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March20 podcast Dr Hazen
anti-TMA pill in a year or 2 ? (scroll 12 mins)

Additional info: https://youtu.be/811v7RLXP9M
MEBO Karen
at UK Findacure conf 2020

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MEBO TMAU TESTING DISCONTINUED
(2012-2017)

MEBO Map Testing & Meetups


Full details : https://goo.gl/TMw8xu
want listed ? contact info@meboresearch.org

MEBO - UBIOME study 2018

'PRESS RELEASE'

NCT03582826
ClinicalTrials.gov

MEBO Gut Microbiome Study
"Microbial Basis of Systemic Malodor and PATM Conditions (PATM)"
Funded by uBiome Research Grant

"Microbial Basis of Systemic Malodor and PATM Conditions (PATM)"

Dynamics of the Gut Microbiota in
Idiopathic Malodor Production
& PATM

Started May 2018 - Ongoing

Current people sent kits : 100/100
3 kits per person

NO LONGER RECRUITING

Participation info : LINK English

MEBO Private Facebook Group
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BO Sufferers Podcasts

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Petitions

TMAU Petition world
TMAU UK end total:262
TMAU UK ends 23/01/20
TMAU Petition USA end total 204
USA : Moveon open
TMAU (Dominican)
Metabolomic Profiling Study
NCT02683876

Start : Aug 2016
Stage 1 : 27 Canadian volunteers to test
Latest click here (26 oct) :
17 samples returned


Note : Stage 1 is Canada only.
Return cut-off date : passed
Analysis can take 6/8 weeks
Analysis start in/before Nov
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UK residents survey : Prof Shephard/MEBO (until 31/1/21) click to visit survey
click to Read more/less

Prof Elizabeth Shephard is conducting a TMAU fact-finding survey for UK RESIDENTS. She plans to use it to raise awareness with decision-makers, such as perhaps MPs. It closes 31 Jan 21.

who is the survey intended for ?
UK residents who identify with TMAU

Living with TMAU study

We invite you to participate in a research project entitled ‘Living with TMAU’.

click to visit survey

survey full url :
https://meboresearch.co.uk/index.php/living-with-tmau-lwtmau-study/

Participation in the project will involve completion of a short questionnaire, which aims to capture the experiences of those living with the condition. There are two questionnaires.

For individuals with TMAU over the age of 18

For a parent or guardian of a child with TMAU.

The results from the questionnaires will be compiled to produce a report that will be available for you to use, for example, to lobby your MP. The findings will be used to reach out to policy makers in the UK to have TMAU recognised as an invisible disability and to make people aware of what it is like to live with the disorder. The report will be made available on the MEBO, UK website.

To complete either questionnaire you must be over 18 and resident in the UK. The questionnaire responses are anonymous and no personal identifiers will be collected.

The questionnaire closes 11:59 pm (GMT) Sunday 31st January 2021.

MEBO Metabolic Malodor Survey (international) for Dr Hazen click here
click to Read more/less

survey for ANYONE who identifies with METABOLIC MALODOR

begun : Oct20
end : no ending for now

Regular readers will know that Dr Stan Hazen et al at Cleveland Clinic are developing a TMA-blocker pill, as they proposed in a 2011 paper that TMAO is a factor in CVD. Recently Dr Hazen and colleagues contacted MEBO as they have always thought they could also help with TMAU. This survey is to give them an idea of the 'state of the community'. It is a "version 1". They may not even look (though they have access permission), but it could be useful to give them an overview of the community

MEBO had a zoom call with Dr Hazen and his team in October. Another zoom call is planned when they have time

This is a GOOGLE FORMS survey

short url for survey :
https://forms.gle/vem2TjepKobYZPBu8

current participants : 113 (update 18dec20)

Thursday, January 7, 2021

Base-editing will cure most TMAU1 cases ?

Crispr was a massive breakthrough (around 2014) in gene-editing, but it's 'natural' purpose is to remove a whole gene, rather than say replace a faulty gene, or just the variant at fault. 


Most people (95%+ ?) with Genetic FMO3 Malodor / TMAU1 probably have missense variants.
A new recent DNA-editing breakthrough is BASE-EDITING, where the actual variant can be replaced.
This looks ideal for correcting variants.
The first report of this seems to have been the last year or 2.  
So far not used in humans (? some sickle cell disease sufferers got gene therapy in late 2019).
A new USA paper used base-editing in mice (given) progeria due to a missense mutation.
First results look encouraging.

Ultimately base-editing (but perhaps Crispr) will likely be (?) the cure for many genetic disorders where missense variants are the problem, including maybe 95%+ of genetic FMO3 Malodor / TMAU cases.

When ? 
NIH Director Francis Collins did not expect it in his lifetime.
Now it is being used in mice.
So who knows, maybe 20 years or much sooner ?
This is a random guess. 

Here, NIH Director Francis Collins writes about the study in his NIH blog (7 Jan 2021) ...

Quotes :

In this same spirit on behalf of the several hundred kids worldwide with progeria and their families, a research collaboration, including my NIH lab, has now achieved a key technical advance to move non-heritable gene editing another step closer to the “can do” category to treat progeria. As published in the journal Nature, our team took advantage of new gene-editing tools to correct for the first time a single genetic misspelling responsible for progeria in a mouse model, with dramatically beneficial effects [1, 2]. This work also has implications for correcting similar single-base typos that cause other inherited genetic disorders. ...

...
It turns out that the original CRISPR system, as powerful as it is, works better at knocking out genes than correcting them. That’s what makes some more recently developed DNA editing agents and approaches so important. One of them, which was developed by David R. Liu, Broad Institute of MIT and Harvard, Cambridge, MA, and his lab members, is key to these latest findings on progeria, reported by a team including my lab in NIH’s National Human Genome Research Institute and Jonathan Brown, Vanderbilt University Medical Center, Nashville, TN.

The relatively new gene-editing system moves beyond knock-outs to knock-ins [3,4]. Here’s how it works: Instead of cutting DNA as CRISPR does, base editors directly convert one DNA letter to another by enzymatically changing one DNA base to become a different base. The result is much like the find-and-replace function used to fix a typo in a word processor. What’s more, the gene editor does this without cutting the DNA. ...

...
We are hopeful this gene editing work might eventually lead to a cure for progeria. But mice certainly aren’t humans, and there are still important steps that need to be completed before such a gene-editing treatment could be tried safely in people. In the meantime, base editors and other gene editing approaches keep getting better—with potential application to thousands of genetic diseases where we know the exact gene misspelling. As we look ahead to 2021, the dream envisioned all those years ago about fixing the tiny DNA typo responsible for progeria is now within our grasp and getting closer to landing in the “can do” category.
    

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Thursday, December 17, 2020

NEW MEBO UK EXECUTIVE DIRECTOR

NEW MEBO UK EXECUTIVE DIRECTOR


Due to my personal health reasons, I am very happy to announce that Cole Flaherty (click on link, scroll down & click on 'Older Posts') has accepted the position of MEBO Research UK Executive Director, effective immediately. MEBO Research (UK) was founded on February 5, 2009, registered in England and Wales as a Not-For-Profit, Limited by Guarantee Company.

In addition, I will now assume the position of Assistant to the Executive Director for MEBO UK and I will remain the Executive Director of the MEBO Research, Inc., 501(c)3 Public Charity registered in 2010 in the State of Florida, U.S. Not only is Cole's leadership in MEBO UK helpful to me personally, but I am confident that his competency, education and drive will propel our community further into research possibilities. I will do everything in my power to support Cole's endeavors moving forward, and I encourage everyone in our community to offer him assistance and support.
Click on icon
and scroll down

Cole has a degree in Genetics and is continuing his studies in the medical field. He is working closely with Professor Elizabeth Shephard, PhD (click on link, scroll down & click on 'Older Posts'), on a new TMAU study in the UK, ‘Living with TMAU’ that will be launched with an online survey on 17 December 2020 at 9:00 a.m./UK time. It is important that only people living in the UK complete the questionnaire, since participants of this study must reside in the UK.

For more information on Cole's vision for MEBO UK, see his posts in this blog. Scroll down to see all posts.

GET INVOLVED IN THE STUDY IF YOU LIVE IN THE UK


For more information about MEBO’s Mission and Prof. Shephard’s study, please refer to the website created by Cole for MEBO.



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Please join me in congratulating Cole in his new role in our community, and feel free to offer him all the support he needs and more. Volunteer work is always welcome!

María

María de la Torre
Founder and Executive Director

A Public Charity
www.meboresearch.org
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Sunday, November 29, 2020

UK lab blocks TMA formation from CARNITINE

The 2 main sources of Trimethylamine in humans (via diet) seem to be (not much research) bacterial enzyme degradation of diet CHOLINE and CARNITINE. 

Choline degradation seems to be the main source, say 80-90% ?? (pure guess).

The upcoming Cleveland / Procter & Gamble tma-blocker pill looks to mainly block the choline path (though we don't know really. Maybe it blocks both?).

Now a (small) UK Uni lab (University of Warwick) which looks at bacterial enzymes has blocked bacterial degradation of Carnitine to TMA.

Bacterial enzymes :
Bacteria (and archeae etc) have enzymes that can break things down.
In relation to TMA formation in the human gut, there seems to be 2 enzymes that can break down TMA precursors :
cut-C enzyme for Choline to TMA ?
and now this lab says CntA enzyme for Carnitine to TMA.

So the lab seems to have blocked CntA enzymes from breaking down Carnitine.

It seems they are at the first stage, and a long way from producing a carnitine-TMA blocker pill (if ever). Including the need for funding (not got money on tap like Cleveland Clinic).

It's also unknown how big an impact a carnitine-tma blocker pill would have, as most of the TMA seems to be from choline pathway.

The lead researchers write in an email :

"Thank you for your email regarding our recent work on the Carnitine to TMA formation pathway.

Yes, this work complements the Choline pathway in that we have a crystal structure model of the carnitine degrading “CntA” enzyme with a better understanding of how carnitine is recognised by the enzyme. And yes, the inhibitors we report are the first of their kind against CntA.  

We envisage, this work establishes a strong platform to progress the research to improve the inhibitors. We are eagerly awaiting to hear if we have been successful in securing follow up funding to progress this work. We’d be looking to test the inhibitors against a wider range of bacteria representative of the gut microbiome and demonstrate that we can indeed inhibit carnitine breakdown with such inhibitors in the gut microbiome. We’d also like to further develop the inhibitors for potency and improved efficacy against the bacteria responsible. Ideally, a combo Carnitine + Choline blocker therapeutic would be the ultimate realisation to treat TMAU in the long run.  

Thank you once again for reaching out, it is a pleasure to know our work is noticed and appreciated; reinforcing our research motivations."

Structural basis of carnitine monooxygenase CntA substrate specificity, inhibition and inter-subunit electron transfer
Mussa Quareshy1, Muralidharan Shanmugam2, Eleanor Townsend3, Eleanor Jameson3, Timothy D.H. Bugg4, Alexander D Cameron3 and Yin Chen3
1School of Life Sciences, University of Warwick, United Kingdom
2University of Manchester, United Kingdom
3University of Warwick, United Kingdom
4Department of Chemistry, University of Warwick, United Kingdom


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