Mini-dCas13X–mediated RNA editing restores dystrophin expression in a humanized mouse model of Duchenne muscular dystrophy
Open accessAbstract
Approximately 10% of monogenic diseases are caused by nonsense point mutations that generate premature termination codons (PTCs), resulting in a truncated protein and nonsense-mediated decay of the mutant mRNAs. Here, we demonstrate a mini-dCas13X-mediated RNA adenine base editing (mxABE) strategy to treat nonsense mutation-related monogenic diseases via A-to-G editing in a genetically humanized mouse model of Duchenne muscular dystrophy (DMD). Initially, we identified a nonsense point mutation (c.4174C>T, p.Gln1392*) in the DMD gene of a patient and validated its pathogenicity in humanized mice. In this model, mxABE packaged in a single adeno-associated virus (AAV) reached A-to-G editing rates up to 84% in vivo, at least 20-fold greater than rates reported in previous studies using other RNA editing modalities. Furthermore, mxABE restored robust expression of dystrophin protein to over 50% of WT levels by enabling PTC read-through in multiple muscle tissues. Importantly, systemic delivery of mxABE by AAV also rescued dystrophin expression to averages of 37%, 6%, and 54% of WT levels in the diaphragm, tibialis anterior, and heart muscle, respectively, as well as rescued muscle function. Our data strongly suggest that mxABE-based strategies may be a viable new treatment modality for DMD and other monogenic diseases.
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Cas13bt3's small size enables applications such as RNA base editing using a single AAV.
“The newfound enzyme has been reported to possess high specificity and its small size enables further applications such as RNA base editing using a single AAV (13–15).”
From Characterization of RNA editing and gene therapy with a compact CRISPR-Cas13 in the retina (2024) · cites this paper as [14]
The Results section says the hypercompact mxABE RNA base editor can be packaged in an AAV vector for in vivo delivery. But this paper studies a mini-dCas13X/Cas13X.1-based editor, not Cas13bt3, so it does not establish the claim about Cas13bt3’s size. (LLM, conf=0.84)
Experimental — accuracy not yet measuredCas13bt3 has been reported to possess high specificity.
“The newfound enzyme has been reported to possess high specificity and its small size enables further applications such as RNA base editing using a single AAV (13–15).”
From Characterization of RNA editing and gene therapy with a compact CRISPR-Cas13 in the retina (2024) · cites this paper as [14]
The Results sections report high editing specificity for mxABE, a mini-dCas13X–based editor, in cells and mice. Our copy does not address the specificity of Cas13bt3; a search for “Cas13bt3” found no passage about that enzyme. (LLM, conf=0.76)
Experimental — accuracy not yet measured
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- Authors
- Li, G., Jin, M., Li, Z., Xiao, Q., Lin, J., Yang, D., Liu, Y., Wang, X., Xie, L., Ying, W., Wang, H., Zuo, E., Shi, L., Wang, N., Chen, W., Xu, C., & Yang, H.
- Affiliations
- Chinese Academy of Sciences (CN)
- Fujian Medical University (CN)
- Agricultural Genomics Institute at Shenzhen (CN)
- Corresponding author
- Wang, Ning
- Xu, Chunlong
- Yang, Hui
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2023-02-01
- Volume
- 133
- Issue
- 3
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC9888377
- OpenAlex
- W4311253233
- Cited by
- 44
- References
- 22
- Citations by year
- 2026: 10 · 2025: 12 · 2024: 16 · 2023: 5 · 2022: 1
- FWCI
- 2.78
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal of Clinical Investigation (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (2021ZD0200900, XDB32060000, 31925016, 81870902, 82021001, 2018SHZDZX05, 31871502, 91957122)
- Chinese Academy of Sciences (2021ZD0200900, XDB32060000, 82021001, 153D31KYSB20170059, 2018SHZDZX05)
- National Science and Technology Major Project (2021ZD0200900)
- 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 › Molecular Biology › Muscle Physiology and Disorders
- Keywords
- Duchenne muscular dystrophy, A-to-I RNA editing, nonsense mutation, dystrophin expression, nonsense-mediated mRNA decay, AAV gene delivery, humanized mice
- MeSH terms
- Gene Editing, Animals, Disease Models, Animal, Humans, Genetic Therapy, Dystrophin, RNA Editing, Muscle, Skeletal, Muscular Dystrophy, Duchenne, Mice, CRISPR-Cas Systems
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