ArticleMolecular therapy : the journal of the American Society of Gene Therapy2024
Engineered mischarged transfer RNAs for correcting pathogenic missense mutations.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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21 citing papers in PubMed, 26 citations in OpenAlex.
- Mistranslation from an endogenous tRNA variant in human pan-genome cell lines.Nucleic acids research · 2026Article
- Mistranslating tRNA variants impact the proteome and phosphoproteome of Saccharomyces cerevisiae.G3 (Bethesda, Md.) · 2026Article
- An engineered UGA suppressor tRNA gene for disease-agnostic AAV delivery.Nature biotechnology · 2026Article
- Mistranslating tRNA variants impact the proteome and phosphoproteome ofbioRxiv : the preprint server for biology · 2025Article
- Calpainopathy (limb-girdle muscular dystrophy type R1): clinical features, diagnostic approaches, and biotechnological treatment methods.Journal of neuromuscular diseases · 2025Review
- An engineered glutamic acid tRNA for efficient suppression of pathogenic nonsense mutations.Nucleic acids research · 2025Article
- Natural human tRNARNA (New York, N.Y.) · 2025Article
- Specific branches of the proteostasis network regulate the toxicity associated with mistranslation.Nucleic acids research · 2025Article
- Serine mistranslation induces the integrated stress response through the P stalk.The Journal of biological chemistry · 2025Article
- Deciphering shared molecular dysregulation across Parkinson's disease variants using a multi-modal network-based data integration and analysis.NPJ Parkinson's disease · 2025Article
- Glutamine missense suppressor transfer RNAs inhibit polyglutamine aggregation.Molecular therapy. Nucleic acids · 2025Article
- Exploring the therapeutic potential of modulating nonsense-mediated mRNA decay.RNA (New York, N.Y.) · 2025Review
- Human TRMT1 and TRMT1L paralogs ensure the proper modification state, stability, and function of tRNAs.Cell reports · 2025Article
- Efficient suppression of premature termination codons with alanine by engineered chimeric pyrrolysine tRNAs.Nucleic acids research · 2024Article
- Impact of tRNA-induced proline-to-serine mistranslation on the transcriptome of Drosophila melanogaster.G3 (Bethesda, Md.) · 2024Article
- Core myopathy in two siblings with a biallelic variant in the CACNA1S gene-A case series study.Clinical case reports · 2024Article
- Mechanisms and Delivery of tRNA Therapeutics.Chemical reviews · 2024Review
- Impact of tRNA-induced proline-to-serine mistranslation on the transcriptome ofbioRxiv : the preprint server for biology · 2024Article
- Missense suppressor tRNA therapeutics correct disease-causing alleles by misreading the genetic code.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
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11 authors at 3 institutions in 1 country.
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Abstract
Missense mutations account for approximately 50% of pathogenic mutations in human genetic diseases, and most lack effective treatments. Gene therapies, gene editing, and RNA therapies, including transfer RNA (tRNA) modalities, are common strategies for genetic disease treatments. However, reported tRNA therapies are for nonsense mutations only. It has not been explored how tRNAs can be engineered to correct missense mutations. Here, we describe missense-correcting tRNAs (mc-tRNAs) as a potential therapeutic for correcting pathogenic missense mutations. Mc-tRNAs are engineered tRNAs charged with one amino acid, but read codons of another in translation. We first developed a series of fluorescent protein-based reporters that indicate the successful correction of missense mutations via restoration of fluorescence. We engineered mc-tRNAs that effectively corrected serine and arginine missense mutations in the reporters and confirmed the amino acid substitution by mass spectrometry and mc-tRNA expression by sequencing. We examined the transcriptome response to mc-tRNA expression and found some mc-tRNAs induced minimum transcriptomic changes. Furthermore, we applied an mc-tRNA to rescue a pathogenic CAPN3 Arg-to-Gln mutant involved in LGMD2A. These results establish a versatile pipeline for mc-tRNA engineering and demonstrate the potential of mc-tRNA as an alternative therapeutic platform for the treatment of genetic disorders.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.