Remyelination in THREE animal models?

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Remyelination in THREE animal models?

Postby TwistedHelix » Fri Jan 19, 2007 6:36 am

I've just seen this on 'Acorda's' website, under "pipeline/R&d". It mentions three different animal models of MS, but I've only ever heard of EAE. Can anyone enlighten me on this?

Dom.

" Acorda’s remyelination programs include two distinct therapeutic approaches to stimulate repair of the damaged myelin sheath Myelin is the insulating layer of membranes that surrounds most nerve fibers. When an axon is demyelinated, nerve impulses “short circuit” much like a wire whose insulation has been stripped.

What is Demyelination?

In 2002, Acorda acquired an exclusive worldwide license from CeNeS, Ltd. to the neuregulins – a class of naturally occurring protein growth factors that have multiple effects on the nervous system and potential therapeutic applications in neurologic conditions.

The most clinically advanced of these agents, Glial Growth Factor 2 (GGF2), is a member of the neuregulin family of growth factors related to epidermal growth factor. The neuregulins bind to erbB receptors, which translate the growth factor signal to the cell and cause changes in cell growth, protein production and gene expression. The molecule was shown in published studies to stimulate remyelination in animal models of MS and to have a range of other effects in neural protection and repair.

Acorda’s remyelinating antibody program is based on an exclusive license to patents derived from more than 15 years of research performed at the Mayo Clinic. The program is designed to promote remyelination of affected areas of the brain and spinal cord.

Studies have demonstrated the ability of this family of antibodies to stimulate repair of the myelin sheath in three different animal models of MS. In particular, these antibodies were found to react with molecules on the surface of the cells that make the myelin sheath and stimulate them in a number of ways, leading to increased remyelination activity. First identified in mice, similar antibodies were subsequently identified in human blood samples by the Mayo team and Acorda has been able to produce a recombinant human antibody that may be suitable for clinical development.

Whereas Fampridine-SR may restore function by pharmacologically compensating for myelin loss in some axons, these antibodies may actually replace the lost myelin, which may provide additional benefit."
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Postby gwa » Fri Jan 19, 2007 9:46 am

Dom,

According to the drug trials list on this site, this treatment is still in the pre-clinical stage. To me that means that the product is still at least 15 years away, if it works at all in humans.

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Re: Remyelination in THREE animal models?

Postby JFH » Fri Jan 19, 2007 12:05 pm

TwistedHelix wrote:I've just seen this on 'Acorda's' website, under "pipeline/R&d". It mentions three different animal models of MS, but I've only ever heard of EAE. Can anyone enlighten me on this?

Maybe EAE in three different types of mice? Sounds daft but labs do buy animals bred to spec dont they.
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Postby gwa » Fri Jan 19, 2007 1:19 pm

JFH,

Three mice would be my guess too since they do not tell what the animals are on their website.

Several researchers have been working on building a better model of MS mice in the past few years.

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Postby art » Fri Jan 19, 2007 1:21 pm

The 3 models I am aware of are EAE, Theiler's Virus, and a marmoset model. Although there are a number of variants of EAE.
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Postby TwistedHelix » Sat Jan 20, 2007 8:45 am

Thanks guys,

I did a bit of digging about Theiler's virus, which is one of those names which rings a bit of a bell, but I can't remember where I'd heard it before. It triggers murine encephalomyelitis, (a condition which closely resembles MS in mice), so is obviously useful as a research tool -- though whether you think mice provide a good model for human MS or not is another matter -- and sent a bit of a shiver down my spine. When I was 11 years old in 1972, I had a two week episode of paralysis down my left hand side; I had a lumbar puncture, and then was hustled into isolation when a viral infection was found in a stool sample. Obviously at that age very little was explained to me, and every time I have tried to pin down neurologists for an answer they are very vague: some say they have seen "old scarring" on MRI scans, some have hinted it might have been a juvenile attack of MS, others say it was viral encephalitis and completely irrelevant. I think it would be important to know because, if it was a first attack of MS with a 15 year-ish gap to my next symptoms, then I have SPMS, if not, most likely PPMS. I suppose I'll never know.

This from PubMed, sorry if it's appeared here before:

"Both genetic background and environmental factors, very probably viruses, appear to play a role in the etiology of multiple sclerosis (MS). Lessons from viral experimental models suggest that many different viruses may trigger inflammatory demyelinating diseases resembling MS. Theiler's virus, a picornavirus, induces in susceptible strains of mice early acute disease resembling encephalomyelitis followed by late chronic demyelinating disease, which is one of the best, if not the best, animal model for MS. During early acute disease the virus replicates in gray matter of the central nervous system but is eliminated to very low titers 2 weeks postinfection. Late chronic demyelinating disease becomes clinically apparent approximately 2 weeks later and is characterized by extensive demyelinating lesions and mononuclear cell infiltrates, progressive spinal cord atrophy, and axonal loss. Myelin damage is immunologically mediated, but it is not clear whether it is due to molecular mimicry or epitope spreading. Cytokines, nitric oxide/reactive nitrogen species, and costimulatory molecules are involved in the pathogenesis of both diseases. Close similarities between Theiler's virus-induced demyelinating disease in mice and MS in humans, include the following: major histocompatibility complex-dependent susceptibility; substantial similarities in neuropathology, including axonal damage and remyelination; and paucity of T-cell apoptosis in demyelinating disease. Both diseases are immunologically mediated. These common features emphasize the close similarities of Theiler's virus-induced demyelinating disease in mice and MS in humans."

PMID: 14726460 [PubMed - indexed for MEDLINE]

The viral connection intrigues me; I have read a bit about epitope spreading and it seems to have enormous relevance to immune system tolerance, B and T cell activation, and immune reactivity. In a nutshell it seems that the epitope, (the peptide chain on the surface of an antigen which fits into the paratope on the surface of the antibody), isn't just a single key which, if blocked, would stop the disease, but a continuously evolving "set of keys" which constantly "remind" the body to attack itself, (not a great explanation, but I can't think of a better one at the minute). Epitope spreading is normally a useful thing because it enables the immune system to attack foreign tissue on a much broader front, but in auto-immune disease, (IF, that is, MS is autoimmune), the normal control mechanisms are faulty, possibly for genetic reasons. Interesting that the virus replicates in grey matter first--a possible route by which the immune system sensitises to axons??

Anyway, I'd better go now because I can't stop laughing... I have to use speech recognition software in order to write and it has quite a few problems with technical words -- below are a few examples:

"epitope"=a Peto, editor of, added Tote,
"paratope " parrot to have, bit parrot top-up it, baritone, Parrott hope, para top-up.
"Encephalomyelitis" in Chevallot my light this, in care poliomyelitis, a Catalan myelitis, Inca Fulham highlight this, and cattle are my lighters, any careful a myelitis , think of Le my life to us.

Technology, eh? Oh well, I have got a rotten cold, so I'm quite hard to understand!

Dom.
Last edited by TwistedHelix on Sun Jan 21, 2007 7:53 am, edited 2 times in total.
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Re: Remyelination in THREE animal models?

Postby beyondms » Sun Jan 21, 2007 6:24 am

TwistedHelix wrote: Whereas Fampridine-SR may restore function by pharmacologically compensating for myelin loss in some axons, these antibodies may actually replace the lost myelin, which may provide additional benefit."


Keep your eye on Accorda, I think they will be the biotech compnay with the most positive surprises for MS. By the way, 15 years? More like 5 to 7 years away.....

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Postby CureOrBust » Sun Jan 21, 2007 11:46 pm

art wrote:The 3 models I am aware of are EAE, Theiler's Virus, and a marmoset model. Although there are a number of variants of EAE.
I can only remember reading studies that have used EAE. I did a search on "Theiler's Virus" and the stuff I get back from google scholar talks about the model itself, not what reverses it. What has been found to be effective against this model? are there results against this model for the crabs?
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