Monday, 3 February 2014

Yet another mechanism for glatiramer acetate

From R, Eilam R, Bar-Lev DD, Levin-Zaidman S, Tsoory M, Lopresti P, Sela M, Arnon R, Aharoni R.Oligodendrogenesis and myelinogenesis during postnatal development effect of glatiramer acetate. Glia. 2014 Jan 30. doi: 10.1002/glia.22632. [Epub ahead of print]

Myelination in the mammal nervous system occurs predominantly postnatally (after birth). Glatiramer acetate (GA), a drug for the treatment for multiple sclerosis (MS), has been shown to induce immunomodulation and neuroprotection in the inflamed CNS in MS and in experimental autoimmune encephalomyelitis (EAE). Here we investigated whether GA can affect myelinogenesis and oligodendrogenesis in the developing nervous system under nonpathological conditions. Towards this end we studied myelination in mice injected daily by GA, at postnatal Days 7-21. There was  a significant elevation in the number of myelinated axons as well as in the thickness of the myelin encircling them  in spinal cords of GA-injected mice compared with their PBS (Saline= salt solution 0.9%)-injected littermates, at postnatal Day 14. Elevation in myelinated axons was detected also in the peripheral ventral roots of the motor nerves. GA induced also an increase in axonal diameter, implying an effect on the overall development of the nervous system. A prominent elevation in the amount of progenitor oligodendrocytes and their BrdU (Bromo deoxyuridine as a marker of cell division) incorporation, as well as in mature oligodendrocytes indicated that the effect of GA is linked to increased proliferation and differentiation along the oligodendroglial maturation cascade. In addition, elevation in nerve growth factors was found in the white matter of the GA-injected mice. Furthermore, a functional advantage in rotating rod test (a accelerating spinning wheel from which the animals fall when they dont have enough movement co-ordination) was exhibited by GA-injected mice over their littermates at postnatal Day 21. These cumulative findings corroborate the beneficial effect of GA on oligodendrogenesis and myelination. 



I know that this has become a bit of a theme as far as I am concerned and this irritates a number of readers, especially those using the drug but this is yet another example of a mechanism of action of this drug. 

It has had more mechanisms of action that most people have had hot dinners. Maybe this is THE action but remember in many EAE models there is no demyelination and yet Glaterimer acetate can have an impact. 


However it has been suggested to support remyelination before and saving nerves and  promoting T cell regulation and.... and....If this is the mechanism of action in MS, do we see rapid functional recovery after treatment.


We are about 40 years on from when GA was first constructed and do we know who it works. Looking forward to the next mechanism....It keeps the drug in the public eye. 


Is this a marketing ploy to keep GA uppermost in the mind?

23 comments:

  1. As mentioned above, considering how many positive things GA is supposed to do, it's perplexing that it has only a modest effect on MS. How can this be?

    ReplyDelete
    Replies
    1. Yes, it has a modest effect on relapse rate in a two year trial in which is your measure of success. As many are discovering this is not a good way of defining the efficacy of a drug, particularly in a progressive disease.

      But we do need to halt measurable disease as quickly as possible, which is what all patients of MS want. Unfortunately having a drug that accomplish this in the short term does not automatically translate to the longterm success.

      After having been on Copaxone a year, I have not had any relapses where before I would have at least one per year. Does guarantee longterm effectiveness? No, but the longterm extionsion studies as well as the results of longterm users gives me encouragement for the future.

      Delete
    2. Is it because MS is destructive in ways that we can't quite figure out? Is there a lot more insidious activity going on in our CNS that we are not yet able to detect?

      Delete
    3. Does anyone really think that if we can cease inflammation then the damaged nervous system will simply heal itself via natural means? Does this mean that even progressive MSers will benefit from such therapies?

      Delete
    4. GA was tested in PPMS, but the trial was stopped early because there was no noticeable difference between the placebo arm and the GA arm. But a post hoc analysis found that GA had a statistically significant effect on slowing down progression in male patients:

      http://www.ncbi.nlm.nih.gov/m/pubmed/17262850/

      So, if we are going to halt progression there needs to be a better way of measuring drug effectiveness because the current process does not work for progressive ms and may be misleading for RRMS.

      Delete
    5. I guess we will never know Teva, are unlikely to redo studies to provide class I evidence.

      I wonder if such studies will be undertaken using COP-2 the son to COP-1 but will COP-2 make it to the MS arena?

      It is interesting that the effects in animals are evident after just a few days.

      If we stop inflammation in progressive MS I have no doubt it will be beneficial

      Finally let us hope you are responding to GA, but in trials there is this thing known as "regression to the mean" which essentially says that you may have active disease when you enter a trial (or go on treatment) but the natural history would suggest that after a period of activity your disease may be less active. So this expected even if you are on placebo then the disease activity goes away. However with drug it may go away more than if you are placebo

      Delete
  2. What if anything do we know about GA and it's inter action with uric acid ? and it it relevant ?

    Regards as always

    ReplyDelete
    Replies
    1. https://www.ncbi.nlm.nih.gov/m/pubmed/11212132/?i=1&from=/11212132/related

      Not sure this answers your question. Why do you ask?

      Delete
    2. Until a few minutes ago I knew nothing, but hey you have found yet another mechanism!!

      GA increases uric acid (http://en.wikipedia.org/wiki/Uric_acid) which is an anti-oxidant (http://www.ncbi.nlm.nih.gov/pubmed/11212132),. This can inhibit EAE and people with GOUT a disease caused byhigh uric acid levels have apparently less MS.

      Delete
    3. It looks like Inosine raises uric acid levels. So the cure for MS is to maintain healthy levels of uric acid. Case solved. Get working on a study.

      http://en.m.wikipedia.org/wiki/Inosine

      Delete
    4. Just gonna throw a few more in. A lot of alternative theories in preventing relapses involve avoiding dairy, look up the interaction between dairy and uric acid. Also anti-oxidants seem to have beneficial action and help support the function of mitochondria by mopping up the free radicals ( I thought they were a pop group :-) look up the latest mitoQ study on eae mice.

      Regards as always

      Delete
    5. These are old papers , but nevertheless interesting.

      http://www.ncbi.nlm.nih.gov/pubmed/12451183

      http://www.ncbi.nlm.nih.gov/pubmed/9435251

      Plenty more out there.

      Regards as always.

      Delete
    6. A possible association between multiple sclerosis (MS), the disease on which EAE is modeled, and uric acid is supported by the finding that patients with MS have significantly lower levels of serum uric acid than controls. In addition, statistical evaluation of more than 20 million patient records for the incidence of MS and gout (hyperuricemic) revealed that the two diseases are almost mutually exclusive, raising the possibility that hyperuricemia may protect against MS.

      Last one from me, well maybe ;-)

      Regards as always

      Delete
    7. Here is the results of a trial for ms to the evaluate iodine, which raises uric acid:

      http://www.ncbi.nlm.nih.gov/m/pubmed/19425822/?i=2&from=/19865105/related

      Delete
    8. Oh my yet another mechanism. GA affects Iodine levels too

      Combined treatment of glatiramer acetate and low doses of immunosuppressive drugs is effective in the prevention of graft rejection. http://www.ncbi.nlm.nih.gov/pubmed/15589456

      Delete
    9. Short of raising the dead, is there anything it doesn't do?

      Delete
    10. This is interesting. A few years ago, I had what the doctor thought was an attack of gout (my big toe was painfully throbbing). Never had one before that. The GA I had been injecting for 2 years at that point might explain it.

      Delete
  3. GA-the Asprin of the of 1970s, 1980s, 1990s, 2000s, 2010s

    ReplyDelete
    Replies
    1. You might think that, I couldn't possibly comment. Oh wait, I already have!

      Delete
  4. You guys should have come up with Copaxone first. You'd be billionaires instead of watching from the sidelines. Don't give up, one day it may happen for you.

    ReplyDelete
    Replies
    1. Millionaire i am not holding my breathe, although I was actually a millionaire once.......in a foreign currency :-)

      Having seen what it does in animals . Would it have been good if we invented it? Maybe.
      Wonder how the Harvard guys who invented COP2 feel.

      Delete

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