Nonsense mutation disorders – ataluren


An orally available drug may hold out some hope for patients suffering from conditions caused by genetic nonsense mutations

Several genetic disorders, including Duchenne muscular dystrophy and cystic fibrosis, can result from genetic nonsense mutations. These are single point mutations that create an erroneous ‘stop’ codon too early in the transcribed messenger RNA sequence, leading to proteins that are truncated or do not work properly being formed.

>p>If it were possible to skip these premature stop codons, it may lead to the synthesis of the protein to be carried out correctly. Even at a low level, this might have a dramatic impact on diseases caused by these mutations.

US biotech PTC Therapeutics has developed an orally available drug, ataluren, that may suppress these diseases by enabling the ribosomal read-through of the premature stop codons.1 There is some debate about its activity, but in diseases of such great unmet need, it represents a glimmer of hope.



Following successful Phase I studies in healthy volunteers,2 its effectiveness has been assessed in several nonsense mutation disorders, including cystic fibrosis. In one Phase II trial, a total of 44 patients with cystic fibrosis and at least one nonsense mutation in the CFTR gene were given either 16mg/kg or 40mg/kg of the drug in three doses every day for 14 days, followed by 14 days without treatment.3 Total chloride transport reached the normal range for 13 of 23 patients in the 16mg/kg dosage group during the treatment phase, and for nine of 21 with the higher dose.

In a longer term trial, 19 subjects were given thrice daily in doses of 4, 4 and 8mg/kg or 10, 10 and 20mg/kg for 12 weeks.4 The two dose levels had comparable activity in the improvement of total chloride transport, and CFTR function improved over time, with accompanying improvements in pulmonary function and coughing related to the disease.

A randomised, double-blind, placebo-controlled Phase III trial has also been carried out; 238 patients with nonsense mutation cystic fibrosis were given three daily doses of 10, 10 and 20mg or placebo for 48 weeks.5 While the forced expiratory volume in 1s measurements was not significantly different between the two groups, in those not also taking chronic inhaled tobramycin there was a slight improvement over those that were, and there were fewer pulmonary exacerbations. It was generally well tolerated.

Trials have also been carried out in Duchenne muscular dystrophy, where about an eighth of boys with the condition have a nonsense mutation in the dystrophin gene.

In a Phase IIa open label, sequential dose ranging trial, 38 boys with this form of the disease, were given three daily doses of either 4, 4 and 8mg/kg, 10, 10 and 20mg/kg or 20, 20 and 40mg/kg for 28 days.6 In all 23 of the patients had an increase in dystrophin expression after treatment.


1. E.M. Welch et al. Nature 2007, 447, 87

2. S. Hirawat et al. J. Clin. Pharmacol. 2007, 47, 430

3. E. Kerem et al. Lancet 2008, 372, 719

4. M. Wilschanski et al. Eur. Respir. J. 2011, 38, 59

5. E. Kerem et al. Lancet Respir. Med. 2014, 2, 539

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6. R.S. Finkel et al. PLoS One 2013, 8, e81302