MICA: Therapy for the body and breath malodour disorder Trimethylaminuria (TMAU)

Trimethylaminuria (TMAU) is a disorder in which affected people suffer from severe body odour often accompanied by severe bad breath. The disorder arises because of mutations in a gene called FMO3 and not because of poor hygiene. Why do changes in the FMO3 gene cause body and breath odour? When we eat food that contains choline (which many foods do, e.g. red meat, seafood, some vegetables, soya, eggs and chocolate) then the bacteria that live in our gut cause the problem. The bacteria break choline down to produce a small molecule called trimethylamine. This chemical is the one to which the human nose is most sensitive and which is also the chemical that gives rotting fish its characteristic smell. In people with a normal FMO3 gene there is no odour problem because the FMO3 enzyme we have in our liver changes trimethylamine into a chemical that does not smell. BUT, if the FMO3 enzyme cannot do this, then the trimethylamine is not changed and is excreted in urine, sweat and breath. Social isolation, ridicule and limited employment prospects are experienced by those with TMAU, this usually means a low quality of life; high levels of depression, suicide and divorce occur in this population. Our study will test a therapy for TMAU that will reduce the amount of urinary trimethylamine excreted. Our pre-clinical findings will prepare the way for clinical studies in humans in the future. A reduction in body and breath odour will contribute greatly to an improved quality of life for those with TMAU.

Trimethylaminuria (TMAU) is an inherited disorder caused by mutations in the FMO3 gene. A lack of active FM03 means affected individuals cannot convert odorous trimethylamine (TMA), produced from breakdown of dietary choline by gut bacteria, to the non-odorous N-oxide. TMAU individuals excrete large amounts of TMA in all bodily excretions, including breath. Social isolation, ridicule and limited employment prospects are experienced by those with TMAU, which translates to a low quality of life; high levels of depression, suicide and divorce occur in this population. We will carry out preclinical animal studies to test a therapeutic for TMAU. We have established very promising early proof of concept data in a rodent model indicating that this therapeutic approach is both realistic and potentially of great use to humans suffering from this condition. The end point measurements of efficacy of the treatment are the amounts of TMA and TMA N-oxide excreted in urine, which are a measure of the severity of TMAU in humans. Affected individuals with TMAU excrete greater than 10 uM TMA /mmol creatinine (> 10% of total TMA excreted as unmetabolised TMA, calculated as a ratio of TMA/TMAO). Severity of TMAU correlates with levels of urinary TMA, this will be our main endpoint indicator in the proposed preclinical studies. Male mice, >6-weeks of age, are natural knockouts for FMO3 and excrete large amounts of urinary TMA. Female mice will be subjected to a choline challenge. Mice will be dosed i.v. or s.c. with the therapeutic. Initially, we will assess route of delivery; therapeutic window of dosage; half-life of therapeutic; pharmacokinetics. A longer-term study, using GLP therapeutic, prepared to the standard for human clinical studies, will determine bioavailability, biodistribution, toxicity and pathology.

The major beneficiaries of the therapy will be those who suffer from TMAU and their families and friends. Through her communications with patients, the PI is aware of the stigma, ridicule and other difficulties the patients face in their daily lives. The results from our pre-clinical study will provide a much-needed boost for those with TMAU. It will represent a pathway to a future therapy in humans. A therapy that can abolish body and breath odour will have a major impact on the quality of life of TMAU individuals, improving self-confidence and esteem, relationships and employment. A barrier to a normal life will be removed. The preclinical study runs for two years. With orphan drug designation and if fast track status is approved we anticipate a therapy to the clinic within five years.

At present clinicians are limited in their help for those with TMAU. Offering antidepressant or antipsychotic drugs is not helpful (as several of these are substrates for FMO3 and thus make the condition of TMAU worse). Therefore, key beneficiaries, when the therapeutic is made available, will be the clinicians treating those with TMAU and the prospect of a therapy that can prove beneficial for their patient. Health providers will be positioned to target the disorder instead of treating the symptoms of despair associated with the difficulties of living with TMAU.

Other beneficiaries include pharmaceutical companies with an interest in both primary TMAU (inherited form and basis of this project) and the treatment of secondary TMAU (acquired form through e.g. gut bacterial overgrowth; bowel surgery; liver dysfunction). Our proposal is focused on primary TMAU but secondary TMAU results from an impairment in, or overload of, FMO3. Results generated from our studies will therefore impact also on a therapy for acquired TMAU. This industry would benefit from development of the therapeutic for clinic and subsequent sales of the product - this would be within 2 to 5 years of the pre-clinical study end.

Researchers interested in the approach we have selected to develop the therapy, will benefit from our findings and be able to use our knowledge in future projects that target metabolic disorders. Anticipated publication of results is during and within one year of the project end.