A missense correcting tRNA therapy platform for genetic diseases

About This Grant

Project Abstract Among the thousands of genetic disorders in humans, most are rare and lack effective treatments. Suppressor tRNA therapy has come a long way to become a realistic treatment option for genetic diseases. Sup-tRNAs read through premature stop codons derived from genetic mutations in translation to generate full-length proteins. Compared to gene or mRNA-based therapies that deal with one gene or one mutation at a time and require safety and efficacy assessment for each therapeutic agent, a major advantage of tRNA therapy is the potential of using the same tRNA to treat many diseases that just share a common genetic mutation in many genes. However, about 30% of human genetic disorders are from missense mutations that cannot be treated with sup- tRNAs. For those disorders, missense-correcting tRNAs are needed which are charged with one amino acid but read the codon of another amino acid in translation. PI's lab has developed a missense-correcting tRNA identification platform and applied it to identify such tRNAs charged with Arg but read Gln/His/Trp/Cys codons which correspond to most frequent missense mutations in genetic disorders. Aim 1 will develop a high-throughput engineering platform for missense-correcting tRNAs that will be more efficient, and at the same time, less toxic to cells. We will screen tens of thousands of potential missense-correcting tRNAs simultaneously in cellular models. Aim 2 will screen for missense-correcting tRNA expression with reduced toxicity to cells. Our studies will establish a foundation for using missense-correcting tRNAs as a new therapeutic modality for rare diseases.