Ataluren as an Agent for Therapeutic Nonsense Suppression

Abstract

The interplay of translation and mRNA turnover has helped unveil how the regulation of gene expression is a continuum in which events that occur during the “birth” of a transcript in the nucleus can have profound effects on subsequent steps in the cytoplasm. Exemplifying this continuum is nonsense-mediated mRNA decay (NMD), the process wherein a premature stop codon affects both translation and mRNA decay. Studies of NMD helped lead us to the therapeutic concept of treating a subset of patients suffering from multiple genetic disorders due to nonsense mutations with a single small molecule drug that modulates the translation termination process at a premature nonsense codon. Here we review both translation termination and NMD, and our subsequent efforts over the last fifteen years that led to the identification, characterization, and clinical testing of ataluren, a new therapeutic with the potential to treat a broad range of genetic disorders due to nonsense mutations.

Disease-proportional proteasomal degradation of missense dystrophins

“…In addition to potentially lacking functional domains, internally truncated dystrophin has been shown to be thermally unstable in vitro (55), and BMD patients often present with a decreased abundance of dystrophin (56). In addition, small-molecule stabilizers of misfolded dystrophin or targeted E3 ligase inhibition may also be useful adjuvants to other personalized therapies dependent on the functionality of sequencealtered dystrophins such as exon-skipping (15), virus-based gene therapy (57,58) and stop codon read-through drugs (14). Therefore, development of any therapy that stabilizes and/or prevents degradation of misfolded dystrophin could potentially benefit the DMD patient community as a whole.…”

“…The types of mutations causing DMD and BMD include insertions, deletions, point mutations, and splice site mutations (12). A recent collaborative data bank has calculated that patients with nonsense mutations account for ∼10% of dystrophinopathies (13), all of whom are the target population for stop codon read-through therapies (14). Patients with small insertions or deletions (indels) represent ∼7% of the total DMD/ BMD population (13).…”

Ataluren stimulates ribosomal selection of near-cognate tRNAs to promote nonsense suppression

“…nonsense suppression | readthrough | Translarna | base mispairing N onsense mutations are responsible for ∼10-15% of the singlebase-pair mutations that cause human disease, with some disease genes having considerably higher nonsense mutation frequencies (1). Patients with genetic disorders attributable to nonsense mutations tend to have more serious ramifications than those with missense mutations, presumably because of marked reductions in specific gene expression.…”

“…Patients with genetic disorders attributable to nonsense mutations tend to have more serious ramifications than those with missense mutations, presumably because of marked reductions in specific gene expression. Because all diseases caused by nonsense mutations share the same key gene expression problems, namely premature translation termination and accelerated mRNA decay, therapeutic approaches to these problems are being investigated, with the understanding that a single drug has the potential to treat a large number of different disorders (1,2). Normally, the in-frame UAG, UAA, and UGA codons that arise in mRNA from nonsense mutations serve as signals for translation termination, but this role can be functionally overridden by alterations in the translation machinery or by the presence of certain small molecules that compromise the fidelity of translation termination (1,2).…”

“…Because all diseases caused by nonsense mutations share the same key gene expression problems, namely premature translation termination and accelerated mRNA decay, therapeutic approaches to these problems are being investigated, with the understanding that a single drug has the potential to treat a large number of different disorders (1,2). Normally, the in-frame UAG, UAA, and UGA codons that arise in mRNA from nonsense mutations serve as signals for translation termination, but this role can be functionally overridden by alterations in the translation machinery or by the presence of certain small molecules that compromise the fidelity of translation termination (1,2). Such nonsense suppression, or nonsense codon readthrough, by a ribosome engaged in peptide elongation has been predominantly observed in the context of premature termination codons (PTCs) and is thought to reflect ribosomal A site acceptance of a near-cognate tRNA and subsequent incorporation of an amino acid into the nascent polypeptide at the position of the PTC (1,2).…”