could PTC124 help with primary trimethylaminuria due to a nonsense mutation ?

As mentioned in the post about the Australian trimethylaminuria research proposal, one of the two proposed experimental treatments for trimethylaminuria is using the drug PTC124 (to be marketed as Ataluren), in cases where the person has primary trimethylaminuria due to a nonsense mutation of the FMO3 enzyme. Nonsense mutations instruct the developing protein (in this case FMO3 protein) to prematurely stop, and in effect abort the development. Nonsense mutations are also known as 'stop codons'. PCT124 (along with some antibiotics which have already been shown to have the same effect, but have side effects) has been claimed to overrule If it was of benefit, it would only be expected to work in a trimethylaminuria sufferer who had primary trimethylaminuria due to a nonsense mutationany nonsense mutation premature stop, and so allow whatever protein that was developing (in trimethylaminuria ; FMO3 enzyme) to fully develop. It must be presumed they expect more protein to develop only to a certain degree (i.e. they don't expect function to become 100%, but perhaps increase the level by 5% or more).

At the moment PTC124 is not available, except for research purposes (so if anyone knew any trimethylaminuria experts, they would be able to use it in research). It is being used in trials for muscular dystrophy and soon in cystic fibrosis. It seems it could get FDA approval in 2010 or shortly thereafter, assuming all goes well in the final trials. In mice and in a small group of human trialists, there seems to be no side effects except apart from upset stomach in a few. The toxicology data looks very promising. It is taken orally as a powder, for instance in water or fruit juice. If it was of benefit, it would only be expected to work in a trimethylaminuria sufferer who had primary trimethylaminuria due to a nonsense mutation. Offhand, it's not known how many have this type of mutation in FMO3. In some other illnesses (it's expected it could work in all genetic disorders due to nonsense mutations), the % due to a nonsense mutation can be anything from 5% to 70%. Perhaps someone could find out how many FMO3 mutations are regarded as being due to nonsense mutations.

At the moment the final phase of the muscular dystrophy trial is underway, and now Dr Christodoulou proposes to trial it for trimethylaminuria too, as other researchers are free to do so as well. It's remarkable that a drug may soon be available that can improve enzyme function in genetic cases.

More posts will follow about PCT124. in the meantime, here are some links about it:

PTC therapeutics webpage for PTC124/Ataluren
PTC124/Ataluren FAQs
PTC124 clinical trials

dailymail.co.uk article: Simple-powder to beat 400+ genetic disorders
www.muscular-dystrophy.org : latest on PTC124 trials
www.sciencentral.com: 2007 interview with PTC therapeutics President


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