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Engineered tRNAs suppress nonsense mutations in cells and in vivo

ABSTRACT: we introduce a strategy to repurpose sense-codon decoding tRNA into efficient suppressors of the three nonsense mutation-induced PTCs (UGA, UAG and UAA). The suppressor tRNAs restore function of a model and disease-related protein

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE191048 | GEO | 2023/04/04

REPOSITORIES: GEO

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Project description:Nonsense mutations are the underlying cause of approximately 11% of all inherited genetic diseases1. Nonsense mutations convert a sense codon that is decoded by tRNA into a premature termination codon (PTC), resulting in an abrupt termination of translation. One strategy to suppress nonsense mutations is to use natural tRNAs with altered anticodons to base-pair to the newly emerged PTC and promote translation2-7. However, tRNA-based gene therapy has not yielded an optimal combination of clinical efficacy and safety and there is presently no treatment for individuals with nonsense mutations. Here we introduce a strategy based on altering native tRNAs into efficient suppressor tRNAs (sup-tRNAs) by individually fine-tuning their sequence to the physico-chemical properties of the amino acid that they carry. Intravenous and intratracheal lipid nanoparticle (LNP) administration of sup-tRNA in mice restored the production of functional proteins with nonsense mutations. LNP-sup-tRNA formulations caused no discernible readthrough at endogenous native stop codons, as determined by ribosome profiling. At clinically important PTCs in the cystic fibrosis transmembrane conductance regulator gene (CFTR), the sup-tRNAs re-established expression and function in cell systems and patient-derived nasal epithelia and restored airway volume homeostasis. These results provide a framework for the development of tRNA-based therapies with a high molecular safety profile and high efficacy in targeted PTC suppression.

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Project description:We constructed the trans/mdx mice as a novel DMD disease model by crossing transgenic mice and mdx mice. The transgenic and trans/mdx mice have UAA incorporation system that can readthrough the nonsense mutation in the dmd gene with additional UAA. The whole transcriptomics of heart and muscle tissues of 5 mouse groups (n=2) were used to determine whether the introduced UAA incorporation system affect the normal gene expression of mice, or the safety of the system. Groups include: a) wild-type C57BL/6N mice; b) transgenic mice; c) mdx mice; d) trans/mdx mice without UAA; e) trans/mdx mice with UAA (50 mg NAEK every 2-3 day, treated for 4 weeks). The total numbers of expressed genes were around 11,000 in all 5 mouse groups. The expression levels of major genes (logFPKM>0) in 5 mouse groups were also close to each other. These data indicated that the UAA incorporation system was safe and could serve as a potential therapeutic strategy for DMD disease. The transgenic mice with UAA incorporation system we constructed could also cross with other nonsense mutation mice to build more functional animal models.

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