Effect of Readthrough Treatment in Fibroblasts of XXXX Affected by Lysosomal Diseases Caused by Premature Termination Codons.

@entity1 @entity801 @entity14045 @entity5292
UNASSIGNED: @entity5292 antibiotics, such as @entity801 , may induce premature termination codon (PTC) readthrough and elude the nonsense-mediated mRNA decay mechanism. Because PTCs are frequently involved in lysosomal diseases, readthrough compounds may be useful as potential therapeutic agents. The aim of our study was to identify @entity1 responsive to @entity801 treatment in order to be used as positive controls to further screen for other PTC readthrough compounds. With this aim, fibroblasts from 11 @entity1 affected by 6 different lysosomal diseases carrying PTCs were treated with @entity801 . Treatment response was evaluated by measuring enzymatic activity, abnormal metabolite accumulation, mRNA expression, protein localization, and cell viability. The potential effect of readthrough was also analyzed by in silico predictions. Results showed that fibroblasts from 5/11 @entity1 exhibited an up to 3-fold increase of enzymatic activity after @entity801 treatment. Accordingly, cell lines tested showed enhanced well-localized protein and/or increased mRNA expression levels and/or reduced metabolite accumulation. Interestingly, these cell lines also showed increased enzymatic activity after @entity14045 treatment, which is a PTC readthrough-promoting compound. In conclusion, our results provide a proof-of-concept that PTCs can be effectively suppressed by readthrough drugs, with different efficiencies depending on the genetic context. The screening of new compounds with readthrough activity is a strategy that can be used to develop efficient therapies for diseases caused by PTC mutations.
