Aminoglycosides and ataluren represent a targeted therapeutic strategy in clinical testing for Duchenne/Becker muscular dystrophy caused by nonsense mutations.
Nucleotide changes within an exon can alter the trinucleotide normally encoding a particular amino acid, such that a new ''stop'' signal is transcribed into the mRNA open reading frame. This causes the ribosome to prematurely terminate its reading of the mRNA, leading to nonsense-mediated decay of the transcript and lack of production of a normal full-length protein. Such premature termination codon mutations occur in an estimated 10% to 15% of many genetically based disorders, including Duchenne/Becker muscular dystrophy. Therapeutic strategies have been developed to induce ribosomal read-through of nonsense mutations in mRNA and allow production of a full-length functional protein. Small-molecule drugs (aminoglycosides and ataluren PTC124) have been developed and are in clinical testing in patients with nonsense mutations within the dystrophin gene. Use of nonsense mutation suppression in Duchenne/Becker muscular dystrophy may offer the prospect of targeting the specific mutation causing the disease and correcting the fundamental pathophysiology.
Richard S. Finkel (Wed,) studied this question.