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FXR/FGF19 gut liver axis – new therapeutic strategies
Antonio Moschetta, Department of Interdisciplinary Medicine, Aldo Moro University of Bari, Bari, Italy
Thursday, Nov. 1, 2018 · 6:04 p.m. · 39m 47s
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thank you very much and it's a big on or for me to be a a
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especially to be in this that pathology unit which is a a very famous actually
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for our field of a raffle be a national the recent contribution
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so um i told of a presentation that would focus uh first
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on the got leave access and apologise if i say something
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that you're more expert than me but it's important to go through the rest of the slides and then i will introduce
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i think so um and i know they're also expert here in the field of ethics are so i
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don't need to to use so much time on that but i would like to bring the history
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of the uh the school wary of this new and the loci this new or more that
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is called f. g. f. fifteen in the mouse and that you have nineteen in humans
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and that will bring you the data from a a lever information fibrosis and then put the casino much
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starting from a turns janet models more though uh reaching pharmacology bold for affix on
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and have jeff nineteen and then concluding with a translation of real events
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so i hope i can get your attention the next thirty minutes but i will try to do my that
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so why they got leave axes uh well this is a uh all the
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story that you know very well but the bile acid are very
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in three because uh the i think that ties in the lever stopping from cholesterol and then as you know
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they get secretly uh and then stored in the global other in the inter triangle state and then after we he
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we get the seclusion of our local this is the kind in from building all
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cells will bother contraction and all the bile acid and the the upper
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part of the small intestine and now they are very important for the bit
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absorption as you know like a soluble vitamins and all this but
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um the real woman stop is that ninety five percent of them are all really absorbed the the
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time not helium they go back to the lever and they make the enter button circulation
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so to pass the doctor even axes is really starting and maybe the enter politics regulation
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or policy does the the first part of the game of the dudley waxes
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now what we're talking of that uh it was two thousand four and uh after my p.
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h. d. in the netherlands i went for post docking abortive david mangled the busted cleaver
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in texas for four years and uh in two thousand four exact well we should study a little bit
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more in testing and affix tar and study with the zapping where we paid balance it out
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to the loom and that would put them back and the the transcription regulation which genes are coming out
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and with that experiment we figured out on a and they're one of the fruits marker a there
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was a gene that was um actually repressed one thousand time when you take out bassett
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i will take out by asking from the got uh just by doing about that quite geisha
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or by using some mice that they cannot sympathise but as it like this it twenty seven knockout mice
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and then we gave back bile acid and affect some like and another marker a ten
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thousand fold induction of this gene which was called five mobiles grow factor fifteen
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and that's where the story started on the centre of canada we figure rather that was it
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and we'll talk topic uh in the humans which is f. g.
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f. nineteen what is the relevance of this for months
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uh this hormone is a prude use transcribed as you created by the turning up the volume
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and it sounds like the and part of the digestive so when lasted
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arrive they are being used the seclusion of this foreman and
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the main goal of your money is to go back to the lever and
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to enter and signals the start of the buses synthesis is like
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you know we the the three with the the they just don't know we don't need more well that's it so stop to
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see this is and then we will need again once how we will go back to the post kind of that
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but your money is very thrilling because you there's also several other action for example it doesn't action
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regulating glucose metabolism it as an action or regulating browning in the wiper the post issue
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so people getting ah uh tina and this action is uh mostly regulated by
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this uh if you have for for beta called all double receptor
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and i will tell it today a little bit or how we de sac apart with because we did
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the big apple to specific knock out in the liver and in the brain together with my girls of all we know
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that the connection between intestinal lever is driven by this foreman and by the tackle so
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don't get confused or go back and this at this party step by step
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but i have to say and this is probably might bias but
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i have to say that the main activity of affix ah
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and of have g. f. nineteen is the feedback regulatory loop on six seventy one
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so you will know because you have been cleaning already add rack that activates affix on and that will
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know that have excel is able to regulate several other failings and protects this this this and that
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to me and too few people like me because the feel things that that pixar makes a lot of things
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to me mother nature gave us a fixed are to be this sensor of the bile acid quantity in the body
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and the main thing is the regulation of its own synthesis is
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the regulation of the feedback negative on six seventy one
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so after you have maintain is the or one of the terminal where union but
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goes back to the lever every presses six seven one via several pop
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and this is very important because the the repression of soup seventy one drives
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the quantity of policy that i mean the lever and this threshold
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is the trigger for lever fibrosis uh we think also for most
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of the reason why enough all the patient presents a nash
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but this is a dream at the moment that we we don't have the final solution that what you will see what
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is happening in the preclinical model and you will see that
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in the clinical model the only to a drag
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that in a way are these are presenting reduction of fibrosis even impression that already have
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r. f. x. alike and although it's not the best of excel i get an average of ninety which is
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already in phase three and there is already paper showing uh these bigger on the prevention of labels
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uh so let's go through uh the presentation or go back to this but this is the focus so what we're gonna talk to
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so what are the nuclear receptor now you're more expert than me but when we are
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a treating a patient with an affix alike and we're changing the gene expression
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into the lever an interesting because nuclear receptor transcription factors they
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most all of them bind d. n. a. via specific
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uh yes i have the specific sequence which is called a direct
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repeat of the a. g. g. t. c. a. model
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and and these are all the members of the family they're very including because
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uh this they will discover there's the endocrine a receptor
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is from the first one was uh um uh
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was in the southeast it'd run events to discover the group record record receptive and uh we have to say
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that is the real father of the internal to reset the family and the all the other mormons
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even the uh targets for a onto tomorrow uh issues
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are all nuclear receptor and affect our was discover
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uh why i'm david mantle softened the like an were discovered
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by david move david mangoes of another call it
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which are the by lasted and the regulation of affect our yeah we have
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several other members uh our laboratory need ideas for shoes on f. x.
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on it and this also alexandre and some of the p. g. c. which
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are quirky later the p. p. r. in the last few years
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but yeah pixar is a very very empty uh nineteen ninety nine was the here which
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the sequence of ethics are uh was discovered two thousand one the first knockout
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and the identification of the likened unto doesn't forty there is a direct link way maybe is
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not the best track but the the driving cleaning this tells you that in thirteen years
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there's been one of the uh fast as the uh a batch too bad side uh rolled which
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is important for us at least that's a passport for our grant what we write a grant
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so uh how was the situation in two thousand four when i finished
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a post doc with every man of also at that time
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uh every three was a bottle centre take what you know a pathologies like we are with the the the lever is everything
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and maybe the lever is ever figure wright brothers sort of what i think i think the traffic is more
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important that it was so i will convince you today that they've got is driving the lever have fit
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so everybody was focusing on the lever uh we uh together with mango we probably several stories
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but also other group we need early in the utopian united states is with someone
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i'm a publisher regulation of examine this was uh what was known into doesn't for
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every town was able to negatively regulates exam anyone in c. p. d. one need to depart aside
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which means regulating a negative regulating the synthesis of blasted
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including agree on the promoter off ah a. b. c. d. e. lemon
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obese at a. b. c. before or and the other two
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an m. r. p. two was find an ethics are binding
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side the promoter were called report uh say gene expression
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all of these genes up target of effect on and you know how important they are for the genetic
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disorder the lever i'd like progressive for meaning to particular states is that by two to three
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seclusion of bile acid free press office supply local you uh secretion of a organic an area
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yeah all target of excel and then and t. c. p. is a negative target of ethics
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at least in humans a boat on the promoter so repressive action right p. c. b.
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and then other colours that the condition in backchannel memorably three and at least the alpha beta on the kind
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of because side to do the so called spool over in this yellow due in cause this is
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so all of this where the target of effect are and if you
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study even our papers everything was at the lever is making it
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the story so i fix are in the lever is driving uh the sense sort of bile acid because when
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you have a high concentration of our other compound what you want to do is to block the synthesis
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to block the entrance and to increase the x. it so it makes complete sense right
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but the end is still like that i'm not saying that is not like that but there was a paper
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uh that was published in g. c. i. based easy johnson tim wilson from black so
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that time there that like a lot of exam was goldie double four six four
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that now is a drug that you can buy a sigma because it's not good on humans with very good
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forward to the issues and they publish a paper doing ball that luggage
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so because the bar that they give g. doubly four six four
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and they still enormous protection of the lever during the treatment with the suffix online
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and they claimed in that paper this is because affix our activation is
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able to use recreational bought last it out of the lever
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but actually wonder product easily gated if you increase the secretion other colour the colour way
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maybe you will make you worse because the pressure is gonna make more and then
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but the story was true we repeated the pay the the the experiment and experiment was through
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and then we sat so we're missing something maybe is not the
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lever maybe when you give g. w. four six four
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you are activity in testing and that's what we started that micro
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array searching for something that was happening in they've got
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we found we have jeff nineteen and that moment that was uh leaving the love oratory
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in two thousand five in the stuff to the laboratory neatly i i got
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uh five years the the ideas for your c. and i said okay i will for 'cause
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on intestinal effects i was a big risk because no one believed at that time
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on the cassette there was someone working pioneering on michael by your time thinking that this microbes where
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we're doing all the face but it was very difficult for the look
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receptor fake uh feel to take the exam exactly when they got
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so i ask it out on the r. c. uh to do the story what they wanted to do is to see
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if the test and was able to signal to the lever repress about us to see this is decrease the concentration
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and this was maybe the reason why sleazy jewels soul the protection in the lever doing about that quite huge
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so we started from there and do this and i decided to full
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study whatever excel was expressed uh we did the inside to ah
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either decision because the the antibodies are terrible and that we were able to do one antibody which was
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more or less okay but we figured out that effect size highly expressed in to the entire side
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of the view i and the and the column is not express under
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uh interesting um you go there is not expressing the crypt weather is regeneration but just in the
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internal so it's no surprise the intel size is the place where policy enter and get yes
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and after that we decided to take uh this uh this approach so
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what what we wanted to do is to get a big
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risk and to get a mouse that was having get 'cause state
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that evacuation of ethics are only into the into our side
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so the idea that we had uh on the lab was okay
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now we need the mouse model where even we don't bassett
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i fix our would because the to to really active all the
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into the interval sides of the uh topic of those
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so we put the veiling promoter we called with a v. b. sixty which is a came era
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that will allow a transcription factor that buys the an eight to transcribe
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the target she's so to recruit yemeni polymerase setting do the transcription
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i would generate the smalls model which add f. x. are active into
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the lounge room in a row and column and the control models
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now we have a mouse that there's a consisted of the work division of ethics are only into the intelsat
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that's why i was very risky because you couldn't work with the the human ah the human trans janet because
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when it this way we could recognise just play real time the presence of the trilogy and the task
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uh what we had as soon as we generated the mouse rejecting the helium
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the main target which we demonstrated to yet before which was the object fifteen and you see seven folding views
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in the the little but that's the same also in the timing on the proximal you
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and when you take the lever use you reciprocal inhibition of sid seventy one amount
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so this tells you that the model works on a chow die on that uh interpret the fasting state
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you have the busiest in effect on that 'cause they totally active it's after fifty
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which is used and signals back to the lever repressive seventy one and
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the the feedback regulation is working so we have a mortal approve of calls
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and then we study is this through for the bar last it so we
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saw that the boss it to topple was reduced by two two percent
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the fickle exclusion is reviewed which we present this the the state the party bosses
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status is is reduced by seventy percent so we have the malls more though
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and what we wanted to do and this was the experiment that we want to the now we want to have the bar that
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radiation which is a bad about catastrophic surgical experiment i agree with
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all of these things but it is very important because separates
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the lever from think that's that we should be never separated because we think it's only one or two right
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so we separated lever from intestine and now we don't have by now i
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think beep to the got right because all that 'cause i dated
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but we do have affix on our which is the inter service as our boss either this considered the reactive
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and this will solve the conundrum well actually the answer could've been also no there's no
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function but at least we didn't we sell what is happening was incredible fruits
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no we show you this because it's important what is happening later on them for what we're working now
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but the first thing you see is what is happening to the intestinal it did when you do the bar
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that radiation which is again an important issue because you
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don't have internet looming all detergent policy you have
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bacterial contamination over go you have trans location wasn't very clean is is
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we're going to use the mortal to study the relevance of the microbes into the data because it
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is the the lady already the only modelling we should have any credible a contamination about it
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not just by activating effects are into the intestine on you cause that
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you could see that is much less still be that stupid humour
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of the new calls that you can see there's much less recruitment of the inflammatory cells there is even
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fifty percent last month location and more than fifty percent reduction in the bacterial but when they got
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we are only activity affix on gene ethically into the
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entire site so that tells us that at least
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one of the major role of excel into the intestine is to regulate got junction
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eventually military response now we're doing a lot of uh feel
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transplantation but the advanced one page uh we'll we'll learning
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a little bit more of this but this is where we stop it and then we went to the lever
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what is happening you you don't have been lasted but a v. p.
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sixteen effect size working perfectly a g. f. fifteen is in use
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six seventy one is read used as a propane and there's a gene and this is true even
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if the ball that is for these calls so what is happening to these up were mice
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you see when you do bother application you they have ah the ah it does
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very high below b. u. k. c. from the yellow colour of the models but in
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you have against it at the back division of affect our delivers somewhat protected
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is protected from up on the crosses is protected when you study a healthy a is the a. o. p.
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and is protected because we believe that the trash hold
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of the interrupted by the bus it concentration
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he's the trigger that drives the main um negative regulation on the colours that the condition
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now this is very important because at that moment we said what if
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all the story is that even via f. t. f. ah fifteen ninety
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so at the moment i was uh driving a laboratory in
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the modern agree institute in in another institution and that
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we decided okay let's do the first recombinant have jeff nineteen or
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more so we call the recall minute with the protein
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we put in to get go to cells we took the super made that way in a way to divide even
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if it was not perfectly purified with bow that radiation we
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injected this recombinant on or more into the mice
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and i ask it's older monica is now in a duty age into the week after
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the post doc without ask us a letter to repeat this experiment four times
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because the data that we had were incredible when you look at it a
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critique are yeah our at the a. s. d. a. o. p.
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a. even though the below being just plain jack thing the f. g.
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f. nineteen you would see that the repression is almost fifty percent
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and only what i would say is still fully protected but is always protected and what about
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the schools but this is due to the fact that it's only one is repressed
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the total pool is reduced by thirty percent but the heathrow yep i think bassett the reviews by ninety percent
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so imagine the situation that you have a a a subject with a stolen
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into the collider 'cause uh with the calendar casino more with the beefy i
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see anything and you have a drive that would decrease the bus
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a concentration deliver without more than any other things that we do nowadays
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because the rising would not work if the ball that is closed
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and what what what would you give right you would give eventually were so but this will probably not have if
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the other party says which is not mind paying you give this or more is that the lever is saved
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and this was the first experiment and i have to say that story started here
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and the field at the beginning was a little bit while not
00:20:05
super happy we received a letter from some prominent call it's
00:20:09
in austria or in the netherlands say wow what are you say have jeff nineteen that could not
00:20:15
be that that really for me the biggest press and was that people were repeating the experiment
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we're getting the same results and two years later by attacking the
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united states started doing the f. t. f. nineteen in humans
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and now we have a phase three in humans actually the phase two on p.
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b. c. n. courses is fast perfectly but now they went to phase three
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and and the phase three is now driven in nash patient this because ah monday or driving most of
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the size not what they and and nash are more important of course that is still pay that
00:20:47
f. j. f. nineteen use that are before cause this is and if i
00:20:51
would have a baby's with the feet mutation that now what they
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half even that ah about the casino my the age of eighteen this is that the
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right to use even the fact that we do now i bet we add okay
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so this was uh the beginning of the story and after the f. g. f.
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maintain uh i will show you two things one is that if if possible
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to modulate this have g. f. fifteen nineteen i fixed are in humans out
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we were working on a big project on the michael your turn
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anybody here there's been a big deal because several other groups of publish
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different things like uh i fix our and paragon is the big
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the the putative uh therapy for i don't know what but they are
00:21:37
in the leadership but they just want to say that obviously
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uh in the testing as you know um d. f. excel is activated by the by i
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think that that entering from the u. m. and this should be the conjugated one
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because as you as you can teach me the community uses a is b.
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he discovered by paul those on to enter into the intel side
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activity affect our use of g. f. and go to deliver if
00:22:00
you have a ah pro biotech bacteria in the dark
00:22:04
if you have b. s. h. driven but peter and you're able to
00:22:07
uh i'd always in the conjugate bassett either terminal william even if
00:22:12
we take that al cone you get it are freely passive defused on the membrane this is not
00:22:18
true because they want to do that then can you get to that you can get it
00:22:22
is much less than the quantity of the carnegie that you will get in into the unit of the four if you'd you call
00:22:28
your grade about as it into the of course part of the nothing you will not get the same activation of affects ah
00:22:34
and that's the explanation of the germ free on antibiotic treatment and all of this
00:22:39
there's no antagonism of affect our there's actually reduction of agony
00:22:44
isn't if you'd you'd call it the the bus in
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that they don't tend we are trying to to write that in the review to tell that but it
00:22:51
well we maybe we need five yes more just as the top and
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for the f. t. f. nineteen to reach a few might
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so i don't wanna i don't wanna show you this but i will i will tell you that if you use
00:23:03
like probably a big mixture that have a very i. b. s. h.
00:23:07
activity and you take it to a like a tough off
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four hundred fifty millions of bacteria per day and you will do for twenty one days
00:23:17
uh you will have a a double the exclusion of bus into your feces and i
00:23:21
still think that some of the protecting affecting maybe the maybe will depend on
00:23:25
the amount of policy that you will exclude instead of a. v. in the in
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total multiples and together with a five year coming out it would publish this
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uh recently i just want to tell the that plane with the back you know the
00:23:38
balance it a concentration is very very important that may be any of that
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uh frontier for for the next huge now let's go back to this uh because
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uh we will i will introduce to you know the question of
00:23:51
the relationship between affix out if jeff making and cancer
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and the reason for that is because all of us have big data all but i see that picks out of g. f. in cancer
00:24:01
and people think that i think some are or have jeff nineteen could be in nineteen cancer
00:24:06
strategy or anti fibre optic strategy and i will show you why but but but
00:24:11
let me tell you that is not because ethics are has anything to do with cell
00:24:17
cycle is not because f. g. have has anything to do with cell cycle
00:24:21
uh we believe that everything started from the toxicity of policy the fibrosis and the
00:24:27
quantity maybe in the future if someone will the school over and noble
00:24:31
or figs are targeting to the so called untie uh prefer eating david age
00:24:36
and we will we will say oh oh wow but at the moment
00:24:40
the anti cancer is working via and pay metabolic event
00:24:44
so this was uh the the the the point of the literature uh regarding the capacity of the
00:24:50
lever or undergoing my to jenny properties uh when the boss it was additional in clean
00:24:55
and i remember um well actually adding my two myself that
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for example we have beefy patient of type two type
00:25:03
three which and younger age they get fact that the t. c. p. fibrosis colour spaces and chance of
00:25:10
i went to the story with that richard thompson is some of these uh where young
00:25:14
guys showing that the f. g. after the activation of the data leave act is
00:25:18
brought back if a company to deliver but when we go to the mice
00:25:22
in two thousand seven while we're working on the idea of the gap
00:25:26
uh the the movie news and publish a very intriguing paper actually that the affix out knockout mice now
00:25:32
these mice they don't have ethics are in a cell of the body when you wait twelve months
00:25:38
they all have cancer in the way and the mood said this
00:25:42
is because they have you see very icy seventy one
00:25:46
very i by massive level because they cannot do the negative regulation on effects on and
00:25:52
therefore but as a lever very i activate beta carotene in an old apart
00:25:58
so it's been taking and people in the field will not believing of course
00:26:02
until they even were the the nature genetics story showing two years ago
00:26:06
all that our families of people with mutation in effect are
00:26:10
the old guy between twelve or eighteen years old with lever damage scorsese's and cans
00:26:16
so we have this my so we said now if this is a really depending on by last it
00:26:24
maybe we have the solution to see if it's true or not and the solution was this taking d. intestinal
00:26:30
close to to to very active of mice and crossing them with the f. x. are knockout mice
00:26:36
so what we're doing we're taking a guy with an ethics annotation every
00:26:40
activating effects are including best and all only into the intestine
00:26:45
and this was very very risky because now if examine the lever is not there at all
00:26:50
right is not that at all so we customise and we asked the mice from david and
00:26:55
that we send us the my so we waited that we crossed yell for years work
00:26:59
and then the data when incredible because we we did twelve months fourteen months sixteen months
00:27:05
is not a matter of law and the two morse versus to
00:27:08
do most is matter that they don't have cancer anymore
00:27:13
so um mobile all spontaneous and particle see the genesis loses
00:27:19
the cancer if you reactivate f. examine the gap and you bring back a. o. p. a. is the
00:27:25
feeling but that'd be good but i see the lever but as it to
00:27:29
normal about this tells you that what they've been was shown it's true
00:27:33
because when you're not down effects are that i bassett activation of sighted toxicity fibrosis
00:27:40
and then sell cycle now you reactivate just think that's no effects are
00:27:45
and you send the message to the lever to decrease the boss it wasn't a joke
00:27:48
when you lose the entire part way which goes via information fibrosis think as so
00:27:54
so starting from base we decided because people were telling us that is all trials
00:27:59
janet we decided to take to approach and then i'm going to the conclusion
00:28:04
the first approach was a chemical approach so we compact intercept
00:28:08
which is this a company that is made a
00:28:10
this a bit to call it added which to me is not the best bassett right and actually is
00:28:16
well i don't know because we are getting into this registration and i'm maybe telling too much today
00:28:22
and i i was not expecting to be ridges that by the way but it's no problem
00:28:26
so uh because this well yes yes yes so uh uh uh
00:28:33
so uh and then we we have the possibility to receive a a drive to using to the mines
00:28:40
and the dry tears into the mice we use it for sixteen months now we took two models
00:28:46
initially before knockout mice which are envious to knockout mice that in a
00:28:50
way although it's not perfect the sample the and the other three
00:28:54
mutation humans which is the p. victory right uh what what what is happening in this my so that they get
00:29:00
increase bile acid concentration actually they get increase kinda legal damage because they don't awful slowly but
00:29:06
then they go information fibrosis and cancer when they get twelve wonderful
00:29:11
i would take the effect on knockout mice but in this case effects on a compromise of the proof of concept because
00:29:17
remember we're activating effects are with is that we want to see the fact sixteen months treatment
00:29:24
or more than forty mice and uh put them in single
00:29:28
katie said yeah and because we need to convince ourself
00:29:32
if it's true or not what was happening which is the gene expression picture
00:29:37
which is really what you're expecting actionable g. f. fifty the pressures
00:29:41
to seventy one in the end you have to look out no change in the f. x. out no my so specific perfect are
00:29:47
when you look at the two words which is what is happening in the c. b. for not probably worse they get
00:29:54
you know seventy percent reduction number of two more per mice to marseilles a lever
00:29:59
to body weight race you any effect on market mice nothing is happening because
00:30:04
the drive is working by affects ah i this was an important proof of concept
00:30:09
so what is happening is that you have of repression of a cheesy formation after sixty months of treatment
00:30:15
but of course if you sacrifice the mice when they have
00:30:18
three months of four months in search for informational fibrosis
00:30:22
the picture if we are because when you study information and you look at
00:30:26
yeah exam no doubt there's no effect of the drive and yeah
00:30:29
five boroughs using bold cases you look at the end you have to know and the fibres is
00:30:34
almost gone but this was in the time point was also or radio or shown by the
00:30:40
group of ah ah michael trombone in austria uh anecdotally we are containing it for showing the
00:30:46
it's easy protection and actually this reduction in fibrosis
00:30:50
drives also reduction in uh information energies
00:30:54
now this was the picture initially and what we wanted to do is
00:30:59
to try if we were able to generate energy f. nineteen which
00:31:03
could uh activate uh the pop in the mouse a water and then
00:31:08
study in the m. yet to any effect on market my
00:31:12
now i have to have nineteen and this is the uh the last ah minutes if there is a
00:31:17
little bit three key is three key because is a member of the final boss grow factor family
00:31:23
uh all these uh family only three have the capacity of travelling our
00:31:28
body because they have a special characteristic which are the ninety
00:31:32
that twenty one of the twenty three they're very very take it twenty three is the vitamin d. and kidney disease
00:31:38
twenty one is the diabetes and anti obesity and after you have nineteen is the bile acid rock
00:31:44
which also as an anti diabetes and obesity i should but now inhabit the casino much
00:31:51
f. j. f. and i see it stretch is actually amplified so if you take at
00:31:56
the casino but issue from patient and jeff writing is amplified which is intriguing
00:32:00
plus doing colour spaces have jeff maintains starts to be transcribed into it
00:32:07
there was a very nice paper by a pretty young son and all the friends internet or showing
00:32:12
uh that that that's because we get uh the the the they're showing that after you have an id is
00:32:18
highly expressed in the lever during college this is on the biopsies and we think this is important
00:32:24
because we think that is what one of the major cool pink or i would say add the response did you get that right
00:32:31
we all ever heard about adaptive response in a pathology
00:32:35
especially the biases feel during the last twenty years
00:32:38
and then add think after you have nineteen as an adaptive response is well it right is righteous one centimetre more
00:32:45
so but it's very interesting because when you go to the energy of anything in the
00:32:49
mice the orange you know what the napkin one then you can induce cans
00:32:55
and the reason for that is actually now a little bit uh the school board
00:32:59
by ah two or three papers to papers in that nature communication one paper
00:33:05
yes i slightly shot magazine actually there's another story in cancer research and and the reason for that is the following
00:33:12
you can have a metabolic activity and you can have a direct probably productive activity in the models
00:33:18
so let me take one minute to to to qualify this issue
00:33:22
when we gave the recombinant they've g. f. ninety the natural one to the models
00:33:28
we saw protection from information and fibrosis in the video
00:33:32
right we saw protection from information and for
00:33:35
browsing and the of the right but if you treat very lock then you get the cancer
00:33:41
but we think although we're not expert in after the casino that is a cancer that now is being shown
00:33:47
by other coloured thing to do with the information i'm
00:33:50
fibrosis is a direct into a portal cellular activity
00:33:56
of the f. t. f. ninety so when you get a long term negative after you have made you you will ask has uh
00:34:02
but do we were will be still protecting some information courses isn't fibres yeah i don't know if i'm making this issue clear
00:34:09
so by by doing these people in united states have separated the proliferation from metabolic activity
00:34:15
and we are physically into uh several studies with mutants
00:34:20
and one of this is this a mutant m. fifty two with five point changes
00:34:26
into the molecules which month raise this to seventy one in addition
00:34:31
and loses completely the pro to moral event into the might even after sixteen months waiting mouth
00:34:37
so we have a drive that could work as have g. f. nineteen
00:34:41
and does not have the affix hardy the pro tomorrow i
00:34:47
and this is this similar to an analogue that is called m. seventy or n.
00:34:51
g. m. two eighty two which is already in phase three uh for you
00:34:56
so what we wanted to do and this is the conclusion we want to
00:34:59
use any of the vector over express where they are eight months
00:35:04
and then ah wait one year and see what is happening to bolt
00:35:10
and the l. two and effects on account so we have
00:35:12
a way to activate energy of ninety constructively just like
00:35:17
you would be with the drag a uh germany um uh i mean is there and see what is happening
00:35:24
now what happened in the and the other to knock out was uh
00:35:30
walter was i don't know why a few people uh took it a little bit purcell was
00:35:36
incredible because if you injected jeff ninety two and then the other two knockout mice
00:35:41
and you wait ten months twelve months and fourteen months use your impression of a transformation
00:35:46
and you see that is not the mother of ah you know twenty percent less
00:35:51
these are difference that we at least we have never see
00:35:56
into the mice what we worked on this but this is um in terms of
00:35:59
of cancer when you go before you could see protection already two months
00:36:04
in terms of the revolt was i mean it is you can see protection that is
00:36:08
the rabbi reduction of thought about as it so precious in seventy one and
00:36:13
being taken phase that similarly is happening in effect um no lights
00:36:17
so this tells you that even if you don't have affix are like these families with f.
00:36:23
x. or mutation that that covers the ceasing cancer addendum nature genetics the mood polish
00:36:29
you can buy a reactive meeting f. t. f. nineteen repress the two more formation but also all
00:36:35
ha decrease the possibility for fibrosis although there are incompatible modulation of
00:36:42
the only be the metabolic battery that we are investigating
00:36:46
and of course the casing a lever probably for that the
00:36:49
issues and doubling time of uh it pop aside
00:36:53
and we believe that one of the reason why i put the casino why yeah but have different doubling time inpatient
00:36:59
as you know we have patient with that because you know what that's about twenty years and we appreciate that survived two years and we don't know why
00:37:06
and this is a a completely not under our control so we believe
00:37:11
that the measures circulating by lasted or circulating c. four or circulating of
00:37:15
j. f. nineteen would be may be an explanation on the
00:37:19
reason why if you are more aggressive and few are less aggressive
00:37:23
together with all the role of the micro environment any information
00:37:27
so i conclude you are just they say that today i present to you a story without any type
00:37:33
of conflict of interest if not uh the fashion for signs that when you activate intestinal effects on
00:37:40
and if you have been passed in in the car wreck condition you will protect your lever
00:37:45
and that to me is the by lassie the effects on it you have to you have nineteen are one part of
00:37:50
the story that one could think also of several other story
00:37:53
involving other related metabolic part oh good cause metabolic part
00:37:57
now we begin phase i think that's the right exactly vision of j. f. nineteen at
00:38:01
least in the preclinical more visible to prevent the progression to happen that's the genesis
00:38:06
and this limits information in fibrosis and i have to say this is already seen in humans
00:38:12
because even if the light is not perfect is you know the feeling study as qualified
00:38:17
by doing biopsy before and after that the fight bosses decreased now you can have
00:38:22
some side effect on l. d. l. whatever we want maybe is not
00:38:25
the basket pixel like it because he's a by super safe increase concentration you
00:38:30
can have some damage by tommy another story that show you decrees fibrosis
00:38:35
on lever biopsies before and seventy two weeks after
00:38:40
including the way you have to have maintain which is on going to the trial on on nash
00:38:45
is undergoing the same type of story because on the lancet they show with an m. r. or reading these
00:38:51
pages or decrease the only big accumulation believer in moderation of on the final scene so we take
00:38:56
that the metabolic changes that are driving a reduction in about a casino my are
00:39:02
actually a very important in those at other question awhile which which have
00:39:06
previously fibrosis information and an intriguing relationship with the with the ah
00:39:12
with e. with a micro why am i so the final conclusion which could be
00:39:17
uh i still i think uh a little bit uh provocative issue is that
00:39:23
to really cute the lever and fibrosis an avid across you know maybe we should treat uh the best
00:39:30
uh let me back the people that work especially so what the remote because now in a th elena vilified which is uh
00:39:36
now everybody nature communication and evan appreciate which is still in the lab
Conference Program
FXR/FGF19 gut liver axis – new therapeutic strategies
Antonio Moschetta, Department of Interdisciplinary Medicine, Aldo Moro University of Bari, Bari, Italy
Nov. 1, 2018 · 6:04 p.m.
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