Engineered APOBEC-PUF editors enabled C-to-U RNA editing with disease-relevant effects in mouse models.
Evidence
Preclinical RNA-editing platform experiments showed ProAPOBEC-PUF editing of Pcsk9 lowered cholesterol in mice and AAV brain editing corrected Mef2c mRNA mutations with phenotype improvement in an autism mouse model.
Caveat
The evidence is limited to mouse models, so human safety, delivery durability, and clinical efficacy remain untested.
Simplified
Base editing stands at the forefront of genetic engineering, heralding precise genetic modifications with broad implications. While CRISPR-based DNA and RNA base editing systems capitalize on sgRNA-guided specificity and diverse deaminase functionalities, the pursuit of efficient C-to-U RNA editing has been hampered by the inherent constraints of cytidine deaminases. Here, we report an RNA base editing platform by refining cytidine deaminases, termed professional APOBECs (), through systematic enhancements and AI-driven protein engineering. ProAPOBECs demonstrate unprecedented catalytic versatility, particularly fused with RNA-recognizing Pumilio and FBF (PUF) proteins. We demonstrate that in vivo RNA base editing of Pcsk9 using ProAPOBECs effectively lowers cholesterol levels in mice. Additionally, AAV-mediated RNA base editing with ProAPOBECs in the brain of an autism mouse model not only corrects point mutations in Mef2c mRNAs but also significantly alleviates disease-associated phenotypes. This work introduces a pioneering collection of RNA base editing instruments, emphasizing their therapeutic potential in combatting genetic disorders.
Key numbers
82.3%
Editing Efficiency Increase
Success rate of CU-REWIRE4.0 vs. CU-REWIRE3.0.
over 70%
Cholesterol Reduction
Reduction in cholesterol levels post -CU5.21 administration.
43%
Social Interaction Improvement
Editing efficiency on Mef2c mRNA in L35P mice.
Full Text
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CRISPR Gene Editing