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mRNA-specific readthrough of nonsense codons by antisense oligonucleotides (R-ASOs). | LitMetric

mRNA-specific readthrough of nonsense codons by antisense oligonucleotides (R-ASOs).

Nucleic Acids Res

RNA Therapeutics Institute, UMass Chan Medical School, 368 Plantation Street, Worcester, MA 01605, USA.

Published: August 2024

AI Article Synopsis

  • - Nonsense mutations, responsible for over 10% of human genetic disorders like cystic fibrosis and Duchenne muscular dystrophy, lead to truncated proteins, prompting the need for therapies that restore normal protein expression.
  • - Current therapeutic strategies often lack specificity, causing potential translation errors, while the study shows that antisense oligonucleotides can effectively promote readthrough of nonsense codons to produce full-length proteins.
  • - The efficiency of readthrough depends on the mRNA context near the stop codon and oligonucleotide targeting, leading to the development of modified readthrough-inducing antisense oligonucleotides (R-ASOs) that may enhance therapies for various genetic diseases.

Article Abstract

Nonsense mutations account for >10% of human genetic disorders, including cystic fibrosis, Alagille syndrome, and Duchenne muscular dystrophy. A nonsense mutation results in the expression of a truncated protein, and therapeutic strategies aim to restore full-length protein expression. Most strategies under development, including small-molecule aminoglycosides, suppressor tRNAs, or the targeted degradation of termination factors, lack mRNA target selectivity and may poorly differentiate between nonsense and normal stop codons, resulting in off-target translation errors. Here, we demonstrate that antisense oligonucleotides can stimulate readthrough of disease-causing nonsense codons, resulting in high yields of full-length protein in mammalian cellular lysate. Readthrough efficiency depends on the sequence context near the stop codon and on the precise targeting position of an oligonucleotide, whose interaction with mRNA inhibits peptide release to promote readthrough. Readthrough-inducing antisense oligonucleotides (R-ASOs) enhance the potency of non-specific readthrough agents, including aminoglycoside G418 and suppressor tRNA, enabling a path toward target-specific readthrough of nonsense mutations in CFTR, JAG1, DMD, BRCA1 and other mutant genes. Finally, through systematic chemical engineering, we identify heavily modified fully functional R-ASO variants, enabling future therapeutic development.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11347175PMC
http://dx.doi.org/10.1093/nar/gkae624DOI Listing

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