Saturday, 1 August 2015

Another new model of EAE in primates

Stassart RM, Helms G, Garea-Rodríguez E, Nessler S, Hayardeny L, Wegner C, Schlumbohm C, Fuchs E, Brück W A New Targeted Model of Experimental Autoimmune Encephalomyelitis in the Common Marmoset. Brain Pathol. 2015. doi: 10.1111/bpa.12292. [Epub ahead of print]

Multiple Sclerosis (MS) is the most common cause for sustained disability in young adults, yet treatment options remain very limited. Although numerous therapeutic approaches have been effective in rodent models of experimental autoimmune encephalomyelitis (EAE), only few proved to be beneficial in patients with MS. Hence, there is a strong need for more predictive animal models. Within the last decade, EAE in the common marmoset evolved as a potent, alternative model for MS, with immunological and pathological features resembling more closely the human disease. However, an often very rapid and severe disease course hampers its implementation for systematic testing of new treatment strategies. We here developed a new focal model of EAE in the common marmoset, induced by MOG immunization and stereotactic injections of proinflammatory cytokines. At the injection site of cytokines, confluent inflammatory demyelinating lesions developed that strongly resembled human MS lesions. In a proof of principle treatment study with the immunomodulatory compound laquinimod, we demonstrate that targeted EAE in marmosets provides a promising and valid tool for preclinical experimental treatment trials in multiple sclerosis research.

Marmosets are rat sized primates, born as twins. Primates may have their part to play in the development of treatments for MS. 

There is a tendency of people working with primates, and often many clinicians to blame the lack of drugs for MS on rodents.

"Rodent models of experimental autoimmune encephalomyelitis (EAE), only few proved to be beneficial in patients with MS". 

Whilst this may in part be the case we, first have to address the human failings.


Likewise, we can ask where primates have been more successful over their rodent counterparts? 

The literature is full of marmoset studies on treatments that have gone nowhere. Is that the fault of the idea, model or the clinical trial. 

The disastrous "elephant head" anti-CD28 super agonist trial  that made people loose their toes and fingers was tested in marmosets. Five minutes of thinking could have save lots of rodents, primates an humans hard as the end result was entirely predictable based on what anti-CD28/anti-CD3 (proliferation signal of the T cell receptor which is similar in function to the proliferation signal delivered by CD28) does. 

The speed at which animals accumulate damage depends on which strain you use and how you induce the disease. In this study they induce sub-clinical EAE and them put inflammatory cytokines in the brain. This model was developed in rodents years before, as it has some refinement capacities over standard EAE because animals. This is because often you do not get clinical disease and you know where the lesion is. This is probably more of a key issue.

You get better demyelination in non-human primates than you do in a mouse and you get brain lesions. This a fact that I would not argue with. However, what about a rat or a guinea pig, do you need to use a primate? 

I am sure you can make the case, but certainly for looking at whether laquinimod is an immunmodulator? 

In rodents it has immunmodulating effects and the efficacy is known in humans already

They will have had  to undergo ethical review for this studies. The views may dependent of the national psyche of the panels. So countries do not bat an eyelid about primate work and in others this means death threats are coming your way and so researcher do not undertake this work lightly.

Laquinimod is very poor at stopping relapses compared to other DMT. So it is not clear why you would validate a model using a drug that is not very good in humans as surely it has to be not very good in animals too for the model to be valid. 

There is a question mark about whether laquinimod has a good neuroprotective effect, could this not be assessed in other ways?

Why do we use non-human primates studies....as a safety tool before going into humans or as a research tool to find treatments? But can you ever do experiments in enough marmosets to be confident? 

Should animals studies be used as marketing tools to keep drugs in the news, whilst the trials are being done? 

Hopefully this new tool can help find a treatment that works.
There are no groups in the UK performing EAE experiments on non-human primates.

3 comments:

  1. They were using Marmosets at Kings College in 2013 for Parkinson's research http://www.theguardian.com/science/2013/oct/13/lab-where-marmosets-are-given-parkinsons

    No easy answers, but at least there is a strong regulatory framework in the UK. That's no solace for the non-human animal but it helps me feel a little less awful about it.

    Marmosets are quite intelligent and emotionally complex, I believe. Maybe mice are too but that doesn't upset me and raise uncomfortable philosophical questions like non-human primate use does.

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  2. Yes there are lots of centres that do primate research but not in relation to ms.

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  3. Does it matter what the illness is, it still bears a heavy responsibility on me. I'm not an animal liberationist but I try to limit my 'footprint' as much as I can, which is a bit woeful in practice (perhaps I just like feeling guilty).

    However, it would be hypocritical for me to claim the moral high ground as so much of our lives are owed to the use/abuse of non human animals from drugs to clothes dye. Never mind food (I'm mainly vegan but not wholly as I eat eggs from a friend's hens).

    Unless I lived on a desert island, wearing only banana leaves and ate just nuts and berries, and never even had a headache, I'm in no position to judge. I just wish we were beyond the need for non human primate modelling.

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