All genes contain a stop and start codon so that the machinery which translates the instructions encoding a protein knows where to start and stop reading. According to the TREAT-NMD DMD global database, about 10-15% of DMD patients are affected by a nonsense stop codon mutation. This is where a stop codon is inserted into the middle of the gene, preventing complete readthrough of instructions so resulting in an incomplete dystrophin protein. Readthrough therapy can recognise a mutated stop signal which differs from the normal stop signal found at the end of a gene. This therapy aims to encourage the cell to ignore the stop codon and allow correct readthrough of the genetic instructions to produce a functional version of the dystrophin protein. Like exon-skipping treatments, read-through drugs require repeated administration for therapeutic benefit.
Aminoglycoside antibiotics (e.g. Gentamicin) interact with ribosomes to interrupt protein synthesis and allow the correct readthrough of protein encoding instructions. Ribosomes can then add amino acids at the point of the stop-codon mutation. So far, Gentamicin hasn’t shown much success in terms of efficacy, however the same concept is being developed for other aminoglycosides. Their side effects and the need for intravenous administration could restrict their use clinically.
Ataluren (Translarna) is an oral agent being developed by PTC therapeutics which acts on ribosomes, similarly to aminoglycosides, without the toxic side effects. In studies it has been shown to produce full length dystrophin in mdx mouse models and could stabilize disease progression as seen in improved results in the distance that boys with Duchenne could walk in 6 minutes in a Phase 2b trial. Ataluren is approved for treatment of ambulant Duchenne patients 5 years and older in Europe by the European Medicines Agency.
Through producing the full length dystrophin protein it acts to establish links between the inside and outside of the cell to stabilize the muscle. It is currently in Phase 3 trial, with PTC Therapeutics hopeful that these results will confirm those of the previous Phase 2b trial.
