To investigate the potential of anticodon-edited transfer RNAs (ACE-tRNAs) to selectively suppress MECP2 nonsense mutations and restore full-length, functional MeCP2 protein in Rett syndrome.
Key Findings:
ACE-tRNAs promote efficient and dose-dependent readthrough of MECP2 nonsense mutations.
Readthrough efficiency varies among different nonsense mutations, with specific variants benefiting from ACE-tRNA optimization.
ACE-tRNA–rescued MeCP2 correctly localizes to heterochromatic foci and can recruit the transcriptional corepressor TBL1.
Scrambled control tRNAs did not restore nuclear localization or protein–protein interactions.
Interpretation:
ACE-tRNAs enable efficient and functionally relevant readthrough of MECP2 nonsense mutations, supporting a precision readthrough strategy for RTT.
Limitations:
Further in vivo validation and delivery optimization of ACE-tRNAs are required.
Conclusion:
ACE-tRNA-based readthrough represents a promising strategy for treating nonsense mutations associated with RTT.
