Abstract
Around 12% of hereditary disease-causing mutations are in-frame nonsense mutations. The expression of genes containing nonsense mutations potentially leads to the production of truncated proteins with residual or virtually no function. However, the translation of transcripts containing premature stop codons resulting in full-length protein expression can be achieved using readthrough agents. Among them, only ataluren was approved in several countries to treat nonsense mutation Duchenne muscular dystrophy (DMD) patients. This review summarizes ataluren’s journey from its identification, via first in vitro activity experiments, to clinical trials in DMD, cystic fibrosis, and aniridia. Additionally, data on its pharmacokinetics and mechanism of action are presented. The range of diseases with underlying nonsense mutations is described for which ataluren therapy seems to be promising. What is more, experiments in which ataluren did not show its readthrough activity are also included, and reasons for their failures are discussed.
Highlights
The underlying cause of a large number of human diseases is the presence of nonsense mutations in the corresponding disease genes e.g., many cases of cystic fibrosis (CF), Duchenne muscular dystrophy (DMD), or Usher syndrome [1,2]
As previous studies with gentamicin showed that induced readthrough of a nonsense mutation in rhodopsin was enough to slightly improve retinal function, the observed two times greater efficiency of PTC124 suggests that PTC124 treatment should be efficient enough to combat retinal degeneration in USH1 patients
Four-day ataluren treatment (2.8 and 8.5 μg/mL) of a lymphoblastoid cell line derived from ataxia-telangiectasia patients with AT153LA (TGA-A), homozygous ATM nonsense mutation resulted in an increase in the ATM kinase activity
Summary
The underlying cause of a large number of human diseases is the presence of nonsense mutations in the corresponding disease genes e.g., many cases of cystic fibrosis (CF), Duchenne muscular dystrophy (DMD), or Usher syndrome [1,2]. The adverse side effects limit their potential clinical uses Molecules such as amlexanox and escin readthrough premature stop codons but inhibit nonsense-mediated decay (NMD) of mRNA [9]. Translarna’s application for marketing authorization to treat cystic fibrosis was withdrawn, as the primary endpoint of the phase 3 study was not met To date, this is the first extensive review summarizing the journey of ataluren from its identification via in vitro experiments and clinical trials in DMD, CF, and aniridia to approved therapeutic use in DMD. The review covers ataluren’s pharmacokinetics and mechanism of action including the most recent reports Results of both successful and unsuccessful readthrough experiments involving models of a wide range of diseases with underlying nonsense mutations are discussed.
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