PTC124 is an orally bioavailable compound that promotes suppression of the human CFTR-G542X nonsense allele in a CF mouse model

被引:200
作者
Du, Ming [1 ,2 ]
Liu, Xiaoli [1 ,2 ]
Welch, Ellen M. [3 ]
Hirawat, Samit [3 ]
Peltz, Stuart W. [3 ]
Bedwell, David M. [1 ,2 ]
机构
[1] Univ Alabama Birmingham, Dept Microbiol, Birmingham, AL 35294 USA
[2] Univ Alabama Birmingham, Gregory Fleming James Cyst Fibrosis Res Ctr, Birmingham, AL 35294 USA
[3] PTC Therapeut Inc, S Plainfield, NJ 07080 USA
关键词
genetic diseases; readthrough; stop mutations; PREMATURE STOP MUTATIONS; MAMMALIAN TRANSLATION SYSTEM; CYSTIC-FIBROSIS; GENETIC-DISORDERS; GENTAMICIN; AMINOGLYCOSIDES; CONSEQUENCES; TERMINATION;
D O I
10.1073/pnas.0711795105
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Nonsense mutations inactivate gene function and are the underlying cause of a large percentage of the individual cases of many genetic disorders. PTC124 is an orally bioavailable compound that promotes readthrough of premature translation termination codons, suggesting that it may have the potential to treat genetic diseases caused by nonsense mutations. Using a mouse model for cystic fibrosis (CF), we show that s.c. injection or oral administration of PTC124 to Cftr-/- mice expressing a human CFTR-G542X transgene suppressed the G542X nonsense mutation and restored a significant amount of human (h)CFTR protein and function. Translational readthrough of the premature stop codon was demonstrated in this mouse model in two ways. First, immunofluorescence staining showed that PTC124 treatment resulted in the appearance of hCFTR protein at the apical surface of intestinal glands in Cftr-/- hCFTR-G542X mice. In addition, functional assays demonstrated that PTC124 treatment restored 24-29% of the average cAMP-stimulated transepithelial chloride currents observed in wild-type mice. These results indicate that PTC124 can effectively suppress the hCFTR-G542X nonsense mutation in vivo. In light of its oral bioavailability, safety toxicology profile in animal studies, and efficacy with other nonsense alleles, PTC124 has the potential to be an important therapeutic agent for the treatment of inherited diseases caused by nonsense mutations.
引用
收藏
页码:2064 / 2069
页数:6
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