Tuesday, 10 June 2014

When is EAE progressive EAE....when you are trying to develop a drug for progressive EAE?

Mindur JE, Ito N, Dhib-Jalbut S, Ito K. Early Treatment with Anti-VLA-4 mAb Can Prevent the Infiltration and/or Development of Pathogenic CD11b+CD4+ T Cells in the CNS during Progressive EAE. PLoS One. 2014 Jun;9(6):e99068.

Natalizumab is a humanized monoclonal antibody against the leukocyte adhesion molecule very late antigen (VLA)-4, and is currently an approved therapy for patients with relapsing-remitting multiple sclerosis (RRMS). However, it is unknown whether natalizumab is beneficial for progressive forms of MS. Therefore, we assessed the effects of anti-VLA-4 monoclonal antibody (mAb) therapy in a progressive experimental autoimmune encephalomyelitis (EAE) mouse model. Notably, we found that early therapy could significantly reduce the severity of progressive EAE, while treatment initiated at an advanced stage was less efficient. Furthermore, we observed the accumulation of a novel subset of GM-CSF-producing CD11b+CD4+ T cells in the CNS throughout disease progression. Importantly, early therapeutic anti-VLA-4 mAb treatment suppressed the accumulation of these GM-CSF-producing CD11b+CD4+ T cells in the CNS along with activated microglia/macrophages populations, and also conferred a protective effect against inflammation-mediated neurodegeneration, including demyelination and axonal loss. Collectively, our data suggest that early treatment with anti-VLA-4 mAb can provide neuroprotection against progressive CNS autoimmune disease by preventing the accumulation of pathogenic GM-CSF-producing CD11b+CD4+ T cells in the CNS.

For many years we thought of EAE as being autoimmune and EAE was focussed on studying autoimmunity. But now that in-roads are being made in RRMS and progressive MS is the major unmet need.

So a real progressive MS model is something that would be exceptionally useful.
The title sounds exciting and suggests that Tysabri will work in progressive MS. Let's hope so. If they treat before disease develops the drug works better than if you give after disease has started. It works by stopping cells getting into the brain.

But is it progressive EAE?...it looks absolutely no different from the standard chronic EAE in mice that has been used to study autoimmunity targeted at relapsing MS. Progressive MS does not respond well to peripheral immunosuppressive drugs, yet in this paradigm immunosuppression reigns supreme. 

So change in name and now it means something completely different. 

Does this model develop progressive disease...yes probably but it after disease has become established.
Whilst it EAE in C57BL/6 is touted by some a primary progressive, it is a one hit neurodegenerative immunological attack and animals do not fully recovery because they are losing critical nerves. However, if left these animals often show progressive worsening. So in this respect it is a bit like primary progressive disease in that you do not need multiple attacks for the progression to start. However, the progressive tag came about probably because of non synchrous disease so the line graph made it look like there was continous worsening. We have posted on this before


http://multiple-sclerosis-research.blogspot.co.uk/2013/04/education-quality-control-of-eae.html


Whilst the data looks solid and it is what it is, don't use this information to judge and pin your hopes whether it will work in Progressive MS. The human result will be known soon.

Why do animal studies when human studies are so advanced and the drug is being already tested in humans for this purpose?.....It may show a mechanism that helps getting the drug through the regulators and also it is something that helps the marketing as it keeps the compound in the public eye, whilst the trials are ongoing.

It is interesting the study was funded by Biogen makers of Tysabri, who are testing their drug for its ability to stop progressive MS. For licensing I have heard that the FDA like a bit of mechanistic animal data. So this all sounds perfect. (Although Biogen had no input in the experimental plan!). One don't need to meddle with the design it's tried and tested..so keep on marketing:-)

2 comments:

  1. "This suggests that natalizumab may be an effective therapy for patients with progressive forms of MS, and thus, may aid to prevent disease progression and severe neurodegeneration as long as treatment is administered early after the disease diagnosis." What constitutes early diagnosis of progressive disease? Transition to SPMS takes years. Is there a therapeutic window for natalizumab and progressive disease?

    ReplyDelete
    Replies
    1. I am sure there are therapeutic windows

      I don't know how early is early based on the animal work some problems occur from the get go, but it takes a whilst for the clinical progression to kick in. Only time will tell, but as many people on DMT may not be in a register accessing the data may be very difficult

      Delete

Please note that all comments are moderated and any personal or marketing-related submissions will not be shown.