an Acr transgene is repressed by endogenous, tissue-specific microRNAs (miRNAs). We demonstrate that miRNAs regulate the expression of an Acr transgene bearing miRNA-binding sites in its 3′-UTR and control subsequent genome editing outcomes in a cell-type specific manner. We also show that the strategy is applicable to multiple Cas9 orthologs and their respective anti-CRISPRs. Furthermore, we validate this approach in vivo by demonstrating that AAV9 delivery of Nme2Cas9, along with an AcrIIC3 Nme construct that is targeted for repression by liver-specific miR-122, allows editing in the liver while repressing editing in an unintended tissue (heart muscle) in adult mice. This strategy provides safeguards against off-tissue genome editing by confining Cas9 activity to selected cell types.
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The risk of off-target gene editing of bystander cells can be mitigated by the addition of tissue- or cell-specific miR binding sites to the mRNA sequence, which results in tissue-specific suppression of mRNA translation.
“This risk can be mitigated by the addition of tissue- or cell-specific miR binding sites to the mRNA sequence, which results in tissue-specific suppression of mRNA translation (47, 48).”
From CRISPR-Cas9 genome editing using targeted lipid nanoparticles for cancer therapy (2020) · cites this paper as [48]
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- Authors
- Lee, J., Mou, H., Ibraheim, R., Liang, S.-Q., Liu, P., Xue, W., & Sontheimer, E. J.
- Affiliations
- University of Massachusetts Chan Medical School (US)
- Venue
- RNA
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2019-08-22
- Volume
- 25
- Issue
- 11
- Pages
- 1421-1431
- ISSN
- 1355-8382 (ISSN-L)
- 1469-9001
- PMC
- PMC6795140
- OpenAlex
- W2969305945
- Cited by
- 100
- References
- 64
- Citations by year
- 2026: 12 · 2025: 9 · 2024: 14 · 2023: 17 · 2022: 15 · 2021: 14 · 2020: 16 · 2019: 3
- FWCI
- 3.97
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- RNA (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- eScholarship@UMassChan (submittedVersion, cc-by-nc)
- HighWire Press Open Archive (submittedVersion)
- Funders
- National Institutes of Health (GM125797, DP2HL137167, UG3HL147367)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Keywords
- anti-CRISPR proteins, microRNA repression, CRISPR/Cas9, miR-122, gene therapy safety
- MeSH terms
- Gene Editing, RNA, Guide, CRISPR-Cas Systems, Dependovirus, Animals, Genetic Vectors, Humans, Promoter Regions, Genetic, Transgenes, MicroRNAs, Mice, HEK293 Cells, CRISPR-Cas Systems
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