June 9, 2023

Thursday, march 31, 2022

Okay so i don’t yeah like i don’t think duchenne presentation introduction is needed here so i just move quickly into next one and what i’m showing you is a paper 2015 papers from the group of stanley fronter from seattle in in which he presented a very exciting effect of simvastatin in in mdx mice and not not only they presented improved biomarkers and

Histology but also a lot of functional improvement of mdx mice that were treated either short-term or long-term with simvastatin so it was in in the paper comparable to gene therapy or even better so this gave a lot of hopes and why shall i be interested in that yeah in a continuity papers they show also cardiac effect and in long-term treatment and so this

Is looks very beautiful and just a year ago in this conference which was over the internet of course i presented this paper so what we have done recently is that we profile microrna in the plasma of the shen patient and got some complex profile with a lot of deregulation and attempted to understand the all-over effect of immunodysregulation by a bioinformatic

Approach and we produce a quite surprising prediction from the bioinformatic approach that cholesterol metabolism might be involved seriously in industrial muscular dystrophy so in the light of these results of course we came to see what happened in literature found this pna’s paper of the frontal group with simvastatin and and decided to contract cholesterol

With classical statin treatment that was already shown to be therapeutically interesting so this is what we have done here we treated the mice by simvastatin very short term and we we faithfully reproduce some of the paper some of the results but uh we’ve been only in three weeks and what we were able to show is reduction of of biomarkers and improve histology

In particular what we were able to see is reduce fibrosis in the diaphragm of the mdx and also uh direct staining for uh for the cholesterol in in the muscle was shown reduce cholesterol content of the muscle and also we were able to pinpoint into the canonical action of the anticholesterol statin which is the hmgcr pathway and the swept activity so the serb

Is a master control of synthesis of cholesterol and they were removed from the nucleus in in the treated mice so if i go back and this i borrow from stanley fronter’s presentation some years ago when he presented his results so uh there was slight differences in what he proposed and what we propose as mechanism because stanley was prefer the left side here

In order to say that symbol stating pleotropic effect of antifibrosis antioxidative stress and anti-inflammation were the major region for the effect aquatic effects that he was detected while our analysis was our result more compatible with a direct effect of the canonical statin activity of of symbol statin whatsoever uh statin therapy is of course might

Be intuitively bad idea for the reason that statin can do can induce myopathy so this is not it was not easy to promote the idea of treating simvastatin of tuition patient yet one need to keep in mind that just the same can be said about gluco glucocorticoid when you treat glucocorticoid chronically normal patient at some moment they will have muscle problem

So it can be considered that also simvastatin merit it’s a serious consideration just same as glucocorticoid will do so however the uk association decided uh yet to finance other studies to uh to to ask the question whether simvastatin might be yes or no good and and so this is just published and from two different groups in the uk in holland and and they

Couldn’t reproduce the beneficial effect of symbiostatin in the muscle and in another just published study from a polish group in sketchup muscle also they were unable to reproduce this positive effect of simvastatin so we are in the middle of a quite serious debate over this issue and well yes or no simvastatin and so for us there was no point of repeating

What has been done by stanley frowner with long-term simvastatin because okay too many things were done already but we’ve been interested in another approach and the other approach is combined therapy so in the combined therapy under the hypothesis that may be restoring dystrophin only is not going going to be good enough we just saw all these results which let’s

Say intermediate they were very good in pre-clinical study but when it comes to patient microdystrophin is still far from let’s say therapeutic efficiency so the combined terpe would suggest that maybe you can treat with another things to to to normalize whatever downstream events and in our case we’re interested in metabolic perturbation uh so uh the idea

Is to mix uh the gene therapy with mycodystrophin just same similar to the one present before and we also treated with simvastatin and so the question were simply can we get better tropical benefit by the combined approach and also what’s very important uh is it possible to reduce the title of the aav and we just discuss a potential risk of of the toxicity of

This aav vector so whatever you can do in order to reduce tighter can be beneficial so the approach that we took okay i don’t have a pointer but if you look at the group four and five and six in group four what we have is low title micro dystrophin in group five we have just same low titer but we added the simvastatin and the idea was to to see if this can

Be comparable to the sixth group which is of the high titer and so very briefly i’m going to present you the results of this study that was just published and what you can see that in term of expression of the micro dystrophin itself if we compare the group of of uh microdystrophin with and without simvastatin in fact we got no improve of expression of the

Microdistrophin maybe on the contrary some smaller reduction in the expression of the microdystrophin when added the symbiostatin and unfortunately also the escape test which is kind of a physical functional test of the muscle was showing also no positive effect by adding the symbiostat into the microdystrophin clearly our microdystrophin approach was working

Because you can see very clear uh the dose response effects the more you put the virus the better you get expression and and functional improvement so what happening uh we were able again to show that when he puts in the statin you get reduction of fibrosis in in the diaphragm this was repeatedly happened but at the same time we were also labeled for necrosis in

In the muscle and what we got is uh indication that simvastatin may increase in fact uh the number and the percentage of necrotic fibers um the escape test and uh another the grip test were as i mentioned already showing no advantage of the symbol studying treatment unfortunately so this is just published and what in term of mechanism mechanistically what i may

Suggest is while quite repeatedly in our hands and others symbol statin is involved in reduction of fibrosis at the same time it seemed to be it’s not unexpected because you the mevalone pathway is required for the regeneration of the fiber so if you reduce the level of of the mevalone pathway you you it’s not that surprising that you may get some increased level

Also of of necrosis and whether or not the treatment of simvastatin would be efficient or not i suppose might depend of of very specific conditions uh which will favor the other end of the the one hand or the other positive or the negative effects that i we’ve been identified here um so all over my conclusion for this study is that so while some biomarker and

Histological parameters are improved uh we didn’t get support for the combined therapy for simvastatin together with microdystrophin and we still believe that the cholesterol and lippy the normalization approach is merit further experiment and what we would like in the future to do is to look for alternative method for metabolic normalization in in combination

With gene therapy and just to finish by giving credit so all these happen in in generaton and the bi is isabella shar and the people here that participated in in this study are mentioned here and i thank you and i take your questions nice talk when you an impinge on cholesterol metabolism using pinch and ultra maybe bile salt so also colic thyroid colic

Acid all these derivatives from the cholesterol have been shown to be important for muscle growth or has a sharpening-like function so have you checked whether in treating with simvastatin you affect the production of the biosols let’s say systemic green liver but also locally in the muscle but we’re unable to discern a clear effect so yeah we try to tackle the

Problem but so far we’re inconclusive in regard to that maybe i i have bad memories but i remember that maybe 10 years ago there were polemics about starting induced myopathy you remember something like that you have in your slides and i was sleeping i don’t know what level how much effort he invested in trying to raise money to to get further invested in

Therapy and of course the the idea is is problematic and it’s just presented here and so that’s why in fact uk association finance another group to be in independent study and and this is where contradicting results were

Transcribed from video
David Israeli – "The co-administration of simvastatin does not boost the benefit of gene therapy…" By EASY AGING in ITALY – the Myology way