New drug for MS in Phase 2: Possible new treatment for CFS? GNbAC1 against MSRV

serg1942

serg1942

Senior Member
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544
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Spain
Hi guys!
This paper just came out:

http://m.neurology.org/content/82/10_Supplement/P2.217.short

It is about a new drug in phase II: "monoclonal antibody agonist of the Multiple Sclerosis associated Retrovirus (MSRV) Env protein", called GNbAC1.

They conclude: "12-month results confirm the favorable long-term GNbAC1 safety profile in MS patients"(...)"These results support the launch of a larger Phase II study testing the efficacy and safety".

My question is how far are we from having a similar drug for ME/CFS, in light of the Lombardi, De Meirleir et al's work on HERVs.

I've been reading about the "Multiple Sclerosis Associated Retrovirus (MSRV), member of type-W Human Endogenous Retroviruses (HERV-W)" and its possible relationship with MS.

Let's see if I got this right: in MS, they have found that the protein env expressed by HERV-W induces the activation of the innate immunity, a predominance of Th1 and autoimmunity. These effects have been shown to occur through the attachment of the env protein to the TLR or CD14 membrane protein of the monocytes that would be induced to become dendritic cells.

I think they have not located the specific cells that would express the env protein though.Have they???

The drug is designed to block the env protein so that it cannot attach to the TLR4 of the monocytes. This way the endoretroviral protein would still be expressed, but it would not induce the activation of the immune cells, hoping this would break the possible pathological pathway.

But, what do we know on CFS? We only have the first study published by K. De Meirleir, Lombardi et al, in 2013, and their poster shown on the recent IACFS conference. (The data of the poster is still unpublished and showed no numbers).

According to their findings, resident macrophages of the gut (plasmacitoid dendritic cells--pDCs) uniquely expressed HERV proteins in ME, and this process would be caused by inhibition of TLR 7 and/or 9 on the pDCs. This inhibition could be caused by exogenous agents such as infections. [An example of this would be borrelia, that has shown to be recognized by these same receptors. (Specific info on this: http://forums.phoenixrising.me/inde...rkers-tlr-defects.29099/page-2#post-443986).]

So, actually, the MSRV env protein in MS would act in the same way than the possible pathogen responsible for the inhibition of the TLRs in CFS.

I am confused with the available data... Two autoimmune diseases, two different HERVs linked, one to MS and another to ME/CFS, with the difference that the HERV on CFS has not been located, but we know the specific cell expressing it, while in MS, the have located the sequence of the HERV, but not the cells which express them.

The mechanisms seem similar: the interaction with certain TLR. Again the differences:

MS: The MSRV env protein (coming from an unknown cell??) would attach to the TLR4 on macrophages, what would induce inflammation and autoimmunity.

ME/CFS: something that could be exogenous (toxin/pathogen) would inhibit the TLRs 7 and/or 9 of the resident macrophages of the gut, thus producing the expression of the unidentified HERV, what could lead also to inflammation and autoimmunity (Not proben yet).

So, it seems we have a similar picture here, just different HERVs acting in different places...

Would it make sense that in MS the instigator would be endogenous, while in ME/CFS the causing agent would be exogenous?

Any ideas would be very welcome!

Do you think a similar approach to the drug they are trying for MS could be applied to ME/CFS? If so, in what context?

Best!

Sergio
 
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NK17

NK17

Senior Member
Messages
592
serg1942 said:
Hi guys!
This paper just came out:

http://m.neurology.org/content/82/10_Supplement/P2.217.short

It is about a new drug in phase II: "monoclonal antibody agonist of the Multiple Sclerosis associated Retrovirus (MSRV) Env protein", called GNbAC1.

They conclude: "12-month results confirm the favorable long-term GNbAC1 safety profile in MS patients"(...)"These results support the launch of a larger Phase II study testing the efficacy and safety".

My question is how far are we from having a similar drug for ME/CFS, in light of the Lombardi, De Meirleir et al's work on HERVs.

I've been reading about the "Multiple Sclerosis Associated Retrovirus (MSRV), member of type-W Human Endogenous Retroviruses (HERV-W)" and its possible relationship with MS.

Let's see if I got this right: in MS, they have found that the protein env expressed by HERV-W induces the activation of the innate immunity, a predominance of Th1 and autoimmunity. These effects have been shown to occur through the attachment of the env protein to the TLR or CD14 membrane protein of the monocytes that would be induced to become dendritic cells.

I think they have not located the specific cells that would express the env protein though.Have they???

The drug is designed to block the env protein so that it cannot attach to the TLR4 of the monocytes. This way the endoretroviral protein would still be expressed, but it would not induce the activation of the immune cells, hoping this would break the possible pathological pathway.

But, what do we know on CFS? We only have the first study published by K. De Meirleir, Lombardi et al, in 2013, and their poster shown on the recent IACFS conference. (The data of the poster is still unpublished and showed no numbers).

According to their findings, resident macrophages of the gut (plasmacitoid dendritic cells--pDCs) uniquely expressed HERV proteins in ME, and this process would be caused by inhibition of TLR 7 and/or 9 on the pDCs. This inhibition could be caused by exogenous agents such as infections. [An example of this would be borrelia, that has shown to be recognized by these same receptors. (Specific info on this: http://forums.phoenixrising.me/inde...rkers-tlr-defects.29099/page-2#post-443986).]

So, actually, the MSRV env protein in MS would act in the same way than the possible pathogen responsible for the inhibition of the TLRs in CFS.

I am confused with the available data... Two autoimmune diseases, two different HERVs linked, one to MS and another to ME/CFS, with the difference that the HERV on CFS has not been located, but we know the specific cell expressing it, while in MS, the have located the sequence of the HERV, but not the cells which express them.

The mechanisms seems similar: the interaction with certain TLR. Again the differences:

MS: The MSRV env protein (coming from an unknown cell??) would attach to the TLR4 on macrophages, what would induce inflammation and autoimmunity.

ME/CFS: something that could be exogenous (toxin/pathogen) would inhibit the TLRs 7 and/or 9 of the resident macrophages of the gut, thus producing the expression of the unidentified HERV, what could lead also to inflammation and autoimmunity (Not proben yet).

So, it seems we have a similar picture here, just different HERVs acting in different places...

Would it doesn't make sense that in MS the instigator would be endogenous, while in ME/CFS the causing agent would be exogenous?

Any ideas would be very welcome!

Do you think a similar approach to the drug they are trying for ME could be applied to ME/CFS? If so, in what context?

Best!

Sergio
Click to expand...
@serg1942 the above is very interesting and I also see the parallels or the possible connections between MS and ME (bona fide ME diagnosed by the few doctors experts in the field through either CCC or ICC), but I'm afraid the ME research field, as far as HERVs are concerned, is a few steps back compared to the MS field (the main group that follows these line of research is Geneuro and Herve Perron, based in Geneva a Swiss company).

I also think that the scenario in ME is as complex as the one that has been slowly come to be recognized through epidemiological studies (here I would definitely mention Dr. Alberto Ascherio from Harvard, who is involved in the CFI - Chronic Fatigue Initiative-), specifically the involvement in all of MS cases of EBV or Infectious Mononucleosis, same herpes virus that pops up frequently in the history of ME/Cfs and that is considered by Prof. Gavin Giovannoni (of the MS Initiative @ UCLondon) as a, if not the principal player in the pathophysiology of MS.

I really hope that the WPI is on the right track this time with their new line of research into the expression of HERV in ME/Cfs patients.

I certainly think that a monoclonal antibody therapeutic approach for ME is not only desirable but realistically right and that's why we have to support and fight with our governments to get clinical trials funded such as the norwegian one with Rituxan (Fluge and Mella) and the one at UCL supervised by Prof. Jonathan Edwards.
 
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anciendaze

anciendaze

Senior Member
Messages
1,841
I just want to add the observation that it may well be that the cause of various diseases which have not been explained by decades of previous research violates preconceptions of researchers. In particular, it seems likely to me that a disease which had a neat explanation in terms of Koch's postulates would have been understood by now.

I'm not sure how useful the distinction between endogenous and exogenous viruses may be in this situation. If the infection persists for years recombination with similar endogenous sequences is almost certain, and the stable end result should closely resemble the progenitor of the corresponding family of HERVs. I believe this is taking place in the case of MSRV.

The idea that a slowly-replicating virus will breed true in an environment dominated by similar sequences from HERVs which are transcribed at the same time seems extremely questionable. This is more of a convenient assumption than any kind of fact.

When you have experimental demonstration that a retrovirus is capable of infecting isolated cells, including mobile immune cells which patrol mucous membranes, and lying latent for long times, the idea that such a provirus could be reawakened and start recombination in a clade of immune cells is not exactly far-fetched. Do you count this as endogenous or exogenous?

Interactions between retroviruses and endemic DNA viruses do take place, and can be of overwhelming importance, as in the case of reticuloendotheliosis virus (REV) in fowl. Assuming the problems of infection by the two classes of virus can be dealt with separately is, once again, a convenient assumption rather than a law of nature. Nature pays absolutely no attention to academic specializations.
 
S

stevesayshi

Messages
97
Hi serg, Naltrexone is a TLR4 antagonist. I suspect that has a lot to do with its efficacy. I will write a bit more on another thread.
 
NK17

NK17

Senior Member
Messages
592
stevesayshi said:
It's a fine joke, we gotta find the humor where we can...
Anyway, this talks about dextro-nalexone, but it is the same for dextronaltrexone. (Dextro- means it is only the right hand molecule, levo- is left, as in d-ribose and l-carnitine. Naltrexone is roughly 50/50 of both)
http://en.wikipedia.org/wiki/(+)-Naloxone
Click to expand...
Very interesting @stevesayshi. Can we get +/- Naloxone? Is it on the market in the US?
From a preliminary research it is used as a treatment to reverse opioid overdose. I presume at a rather large dose, if you want to have antidote properties.
In our case if we want to have TLR4 antagonist action, what would the proper dose be?
Please let me know when you start the new thread.
Thnx!
 
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S

stevesayshi

Messages
97
Sushi said:
@NK17, isn't Naltrexone also a TLR4 antagonist?
Click to expand...
Yeah, naloxone is like a dirtier version of naltrexone, in that it hits more of the opioid receptor types (I think). But both act on TLR4.

Now, the problem with naltrexone is that because of the opioid blockade, you can't have it in your system long term. So the effect is part time, until your receptors gradually downregulate themselves. Dextro- (aka +) naltrexone doesn't bind to the opioid receptors at all. So you could take 3 or 4 doses of a few mg a day.

Unfortunately it is not directly for sale. But, if you buy the pure naltrexone powder from your compounding pharmacy, there may be a way to use a chiral reagent to separate out the levo-naltrexone. I dunno. I haven't taken chemistry in about 20 years.

Working on a few things... One of them is my magnum opus about LPS and TLR4...
 
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