Background:

PTC124 is a selective inhibitor of nonsense mutations with IC50 value of 0.1μM [1].
Nonsense mutation is a point mutation in a sequence of DNA which promotes premature translational termination. Different from missense mutation, nonsense mutation means a single nucleotide is changed and results in the substitution of a different amino acid. It has been reported that some genetic disorders (thalassemia, DMD, CF, Hurler syndrome) are correlated with nonsense mutation [1, 2].
PTC124 is a potent nonsense mutations inhibitor. When tested with human or mdx mice primary muscle cells expressing dystrophin nonsense alleles, 2-8 weeks treatment of PTC124 enhanced the production of dystrophin [1]. In iPSC-derived RPE cells with nonsense mutation c.519C>T (p.R120X), PTC124 treatment restored endogenous, full-length RP2 protein with near 20% [3]. When tested with COS7 cells carrying the nonsense mutation pDsRed-EGFPmtag-Y445X, EGFP transcript level was increased after treated by PTC124 in a dose-dependent manner [2].
In mdx mice model, oral administration of PTC124 for 2-8 weeks rescued striated muscle function [1]. In a model of Cftr-/- mice expressing a human CFTR-G542X transgene, s.c. injection or oral administration of PTC124 restored a considerable amount of human (h) CFTR protein and function via suppressing G542X nonsense mutation [4].
参考文献:
[1].    Welch, E.M., et al., PTC124 targets genetic disorders caused by nonsense mutations. Nature, 2007. 447(7140): p. 87-91.
[2].    Shen, Q., P. Guo, and B. Chai, pDsRed-EGFPmtag-, an effective dual fluorescent reporter system for cell-based screens of premature termination codon. Cytotechnology, 2014.
[3].    Schwarz, N., et al., Translational read-through of the RP2 Arg120stop mutation in patient iPSC-derived retinal pigment epithelium cells. Hum Mol Genet, 2015. 24(4): p. 972-86.
[4].    Du, M., et al., PTC124 is an orally bioavailable compound that promotes suppression of the human CFTR-G542X nonsense allele in a CF mouse model. Proc Natl Acad Sci U S A, 2008. 105(6): p. 2064-9.