Could PTC124 be used in other trimethylaminuria trials ?

PTC124 (to be marketed as Ataluren) is currently not available to the public (although it has been fast-tracked by the FDA and approval could be as near as 2010). However it is available to researchers, and so if anyone had any influence over any fmo3/TMAU researchers, it could be used in research. It seems to be anticipated to possibly of benefit in any genetic disorder due to a nonsense mutation. Dr Christodoulou's research proposal, in which he says "No new approaches to the treatment of trimethylaminuria have been developed in recent decades" (aside from the diet, low PH soapwashes etc), is a reasonable summary of the research previous and forthcoming that has been devoted to this issue, aside from his own research proposal. It is tragically a neglected and probably quite common disorder, but falls between all the criteria that usually stimulate research ("not serious enough", "not common enough", "the protocol is enough", "they only smell of fish and transiently", "no doctor reports cases", "family can monitor the problem" etc).

With regards PTC124 and trimethlyaminuria, possibly the 3 questions at this stage would be:

1. Can primary trimethylaminuria be caused by genetic nonsense mutations; and if so, how many ?
2. What researchers may be interested and who would fund them ?
3. Would PCT124 trials for TMAU need to start at the 'in vitro' or 'mouse model' stage. or could it be trialled on humans with TMAU straight away ?

Can primary trimethylaminuria be caused by nonsense genetic mutations and if so, how many ?
Yes it can, including severe cases. Hopefully someone knows the statistics (what % etc), but nonsense mutations (stop codons) have been documented as causing even severe cases.
Perhaps Dr Christodoulou's research was inspired by this paper from 1998:
Mutations of the flavin-containing monooxygenase gene (FMO3) cause trimethylaminuria, a defect in detoxication
There are also other documented 'nonsense mutation' cases
Arg500Stop and/or Cys197Stop have been shown to be severe nonsense mutations : http://www.ncbi.nlm.nih.gov/pubmed/17584019
This 2005 paper says only 3 of the 28 known mutations are nonsense, but it's not known how accurate this is : http://www.ncbi.nlm.nih.gov/pubmed/15975041
Another example : Trimethylaminuria is caused by mutations of the FMO3 gene in a North American cohort

It's not known if a worldwide accurate database of FMO3 mutations is kept (including variant genes), although one was published as being available online here, although it often seems to be offline.
http://www.ncbi.nlm.nih.gov/pubmed/12938085

Perhaps Dr Christodoulou's year 1 aims in his proposal will turn out to be the gold standard in FMO3 genetic and phenotype testing. Or it may just be as a gold standard for the Australian Health system.

1. To develop comprehensive biochemical screening for trimethylaminuria

Previous methods have used an HPLC approach to quantitated trimethylamine in urine samples. This is a labour intensive method that has the added disadvantage that it does not easily lend itself to the quantitation of trimethylamine-N-oxide as well. We plan to use a mass spectrophotometric approach similar to that described by Johnson²⁰. Co-chief investigator, Kevin Carpenter, head of the NSW Biochemical Genetics Service based at the Children’s Hospital at Westmead, is an international authority on the use of mass spectrometric techniques in the diagnosis of inborn errors of metabolism. He will oversee the development of the new more complete biochemical testing for TMAU. We have urine samples from patients with TMAU already in storage, and these will be used as positive controls for the development phase. This new testing procedure, coupled with a marine fish or choline load as needed¹, will provide a very powerful means for diagnosis of the majority of TMAU patients.

1. To develop complete molecular genetic screening of the FMO3 gene for individuals suspected of having trimethylaminuria.

John Christodoulou has nearly two decades of experience in the analysis of gene mutations, and his research laboratory has all of the facilities to be able to develop comprehensive mutation testing of the FMO3 gene. Once this testing has been developed to a robust stage, the methodology will be transferred to the molecular genetics diagnostic laboratory at the Children’s Hospital at Westmead, for which he is the administrative head, and so will be available as a routine diagnostic test on referral by clinicians in Australasia.

2. What researchers may be interested, and who would fund them ?

An ideal situation for a problem like metabolic body odor and/or halitosis would be for a government set up an International Body Odor and Halitosis Research center and clinic, and then the researchers would be getting their instructions and funds from politicians, with a clear aim. Unfortunately, while a smell and taste clinic has been set up for disorders of those senses, no such clinic was set up for what many may consider a more 'serious' disorder, both on the person and on the economy.

Very few researchers have been 'actively' involved in FMO3/TMAU research, and even then it's mostly 'pediatricians' or others who have other important duties, with perhaps FMO3/TMAU being regarded as not so important. Also, when FMO3 DNA was first discovered, there was a surge of interest by these researchers over a decade or so, whereas now it seems to have tailed off as a phenomenom (or so it seems). There were 2 TMAU conferences (1999 and 2002), with none scheduled for the future.

Dr Cashman at the HBRI institute is possibly the world expert in FMO3 genetics, but as his website says:

HBRI currently receives no funding for its TMAU program other than through donations. The program is quite expensive to maintain but we beleive that this important research should be continued.

http://www.hbri.org/TMAuria.htm

So it seems an (much appreciated) act of mercy outwith the normal medical system.

Dr Fennessey of University of Colorado Denver Health Sciences Center is the other great pioneer in TMAU in the USA, and allows phenotype testing as an act of mercy too (currently unavailable).However, it is unlikley any further TMAU research will be published by him in the near future (he has a pediatric background).

Two of the recent interesting FMO3/TMAU papers were likely sourced either by HBRI or Dr Fennessey's lab, but possibly as part of someones qualification program. Perhaps TMAU was suggested to them as an act of pity. This 2009 paper was led by 'Motika MS' at HBRI http://www.ncbi.nlm.nih.gov/pubmed/19321370; and this 2008 paper, which was an important case study which won't be followed up (the abstract finishes with "These results indicate that further experiments are needed to further delineate the full mutational spectrum of the FMO3 gene") is possibly linked to Dr Fennessey (the person seemed to have an association there) : Genotypic spectrum and genotype-phenotype correlation of trimethylaminuria

Elsewhere worldwide, the picture is just as grim. Montreal Children's Hospital seems to have a history of TMAU research, possibly due to the term of Dr Eileen Treacey there. in the UK, there was much research in the 1990's by Dr Stephen Mitchell at Imperial College London, and Phillips and Shephard still do some FMO research.

However, Dr Christodoulou's proposal seems to be the most promising research into trimethylaminuria for a long time, and makes you wonder what could be achieved if someone was working solely on solving metabolic body odor ? Of the PCT124 idea, possibly Dr Cashman or Dr Fennessey would be good first contacts. Others with previous papers in FMO3/TMAU include Dr Sharon Krueger at The Linus Pauling Institute, who seems to be one of the few (if any) fulltime FMO3 researchers, and Dr Ronald Hines at Medical College of Wisconsin.

Funding and volunteers

Normally researchers will try the NIH first. As for voluntary groups, The Muscular Dystrophy Association is an example to all, in its ability to raise funds. It's a charitable non-governmental organisation that has raised millions over decades, for research purposes, and funded the research that discovered the gene responsible for muscular dystophy. With trimethylaminuria as the example of metabolic body odor, it's estimated perhaps 1% could be at risk, or maybe even more (given that almost all seem transient, and the 'mild' cases seem to be the most common). So it is likely there is money out there if tapped into. Currently trimethylaminuria is included in the NORD group of rare disorders. However, it is unclear in this online process how to make sure the money goes to the TMAU fund in particular, which may put people off donating. But NORD is a well run charity and has a lot of influence. In the UK, the Wellcome Trust has been known to fund much research into TMAU/FMO3 in the past.

As for volunteers (with nonsense mutations), there are plenty on the forums listed above. There is also the TMAU Foundation in New York.

And Maria (Mpdela) could be contacted here by email at mpdela1@gmail.com

3. Would PCT124 trials for TMAU need to start at the 'in vitro' or 'mouse model' stage. or could it be trialled on humans with TMAU straight away ?
Not knowing the details of general medical trials, it's not possible to comment on this authoritatively. Possibly Dr Christodoulou is perhaps setting the 'cell' and 'mouse' standard for any researchers to learn from in the future, so that they can quickly start at that stage.

The PCT124 Muscular dystrophy trials are currently at stage 3 and humans are using it, and the toxicology and side-effects profile is very encouraging. Whether this means trials could start in hmans for TMAu straight away, presumably it is unlikely.

So overall, PCT124 is a very interesting new 'weapon' in genetic disorders, and hopefully more trials in TMAU due to nonsense mutations will occur in the near future. Where there is a will, there is a way.

PTC124/Ataluren FAQs