This research article introduces CU-REWIRE5, a pioneering RNA base editing platform that utilizes AI-assisted protein engineering to achieve precise genetic modifications. By fusing programmable PUF proteins with engineered cytidine deaminases called ProAPOBECs, the researchers expanded the targeting range to include previously difficult sequence contexts like GC, CC, and AC motifs. The study demonstrates the platform’s therapeutic potential by effectively lowering cholesterol levels in mice and reversing autistic-like behaviors in a disease model. Unlike permanent DNA editing, this AAV-mediated RNA approach offers a transient and potentially safer alternative for treating genetic disorders without inducing genomic mutations. The authors emphasize that these structural optimizations significantly minimize off-target effects while maintaining high catalytic efficiency in vivo. Use of AlphaFold2 was instrumental in predicting functional hybrid enzymes, marking a significant advancement in modular biotechnology for precision medicine.

References:

• Han W, Yuan B, Fan X, et al. Effective in vivo RNA base editing via engineered cytidine deaminase APOBECs fused with PUF proteins[J]. Nature Communications, 2025, 16(1): 9727.