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New report on BBB from Eurekalert:

Public release date: 5-Apr-2007
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Contact: Steve Benowitz
steven.benowitz@jefferson.edu
215-955-5291
Thomas Jefferson University

Jefferson immunology researchers show blood-brain barrier damage could affect MS severity
(PHILADELPHIA) -- Immunology researchers at the Kimmel Cancer Center at Jefferson studying a multiple sclerosis (MS)-like disease in mice have shown that the amount of "damage" to the central nervous system’s protective blood-brain barrier – in essence, opening it – almost always correlates to the severity of the disease. The findings, reported online in the Proceedings of the National Academy of Sciences, can be used for testing potential MS therapies and for better understanding the role of the blood-brain barrier in disease processes.

Scientists led by D. Craig Hooper, Ph.D., associate professor of cancer biology at Jefferson Medical College of Thomas Jefferson University in Philadelphia, and Hilary Koprowski, M.D., professor of cancer biology at Jefferson Medical College and director of Jefferson’s Center for Neurovirology and the Biotechnology Foundation Laboratories, wanted to find out what factors might affect the onset and severity of EAE (experimental allergic encephalomyelitis), an MS-like autoimmune disease often used as a model. They studied various strains of mice, each lacking some genes associated with inflammation and immunity, and looked at what happened to the blood-brain barrier.

They discovered that the amount of blood-brain barrier damage and subsequent permeability increase correlated to the severity of disease, and surprisingly, in nearly every case, the mouse’s genetic make-up didn’t matter. The mice developed EAE even without supposedly crucial factors in inflammation and autoimmunity – and disease.

"We’ve now shown in all of these mice missing certain components of the immune system that, as expected, opening the blood-brain barrier and letting cells and factors in from the circulation is critical to the development of disease," Dr. Hooper says. "The fact that the extent of the permeability change correlates with the severity of clinical disease signs shows that this is an important element in determining how sick these animals can get.

"This puts an emphasis on the fact that blood brain permeability changes are an important aspect of the development of a CNS inflammatory disease like EAE, an animal model of MS," he says.

According to Dr. Hooper, previous studies by his group and other researchers have shown that blood-brain barrier permeability is critical in the development of MS. To study this permeability, he and his co-workers looked at a range of mice lacking certain genes for various types of immune system and inflammatory cells such as NF kappaB, TNF-alpha, and interferon alpha, beta and gamma that contribute to disease. The researchers established EAE in each mouse strain and examined what was common to all of the animals when they developed disease.

"What’s astounding is that mice that wouldn’t be expected to develop EAE because they have major defects in their immune system are still able to develop disease," though at different rates, he notes.

However, mice missing the immune protein TNF-alpha often did not show disease, despite the increase in brain barrier permeability, causing the scientists to speculate about its role in the disease. "This is the first proof that there are permeability changes in all of these animals and the first hint that permeability doesn’t always equal disease," he says.

Dr. Hooper notes that the work is part of the long-range goal of determining the exact role of blood-brain barrier permeability in disease. "These results tell us a great deal about the mechanisms that damage the blood-brain barrier," he says. "All of these factors that are missing in the mice aren’t essential to opening the blood brain barrier."

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Well, rounds we go, let's keep our labs busy.

About EAE and MS

First, a couple of words about inflammation. Biological role of inflammation – get rid of intruders and clean up the place.

In EAE model the lesions of demyelination produced in absolutely non-physiological way by injection of brain extracts (extremely antigenic, esp. myelin basic protein) with the Freund adjuvant (adjuvant serves as BBB breaker).
There we have a sudden great load of “intruders” and enormous “loose” of BBB in the brain; immune system of the animal ‘goes wild’ and multiple small disseminated lesions of demyelination (as well as micro-necroses) appear simultaneously in the brain, the main antigen (MBP) is in charge.

Sharing some features, mostly demyelination, this model, first introduced in 1930-ties, can not be considered similar with human MS.
Scientifically we can call it – acute allergic multifocal progressive leukoencephalopathy.
Having load of MBP and other brain proteins delivered directly to the brain, combined with total breakdown of BBB, the response from the body in this case could be one only – massive immunoresponse.
EAE either kills animals or leaves them with permanent disabilities, animals with EAE also suffer severe nerve inflammation, and the time course of EAE is entirely different to MS (one time show).

Treatment protocols based on the findings in animal EAE unconditionally used for creating treatment protocols for human MS, despite great differences known and disputed for many decades.
Furthermore, because research into MS has, for many years, been based on these misleading animal experiments, vital research into the human condition has actually been delayed.

It is extremely sad that all disease-modifying drugs for MS were developed using this model.
So, take your guess, why it is still around?


Kind regards,
Tony

PS -finn

My last sentence is not rhetoric, I know the answer, but I would like to hear your opinion.
Happy Easter!

_________________
"All truth passes through three stages.
First it is ridiculed.
Second it is violently opposed.
Third it is accepted as being self-evident."
Schopenhauer

Tony,



I've had this opinion for quite some time and haven't made too many friends in following MS research over the years by stating such. It's nice to see someone such as yourself, who appears to be very knowledgeable in this area, have the same opinion.

Harry

oo

Hi Bob,



I'm sure that Tony will have a good scientific answer to that question. In my opinion, you would have thought that the researchers would have looked for another route to go when time after time, successes in that poor mouse ended up in constant failure when applied to humans.

I go back to the clinical trial my wife was in 10 years ago...the drug called TNF stopped and reversed MS in the mouse but ended up killing one of the trial participants within a year. That ended the trial abruptly. Here we are 10 years later and they are STILL using the mouse to announce new successful findings in MS therapies. And there still isn't one drug that has worked in the mouse that has translated to any kind of meaningful therapy in humans.

Harry

Tony,

Rhetorical or not, I appreciate your question.

I believe in this case we share the same opinion. EAE is a lousy model for MS because it is based so much on inflammation. IMO, that feature alone has made it possible to use it for developing "disease modifying" drugs. Immunomodulators have been around for long, and finding new analogues that work well enough in EAE seems to have been quite easy (and profitable) for drug companies and individual researchers.

I just wonder how many good drug candidates we have lost because they haven't worked in EAE.

Be well.

-finn

_________________
"The great tragedy of science - the slaying of a beautiful hypothesis by an ugly fact.” -Thomas Henry Huxley

-Bob, -Harry,-finn

Thank you all for response.

No one will make a lot of friends disputing EAE as unsuitable model for MS drugs discovery, that's true. Mouse MS does not exist, that's true also.
All new developed drugs for human MS are drugs designed to treat mouse/rat EAE. They will work partially on MS, esp. on very progressive form, but this form is pretty rare. Also they could be used on a bunch of other disorders and we will see that soon.
To discuss about better drug alternative you need to come up with new model of MS which will be analogous to human MS, and if you will have this model it is really not so difficult to see how you can alter/treat it.
We lost not only ‘many drug candidates” for MS, now we forced to use the made up/changed MS treatment protocols tailored for using drugs against mouse EAE at the first place, and this is much worse.

This is a great mix of greed (billions, by the way), ambitions, politics, and growing incompetence together with rising commercialization in modern science.
Growing incompetence sounds weird but there is a lack of total view or global conceptuality compare to enormous amount of pinpointing of tiny details, or search for single agent of influence (among thousands participants) which attracts more efforts then ever. If two will try to get a grant for concept development or for ‘promising’ agent/compound search, take your guess which one will be approved.
Let’s use the analogy. Get 1000 blind people, provide them with everything they need and ask them to describe the Sears Tower, could they do that? I don’t think so. But you will get plenty reports about almost everything, for ex.: -the great difference of the brick surface on the north side wall comparing to south wall, or -influence of sun light exposure to office rooms temp. in various sides/ heights, whatever.

Kind regards,
Tony

_________________
"All truth passes through three stages.
First it is ridiculed.
Second it is violently opposed.
Third it is accepted as being self-evident."
Schopenhauer

Tony,

Does the FDA require that trials for any new products be made on mice first?

Second, I am getting the sense that you do not think that the current research will do anything to reverse MS symptoms. What discovery is needed to at least stop the progression of brain atrophy?

I read all of your posts in depth and appreciate the knowledge that you are sharing here.

gwa

I think that the problem in trying any MS drug in animals, particularly rats with EAE, is that doesn't show a true MS. As nobody knows MS cause (we have hundred hypothesis), it is impossible to make a effective MS animal, to find effective drugs. It is like building a house from the roof.

Does anybody know if some team is seriously working just in the cause of MS?

The Myelin Repair Foundation is one that is working to find a cure/treatment for MS. There is some info on this board about this group of researchers.

gwa

Harry,

I didn't realise you'd had such a bad experience with people who support the use of EAE: I was under the impression that everybody knew it was a pretty poor analogue. This is from the "Handbook of Laboratory Animal Science" by Jann Hau and Gerald L. Van Hoosier:
"most induced models are partial or isomorphic because the aetiology of a disease experimentally induced in an animal is often different from that of the corresponding disease in the human. Few induced models completely mimic the aetiology, course, and pathology of the target disease in the human."

However if, as Tony said, drugs developed for human MS will be used for "a bunch of other disorders", that prompts an obvious and critical question: if drugs developed from animal models , using induced experimental disease, are successful for other conditions, what is different about human MS that makes them not work there? The same can be asked about drugs which work for progressive MS but not relapsing: the differences in method of action should give us enormous clues about what is going on.
As Bob said: what alternatives are there at the moment? If you can't find an animal which naturally gets MS, you have no choice but to induce it artificially and work with what you've got. If you could cause "real" MS in an animal, the chances are you'll be pretty close to understanding the causes in humans.
Although individual labs and researchers often narrow their focus and appear to be nit-picking, attending to the tiny details may be vital, (I seem to remember the first Aids drug, AZT, was discovered by someone studying the sperm of salmon), and hopefully organisation such as the MRF can provide the necessary broader overview,

Dom.

Tony,

thanks again for taking the time to comment these issues. Your posts always seem to generate more discussion, which is good. This time I got a bit puzzled with these statements:

I'm sorry, but I'm not sure if I got it right. Are you saying that drugs that work on EAE would work better on very progressive forms of MS? If so, I'm slightly confused.

Absolutely, but like Rita wrote earlier, it might be even impossible to create a good animal model for mimicing a human neurological disease with unknown pathogenesis.

Well, as long as the major source for funding MS research will be drug companies, I'd say the situation won't change. MS is big business, a couple of years ago the global annual sales of ABCR-drugs alone was almost 4 billion dollars.

As Ludvig Mies van der Rohe once said, "God is in the details". Of course putting all existing pieces together for a "global MS concept" would be important, but creating a valid outcome might need a lot of resources and a multidisciplinary group of researchers. Otherwise it might be concidered as just another hypothesis by an ambiguous researcher who wants to get something published.

On the other hand, I think a good example of focusing on details is KDI-tripeptide, a highly neuroprotective substance with an ability to promote neuroregeneration. It was discovered by a Finnish researcher Päivi Liesi over 20 years ago, and now she is ready to take it to clinical phase. If it works as well in humans as in mice with spinal cord injury, I'd say it will be one of the greatest therapeutic discoveries in neurobiology so far. IMO, the best part is that it is a natural protein, and it will be difficult for any drug company to gain profits with it :-)

Be well.

-finn

edit: added word "annual"

_________________
"The great tragedy of science - the slaying of a beautiful hypothesis by an ugly fact.” -Thomas Henry Huxley

oo

Hi Bob and Rita,

I really like the "house" analogy too! If MS is the roof, each piece of research and new understanding removes a brick until we get down to the foundations. Sometimes, unfortunately, we go off at a tangent: led astray to move along the wall instead of down it. Hopefully, just removing one key brick will make the roof collapse before too long, even if we haven't reached the basement. I think we're somewhere near the bedroom windowsill... let's hope it's a single storey building!

Dom .

oo