Suppressor tRNA gene therapy for nonsense mutations

Gene therapy delivering an engineered suppressor tRNA could help treat Mucopolysaccharidosis type 1 (MPS1), by enabling read-through of mRNA transcripts containing a disease-causing nonsense mutation in the IDUA gene. Seven natural tRNAs that have near-cognate pairing to the UAG stop codon and endogenously enable low levels of read-through were engineered to completely pair with UAG, and a cell-based screen for the ability to induce UAG stop codon rescue identified a tyrosine-bearing suppressive tRNA as the most effective construct.

In MPS1 patient fibroblasts, lentiviral delivery of the suppressor tRNA restored IDUA enzyme activity to 6% of wild-type levels; previous studies have shown enzyme activity levels as low as 0.5% of wild-type are associated with less severe disease in patients. ...