MICA: Therapy for the body and breath malodour disorder Trimethylaminuria (TMAU)
Lead Research Organisation:
University College London
Department Name: Structural Molecular Biology
Abstract
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.
Technical Summary
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.
Planned Impact
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.
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.
Organisations
People |
ORCID iD |
Elizabeth Shephard (Principal Investigator) |
Publications
Fennema D
(2016)
Trimethylamine and Trimethylamine N-Oxide, a Flavin-Containing Monooxygenase 3 (FMO3)-Mediated Host-Microbiome Metabolic Axis Implicated in Health and Disease.
in Drug metabolism and disposition: the biological fate of chemicals
Shephard EA
(2015)
Clinical utility gene card for: Trimethylaminuria - update 2014.
in European journal of human genetics : EJHG
Veeravalli S
(2018)
Effect of Flavin-Containing Monooxygenase Genotype, Mouse Strain, and Gender on Trimethylamine N-oxide Production, Plasma Cholesterol Concentration, and an Index of Atherosclerosis.
in Drug metabolism and disposition: the biological fate of chemicals
Title | FMO3 database |
Description | Database of FMO3 variants that are known to cause trimethylaminuria. Database also lists common SNPs. |
Type Of Material | Biological samples |
Year Produced | 2013 |
Provided To Others? | Yes |
Impact | Patient group MEBO have access. Practioners and public have access. |
URL | http://databases.lovd.nl/shared/genes/FMO3 |
Title | update of LOVD FMO3 mutation database |
Description | Categorising FMO3 mutations |
Type Of Material | Biological samples |
Year Produced | 2016 |
Provided To Others? | Yes |
Impact | Information available to genetic testing labs |
URL | https://databases.lovd.nl/shared/genes/FMO3 |
Title | LOVD FMO3 mutation database |
Description | Resource for those testing for trimethylaminuria Resource for researchers to deposit their novel mutations found for FMO3 |
Type Of Material | Database/Collection of data |
Year Produced | 2013 |
Provided To Others? | Yes |
Impact | Accessed by researchers etc |
URL | http://databases.lovd.nl/shared/genes/FMO3 |
Description | Meeting with patient group |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | Meeting with TMAU patients from across UK to discuss how we might move froward on thier priorities and to detail their problems, which we hope to help solve. |
Year(s) Of Engagement Activity | 2019 |
Description | Meeting with patient representatatives (TMAU) |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | Planning meeting with TMAU group to ascertain their priorities |
Year(s) Of Engagement Activity | 2019 |
Description | NHS Choices website |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | NHS Choices information for patients or public on trimethylaminuria |
Year(s) Of Engagement Activity | 2013,2014,2015 |
URL | http://www.nhs.uk/conditions/trimethylaminuria/Pages/Introduction.aspx |
Description | NORD update for patients and public on trimethylaminuria |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | NIH Office of Rare diseases - information online on trimethylaminuria for patients, families and practioners |
Year(s) Of Engagement Activity | 2006,2007,2008,2009,2010,2011,2012,2013,2014,2015,2016 |
URL | http://rarediseases.org/rare-diseases/trimethylaminuria/ |
Description | Open Day |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | 40 students and their parents/relatives attended an Open Day, the talk on trimethylaminuria sparked questions and discussions Follow-up interest in the topic. |
Year(s) Of Engagement Activity | 2014 |
Description | Open Day 19th February research talk |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Type Of Presentation | Keynote/Invited Speaker |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | 40 students and their parents attended an Open Day at UCL for prospective Life Sciences students. participants engaged with the presentation and asked questions |
Year(s) Of Engagement Activity | 2014 |
Description | Open Day 5th March |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Type Of Presentation | Paper Presentation |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | About 50 students and their parents attended an Open day for prospective Life Science students. Talk was well received and parents engaged well with the topic covered. |
Year(s) Of Engagement Activity | 2014 |
Description | Radio Interview |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Type Of Presentation | Keynote/Invited Speaker |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Radio Cardiff interview on the inherited disorder trimethylaminuria. Audience numbers not known. Pythagoras' Trousers: The Science & Technology Radio Show The patient Advocacy Group for trimethylaminuria, MEBO, picked up on the recording and advertised the link on their website. This is a global network. |
Year(s) Of Engagement Activity | 2013 |
URL | http://www.rhysphillips.co.uk/pythagoras-trousers/episode-131/ |
Description | Talk for patients MEBO Miami meet-up March 2017 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | A talk explaining the complex nature of diet and the varying gut microbiome in the generation of trimethylamine. |
Year(s) Of Engagement Activity | 2017 |
Description | Undergraduate research talk |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Undergraduate students |
Results and Impact | 200+ students attended a research talk, which sparked questions and discussions. |
Year(s) Of Engagement Activity | 2018 |
Description | United Biosciences London Talk (Oct 2013) |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Type Of Presentation | Keynote/Invited Speaker |
Geographic Reach | Local |
Primary Audience | Undergraduate students |
Results and Impact | about 120 ug students attended an evening session of 3 presentations. Student association - UCL, Kings, Imperial Students expressed interest in the topic and asked many questions. |
Year(s) Of Engagement Activity | 2013 |
URL | http://www.unitedbioscienceslondon.co.uk |
Description | Update on trimethyalminuria for public |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | Yes |
Geographic Reach | International |
Primary Audience | Participants in your research and patient groups |
Results and Impact | This is an online resource that sees multiple hits Patients and practioners utilise the information. |
Year(s) Of Engagement Activity | 2014 |
URL | https://www.rarediseases.org/rare-disease-information/rare-diseases/byID/997/viewAbstract |