Good news - Major milestone in identifying ms genes

If it's on your mind and it has to do with multiple sclerosis in any way, post it here.

Postby OddDuck » Fri Mar 18, 2005 7:18 am

Hi, rasnet!

I was wondering, how on earth do you grasp all this medical crap so easily - is it your profession, or do you read lots and lots? im just being nosey... so tell me to bugger off if you like!!


Naw, I'd never tell you to bugger off! :)

Heck, I don't know how I grasp half the stuff I do. I was always like that as a kid, too. I just call it all a "knack". It's not just "medical" stuff that I grasp like this, either. (And that's not really saying anything great or bragging or anything), but I have heard that before, as I said, ever since I was a kid. I've always been asked "how do you know that?" or "where or how did you learn it?"

I do read a lot, but I've never had to study that hard, and I only have a high school education. I was being recruited once when I was about 14 by Mensa (after I took their tests), but I never joined.

Just a "knack", I guess.

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MS and diabetes

Postby Trudy » Fri Mar 18, 2005 1:35 pm

Of course Robin. However, it does not seem enough to say that there is crossover of medications because these (MS, diabetes etc.) are all autoimmune diseases. For two reasons: (1) presumably, not all autoimmune diseases are the same. Nor, again presumably, does the immune system work in only one way. If that were the case, we would only need one medication. (2) It is not (or no longer) clear whether MS is primarily an autoimmune disease. Given that the CRAB drugs, which modulate the immune system, are not all that effective, it does not seem likely. So if the diabetes drug works for MS, one does have to wonder in what specific way MS and diabetes are similar. Also, whether they are effective, if at all, only in the case of RRMS.
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Postby OddDuck » Fri Mar 18, 2005 2:14 pm

Trudy,

A TZD also can be thought of as a "gene therapy". It isn't thought of as affecting the immune system much at all, really. (EDIT: I need to clarify when I say that. I mean "affecting the immune system DIRECTLY. And/or as it pertains specifically to "inflammation". I'm talking and typing fast and probably not being clear.)

As I posted, TZDs appear to be effective particularly in the progressive forms of MS (where little to no inflammation is involved).

Let me go find more specifics as it pertains to MS treatment.

As we all know, anti-epileptic medications are used in MS to treat pain. Not because MSers are necessarily having epileptic seizures, but many drugs have broad spectrums of action in addition to treatment of specific diseases they were originally intended for.

I don't necessarily believe that it is helpful to make such a direct comparison of diabetes with MS, the same as it isn't for epilepsy and MS. Also, Novantrone, which is a chemotherapy drug for cancer, is used to treat MS, but again, MS and cancer are not the same diseases, either.

Let me go see what I can find to explain which mechanism of action of a TZD is what they believe helps in MS.

Deb
Last edited by OddDuck on Fri Mar 18, 2005 2:27 pm, edited 2 times in total.
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Postby OddDuck » Fri Mar 18, 2005 2:19 pm

Ok...here we go....here's a start.

Here is what I posted in another thread some time ago entitled "TZDs and SPMS":

First, here's a very brief explanation of a TZD:

Normal cells tightly control cell growth and ACTH secretion by what genes are tuned on or off and how much of a gene product is present (expressed). Some gene products are often over-expressed in tumor cells when compared to normal cells. PPAR-g is a member of the nuclear receptor superfamily, like the better-known estrogen receptor, and regulates expression of other genes. Compounds that bind to PPAR-g and mediate its actions (called ligands) include the thiazolidinedione compounds (TZDs) that are commonly employed in the treatment of type II diabetes. The PPAR-g is expressed at high levels in several cancers including breast, prostate and colon cancer, and treatment of cancer cells with PPAR-g ligands, such as TZDs, inhibits prostate and colon tumor cell growth.


"TZDs inhibit T lymphocyte proliferation and activation, reduce expression and production of inflammatory molecules including interleukin-1β, tumor necrosis factor-α and inducible nitric oxide synthase, increase astrocyte metabolism and resistance to cytotoxicity [11], and reduce clinical symptoms in experimental autoimmune encephalomyelitis (EAE), an autoimmune-mediated, demyelinating disease which provides a model for MS [2,3]. "


It has to do with PPAR. Again, I posted some research regarding PPARs somewhere around here, too. Let me go find it. :D

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Postby OddDuck » Fri Mar 18, 2005 2:23 pm

Here 'tis:

http://www.thisisms.com/modules.php?nam ... light=ppar


Douglas Feinstein, PhD
University of Illinois at Chicago
The School of Medicine
Chicago, IL
Region: Greater Illinois Chapter
Award: Research Grant
Term/Amount: 10/1/04-9/30/07 $360,113

Therapeutic potential of PPAR delta agonists in demyelinating disease” Determining whether a natural brain chemical can stop MS-like disease and stimulate myelin repair by replacement cells.

MS is thought to result from an immune attack on nerve-insulating myelin and nerve fibers, with immune cells migrating into the brain and increasing production of inflammatory immune proteins. Recent evidence suggests that certain medications approved by the FDA to treat diabetes, known as PPAR-gamma agonists, can reduce the activity of genes that regulate such immune responses in the brain.
Douglas Feinstein, PhD, has found that treatment with PPAR-gamma agonists reduced the incidence and the severity of EAE, an MS-like disease, in mice by reducing inflammation and blocking immune T cells. His team also has shown that treatment with a slightly different drug – a PPAR-delta agonist – results in the growth and development of myelin-making cells. Together, these two agonists might control immune responses early in disease, and stimulate myelin repair later on.

Dr. Feinstein is exploring the mechanisms by which PPAR-delta can stimulate myelin growth, focusing on the effects of this agent on mice with EAE and in laboratory experiments using isolated mouse and human nervous system cells. This project should provide vital information necessary to determine whether PPAR-delta agonist will be a useful treatment for people with MS.


Ok, I need to edit and clarify a little more. This post above refers to PPAR-delta. The posts previous to this refers to PPAR-gamma. Two slighty different things, but the bottom line is that a TZD, due to its "gene therapy" type of action, ends up affecting or "regulating" how the immune system functions, whether or not inflammation is involved. "Inflammation" is not the main "target" with this particular treatment.
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Postby OddDuck » Fri Mar 18, 2005 3:11 pm

Ok.........I'm on my way out the door, but here is what I started to find regarding this on the thread http://www.thisisms.com/modules.php?nam ... 54&start=0

Wesley and I talked about it a little bit, but then got off track again, and didn't continue much farther.

Here is what I said at the time, though:

Hey...........there's a common denominator here! Between epilepsy, multiple sclerosis, and diabetes. PPAR: "peroxisome proliferator-activated receptor-alpha (PPAR), a transcription factor that regulates the use of fatty acids within cells."


Maybe all this only makes it as clear as mud, as they say! :wink:

Deb

EDIT: I will say, also, that when I was talking to Vanderbilt about desipramine, the neuro/researcher there asked me if I had looked into PPAR yet, and if not, I should do so. Anyway, that might be another "to do" for another day. Have a good one, folks!!
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Postby OddDuck » Fri Mar 18, 2005 3:20 pm

Always one last thing.......... :lol:

If you will note above the mention of ACTH. There is our connection to the HPA axis again.

Round and round.

Anyway, I think TZD treatment is VERY promising!!!

Ok.......NOW I'm gone for the night! Night all!!

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Postby Trudy » Sat Mar 19, 2005 7:04 am

Thanks Deb. This is very helpful. Makes me wonder though: has the research gone off track with its emphasis on the inflammatory side of MS? And if so, why hasn't anyone noticed? Wrong question. Obviously some people have noticed. But why hasn't anyone taken them seriously?
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Postby OddDuck » Sat Mar 19, 2005 8:03 am

Hi, Trudy!

Well, I hate to say this, but RRMS does have the inflammatory aspect to it, and more people are diagnosed with RRMS, and there is a mouse model for MS which includes inflammation (whereas there are no mice models of progressive types of MS), so put all together, research for RRMS is easier, will treat more people, and for pharmas is more profitable.

There is research going on for progressive MS, but since there are no mice models of that pattern of disease, it is hard to study and try to treat. Getting pharma companies to "focus" on progressive types of MS doesn't prove to be quite as profitable for them. They don't get as big of a return for their research investment dollars.

Anyway, I speculate that's why you see more emphasis and studies regarding inflammation associated with MS. It's easier to target and try to treat.

But........in the long run, does it appear to be the overall BEST aspect of MS to focus on or treat to the exclusion of everything else? I'd say no, because eventually, even RRMS will turn into progressive types of MS in a lot of cases. I think the thought also is that if they find something that will treat RRMS and keep it from progressing in the first place, then maybe the more progressive types of MS can be prevented or delayed.

Except, that leaves out the poor folks who develop progressive MS right from the get go.

And personally, I agree with you. I'm not certain that treating the "inflammation" aspect of MS, even in RRMS, is necessarily the best avenue to follow.

Again, there are many other things that are being researched, but it isn't publicized much, because what the pharmas try to treat is going to be whatever is going to be the most "profitable", hence inflammation and RRMS being their main focus. And since it is mainly the pharma companies who turn out press releases (again due to profitable gain incentives), that is mainly what the public hears about and why it appears so one-sided.

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Postby bromley » Sat Mar 19, 2005 12:48 pm

OddDuck wrote: (I can't work out the quote option)

'As a matter of fact, one that comes to mind right off the bat, that I believe we just might see come out soon (based on just "gut feeling" of mine) is a TZD (pioglitazone)! I believe that is currently in clinical trial.

In my opinion (I researched this quite a bit a while back), THIS particular treatment is by far the most promising with the very least possible adverse side effects. And the good thing is, it IS on the market now. So, is it "possible" that you MIGHT get a physician to prescribe it for you off-label to try? I'd say it might be. Especially since it is already being studied for MS, is in clinical trials, and has had good results so far'.

My question - does anyone know when the trial is due to end / initial results?

Also, if effective - how long would it take to get to the market given it's already used for another disease?

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Re: Quoting authors

Postby NHE » Sun Mar 20, 2005 12:52 am

bromley wrote:OddDuck wrote: (I can't work out the quote option)


That would be [quote="author"] followed by the end quote.

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Postby OddDuck » Sun Mar 20, 2005 4:03 am

OddDuck wrote: (I can't work out the quote option)


Uh.............when and where did I say that? I've looked and looked and I don't see where I wrote that at all! I use the quotes all the time. :lol:

bromley, are you hallucinating? :wink:

And yes, I was talking about pioglitazone. (I guess it was in that other thread that is sort of connected to this one.) Anyway, the Chicago trial is supposed to be ending any time now. [No, it WAS in this thread......I posted about Actos (i.e. pioglitazone) on the first page of this thread.] :?: (And then there is more about pioglitazone in the thread called "PPAR Gamma).

Anyway, a drug that is already on the market can be prescribed by your physician NOW off-label, if he "will". There is no "waiting" for something that is already on the market.

Deb

EDIT: OH!!!!! I'm dying laughing at myself!!! THAT was BROMLEY talking, saying HE couldn't work out the quote option!!!! :lol: I wondered what the heck? I guess I was hallucinating! HAH! No wonder I was confused! :lol:
Last edited by OddDuck on Sun Mar 20, 2005 5:06 am, edited 2 times in total.
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Postby OddDuck » Sun Mar 20, 2005 4:28 am

Ok, it looks like even though the initial small trial with that one woman was on SPMS (article posted earlier herein), this clinical trial is on RRMS. In any event, here is the information on what the U. of Illinois in Chicago is doing. (Doggone it, WHY do they always do that? I guess they have trouble getting funding for trials on SPMS???) EDIT: Oh, I see why.........it's because it is being funded by a pharma company, which as I mentioned to Trudy, my opinion is whenever a pharma company is involved, they want to test RRMS, because that is where the "money" will be. This website (i.e. thisisms) posted an article about pioglitazone on its home page a little while ago, also:

http://www.nationalmssociety.org/pdf/re ... trials.pdf

Agent: Actos® (pioglitazone)
Purpose of study: To test safety and tolerability
Possible mechanism: Reduces proinflammatory gene expression and T cell activation
Study description: Pilot, double blinding
Dose/route: Actos 30 mg/d po vs. PBO
Outcome parameters: Frequency of relapse, MSFC, EDSS, MRI, liver function
Type of MS: RR
Number of Subjects: 15
Start date: April 2004
Observation period: 2 years
Investigators: D. Skias, D. Hier, D. Feinstein
Sites: University of Illinois at Chicago
Results/Publications: Not Available
Funding: Takeda Pharmaceuticals North America, Inc.
Last update: Summer/Fall 2004



Drug commonly used for diabetes might be effective in treating multiple sclerosis

Pharmaceutical News
Published: Thursday, 10-Jun-2004

Researchers at the University of Illinois at Chicago are launching a clinical trial to determine whether a drug commonly used for diabetes might be effective in treating multiple sclerosis, an autoimmune disease that affects 350,000 Americans.

In an animal model of the disease, the researchers found that the drug reduced the inflammation of nervous tissue that occurs with multiple sclerosis and prevented the aberrant immune response that ends up destroying the body's own brain and spinal cord.

"At present, few medications have been approved by the Food and Drug Administration for the treatment of multiple sclerosis," said Douglas Feinstein, associate professor of anesthesiology in the UIC College of Medicine. "These drugs are only partially effective, and none helps significantly in the later, progressive forms of the disease. The drugs also have undesirable side effects, and they need to be injected, making them difficult to administer."

The drug being tested, called pioglitazone, is prescribed for the treatment of type 2 diabetes. Marketed by Takeda Pharmaceuticals North America, pioglitazone "sensitizes" the body's cells to insulin, a hormone produced by the pancreas that lets sugar into cells so that it can be converted into energy. People with type 2 diabetes are unable to use insulin efficiently, leading to elevated blood sugar levels (hyperglycemia) and tissue damage.

Research has shown that drugs like pioglitazone not only raise the levels of certain proteins involved in the uptake and metabolism of glucose but also lower the levels of other molecules involved in the immune response and inflammation.

"It is amazing that this drug, at least in animal tests, has shown a dramatic effect on two different targets of multiple sclerosis, namely the immune system and the inflammation process," Feinstein said.

Feinstein also noted that the drug is available as a tablet, simplifying its administration.

The clinical trial will enroll about 30 patients with relapsing remitting multiple sclerosis, the most common form of the disease. People with this type of multiple sclerosis experience episodes of acute worsening of neurological function, followed by partial or complete recovery. In most patients, the disease will eventually change into a chronic, persistent form, with symptoms worsening throughout life.

Participants in the trial will take a 30-milligram dose of pioglitazone daily for a period of 18 months, during which they will be monitored for any side effects or changes in their symptoms.

"At this stage in the drug trial, we are simply trying to determine whether the drug is safe and can be tolerated by people with multiple sclerosis," Feinstein said. "But we'll also be doing neurological examinations and biochemical analyses of blood samples, looking for signs of inflammation and immune cell activation to determine whether the drug is having any effect on symptoms of the disease."

Employing UIC's state-of-the-art magnetic resonance imaging technology, the researchers will do a series of three brain scans over the course of the trial to look for changes in the cerebral lesions associated with multiple sclerosis.

In multiple sclerosis, the T cells of the immune system go awry, attacking proteins in the myelin sheath that insulates the nerve fibers. When the sheath is destroyed, electrical signals that are normally transmitted throughout the brain and spinal cord are disrupted, and the brain is no longer able to correctly send or receive the messages that help control muscle movements.

Patients with multiple sclerosis suffer a range of symptoms, including tingling and numbness, loss of balance, blurry vision, weakness in the limbs, difficulty walking, impaired thinking and even paralysis. The disease affects women about twice as often as men.

In the United States, health care costs for multiple sclerosis are second only to those for Alzheimer's disease.

Co-directors of the UIC study are Drs. Daniel Hier and Demetrios Skias, in the department of neurology at UIC, and Dr. Dusan Stefoskil, director of the multiple sclerosis clinic at Rush University Medical Center.


EDIT: Actually, I see a little bit of conflicting information. I think the clinical trial at the University is going to actually be on 30 patients, not just 15.
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Postby OddDuck » Sun Mar 20, 2005 4:52 am

Here is that article regarding pioglitazone and SPMS that was posted under "PPAR gamma" thread - that is what pioglitazone (i.e. Actos) is - it is a PPAR gamma agonist:

Ann Neurol. 2002 Jun;51(6):694-702.

Peroxisome proliferator-activated receptor-gamma agonists prevent experimental autoimmune encephalomyelitis.

Feinstein DL, Galea E, Gavrilyuk V, Brosnan CF, Whitacre CC, Dumitrescu-Ozimek L, Landreth GE, Pershadsingh HA, Weinberg G, Heneka MT.

Department of Anesthesiology, University of Illinois, 11819 West Polk Street, MC519, Chicago, IL 60612, USA. dlfeins@uic.edu

The development of clinical symptoms in multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE) involves T-cell activation and migration into the central nervous system, production of glial-derived inflammatory molecules, and demyelination and axonal damage. Ligands of the peroxisome proliferator-activated receptor (PPAR) exert anti-inflammatory effects on glial cells, reduce proliferation and activation of T cells, and induce myelin gene expression. We demonstrate in two models of EAE that orally administered PPARgamma ligand pioglitazone reduced the incidence and severity of monophasic, chronic disease in C57BL/6 mice immunized with myelin oligodendrocyte glycoprotein peptide and of relapsing disease in B10.Pl mice immunized with myelin basic protein. Pioglitazone also reduced clinical signs when it was provided after disease onset. Clinical symptoms were reduced by two other PPARgamma agonists, suggesting a role for PPARgamma activation in protective effects. The suppression of clinical signs was paralleled by decreased lymphocyte infiltration, lessened demyelination, reduced chemokine and cytokine expression, and increased inhibitor of kappa B (IkB) expression in the brain. Pioglitazone also reduced the antigen-dependent interferon-gamma production from EAE-derived T cells. These results suggest that orally administered PPARgamma agonists could provide therapeutic benefit in demyelinating disease.

PMID: 12112074 [PubMed - indexed for MEDLINE]


You can find the article regarding the trial of pioglitazone on the woman with SPMS posted at: http://www.thisisms.com/modules.php?nam ... hlight=tzd

There, we've got all the pertinent references all in one thread now for ease of use, I guess you could say. :wink:

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