Design of Safe and Efficient Adenine Base Editors via Protein Language Model Screening for Osteoarthritis Treatment.

Base editors enable precise genome modification and have emerged as a promising therapeutic approach for correcting diseases caused by single-nucleotide variants. While the current efficient version of adenine base editors (ABEs), such as ABE8e, exhibits exceptional efficiency for A-to-G conversions, their clinical translation is hindered by persistent high off-target editing effects. Here, we applied artificial intelligence-assisted design a safe ABE variant, RDLot-ABE, with a narrow(4 nt) editing window and substantially lower DNA off-target editing activity compared to ABE8e. Moreover, targeted knockdown of Fscn1 for osteoarthritis treatment using RDLot-ABE alleviates cartilage degradation in explants derived from human patients. Notably, intra-articular delivery of the RDLot-ABE to reduce Fscn1 effectively arrests disease progression in a murine osteoarthritis model. These findings establish RDLot-ABE as a safe and precise tool, expanding the clinical potential of gene editing therapies.