Duchenne muscular dystrophy(DMD)is a fatal X-chromosome-linked genetic disease caused by dystrophin gene mutations,including nonsense mutations.1 Nonsense mutations are caused by the introduction of premature terminat...Duchenne muscular dystrophy(DMD)is a fatal X-chromosome-linked genetic disease caused by dystrophin gene mutations,including nonsense mutations.1 Nonsense mutations are caused by the introduction of premature termination codons,which prevent translation of full-length proteins.Read-through therapies show potential for addressing DMD's genetic basis;however,issues such as non-specific amino acid insertions,gene-editing delivery challenges,and clinical safety concerns have limited their progress.2,3 To address nonsense mutations,nonsense suppressor transfer RNAs(sup-tRNAs)have been proposed as a genetic therapy approach.3,4,5 In this study,we propose a new MyoAAV-delivered suppressor tRNA(sup-tRNA)strategy to restore dystrophin expression.Our approach specifically targets nonsense mutations in mdx mice and patient-derived myoblasts and cardiomyocytes,significantly increasing dystrophin levels,especially in the heart(up to 61.43%when combined with CC-90009).This combination alleviates dystrophic symptoms and improves read-through efficiency,likely by reducing translation termination factor activity.These findings highlight the potential of sup-tRNA in DMD and other nonsense mutation-related diseases.展开更多
基金supported by the National Key Research and Development Program of China(No.2022YFC2703600)the National Natural Science Foundation of China(No.81930121).
文摘Duchenne muscular dystrophy(DMD)is a fatal X-chromosome-linked genetic disease caused by dystrophin gene mutations,including nonsense mutations.1 Nonsense mutations are caused by the introduction of premature termination codons,which prevent translation of full-length proteins.Read-through therapies show potential for addressing DMD's genetic basis;however,issues such as non-specific amino acid insertions,gene-editing delivery challenges,and clinical safety concerns have limited their progress.2,3 To address nonsense mutations,nonsense suppressor transfer RNAs(sup-tRNAs)have been proposed as a genetic therapy approach.3,4,5 In this study,we propose a new MyoAAV-delivered suppressor tRNA(sup-tRNA)strategy to restore dystrophin expression.Our approach specifically targets nonsense mutations in mdx mice and patient-derived myoblasts and cardiomyocytes,significantly increasing dystrophin levels,especially in the heart(up to 61.43%when combined with CC-90009).This combination alleviates dystrophic symptoms and improves read-through efficiency,likely by reducing translation termination factor activity.These findings highlight the potential of sup-tRNA in DMD and other nonsense mutation-related diseases.
