Good news - Major milestone in identifying ms genes

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Good news - Major milestone in identifying ms genes

Postby bromley » Thu Mar 17, 2005 1:54 pm

Dear all,

A bad month may look a bit better with news that Serono has announced a major milestone in identyfing the genes involved in MS. Link attached.

Serono says that that the identification of 80 genes involved in the inflammatory and neuro-degenerative pathways of MS should provide potential new drug targets


http://www.serono.com/media/latestPR.js ... =4&minor=0

Would be grateful if those with the relevant knowledge could translate into what this might mean (OddDuck - one for you?).

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Postby OddDuck » Thu Mar 17, 2005 2:17 pm

Ok.........I'll bite. :D (Actually, my bark is much worse than my bite. hehehe....) Anyway.......

The understanding of the disease genetics in MS will enhance Serono's drug discovery in identifying proteins that can be used either as targets for drug development or directly as therapeutics. In addition, the knowledge of genetics in MS provides a basis for better designing safer and more effective drugs and enabling physicians to address unmet needs and potentially better match treatments to the individual patient.


Sounds promising, but...........gene therapy is tricky, and my question is: Are they "assuming" that MS is a genetically caused disease?

What exactly are the medical implications of this release? You know me, in my world, it sounds "vague". BUT..........still promising. Just perhaps not anything extraordinarily expediently imminent, is all.

As we have learned, (I think), be "cautious" regarding press releases generated and issued directly from the pharma corporations themselves. "Beware of the Bias". (Hey, that's pretty clever, if I say so myself!)

But, yes, this knowledge will open up many new avenues for exploration. Definitely.

Deb

EDIT:
For the first time in this disease area, researchers at the SGI have identified 80 genes involved in the inflammatory and neuro-degenerative pathways of MS, ....


Ok........let's think about this for a second. So far, 80 genes? Which ones do you try to target? Or which combinations? If you affect say.....10 of them, what will that cause the other 70 to do? And on and on and on......... Does this make things easier or more complex in the end? Say you find a drug that helps correct 20 genes, but the drug adversely affects 40 other genes and leaves 20 alone. Do you try the drug anyway? I'm just not certain where this leaves us.

In addition, the knowledge of genetics in MS provides a basis for better designing safer and more effective drugs and enabling physicians to address unmet needs and potentially better match treatments to the individual patient.


BUT..........truly.........it is promising, and DOES indicate that drug treatment for MS sufferers is appearing to be more as we expected. It will need to be tailored specifically for each individual precisely. No "one drug for all".
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Postby BioDocFL » Thu Mar 17, 2005 6:02 pm

Serono's annual meeting is April 26. Timing of the announcement seems calculated to me.

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Postby JFH » Fri Mar 18, 2005 3:52 am

OddDuck wrote:Sounds promising, but...........gene therapy is tricky, and my question is: Are they "assuming" that MS is a genetically caused disease?


Haven't the studies on twins (mono and di) shown conclusively that there is a genetic component? No references to hand but I'm sure I've seen that somewhere.
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Postby OddDuck » Fri Mar 18, 2005 4:34 am

Wait. No....just the opposite. That there does NOT seem to be. Identical twins have the same DNA and genetic makeup and sometimes one twin can have MS and the other doesn't. Hence what has prompted my question about what it is that Serono is "assuming" with this particular type of press release. There is nothing conclusive regarding genes and MS.

Let me rephrase, because I still don't think I'm being clear. How would they explain the contradictions in what they have just "implied". If people with MS ALL have the same 80 genes out of whack, isn't that implying that MS is definitely genetic? Or are they implying that? Or are they saying that there IS one cause that makes all 80 genes mutate AFTER birth? In EVERY single person? It's not clear.

And, there are some extrinsic causes which can result in some genes being "altered" (for lack of a better word). Like Wesley points out to us (epigenetics). What is the likelihood that everybody has come into contact with the same extrinsic factor which resulted in all 80 genes to mutate similarly? So, see what mean? Just what IS that press release really trying to say? Hence why it is "vague" to me.

Wesley and I already have talked about DNA fragmentation, epigenetic influences, etc. Identifying WHICH genes are somehow messed up might make things more complicated, if there are so many.

Take ALS for example. There is only one or two genes that will tell predisposition to ALS. SOD1 on chromosome 21 and SOD2 on chromosome 6, I believe. They can test for any mutations in SOD1 to determine familiar ALS. There are not 80 different genes. So, what are they telling us?

Anything "new" really?

Deb

EDIT: If that were the case, I'd rather ascribe and follow Dr. John Richert's theories regarding the common factor of SP3.
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Postby OddDuck » Fri Mar 18, 2005 4:56 am

Let's take a look at Dr. Richerts' research for a second. Here's what I posted a while ago in another thread, but then we got a little off this track:

Oh, yeah...........Wesley, have you run across the research that Dr. John Richert (the new VP of Research for the NMSS) has been doing regarding SP3? Dr. Richert is/has been doing extensive research on SP3 gene transcription expression in MS (or more to the point, the lack thereof of activation of SP3 in MS). He found that MSers do not have SP3 activation (which also explains why there is a difference between twins).

The theory he throws back into everything is toxins or environmental influences which causes the lack of SP3 activation.

I think I'll go look into that one for a bit - especially WHERE SP3 transcription takes place. If it is the hypothalamus, I think I'll croak!

Deb


http://mscenter.georgetown.edu/v1i1.htm

... So, genes are important in MS both from the standpoint of which ones are inherited (that may increase a person’s genetic susceptibility to developing MS) and from the standpoint of which genes might be abnormally turned on or off (perhaps by environmental agents such as viruses) and thereby lead to inflammation in the nervous system and loss of myelin.

The work in Dr. Richert’s lab that identifies the Sp3 gene as being abnormally turned off in MS immune cells came from studies designed to search for genes that are inherited and are either abnormally turned on or off in immune cells (white blood cells) in people with MS. In order to distinguish genes that are abnormnally turned on or off from abnormal genes that are inherited, Dr. Richert’s research team initially studied identical twins, one of whom has MS and one of whom is healthy. Thus, since they are genetically identical, any difference in their gene expression would have to be related to genes that are turned on or off in one twin and not the other. The method for looking at this involves searching for messenger RNA molecules that are present in immune cells from one twin and not present in the other twin. Once a particular messenger RNA is so-identified, then larger populations of people with MS and people without MS are screened to determine if the difference found in the twins is also reflected in the MS and non-MS populations in general. This is how Sp3 was identified. Sp3 messenger RNA was found in white blood cells from the normal twin but not from the twin with MS. Subsequently, we found Sp3 messenger RNA in immune cells from most people who did not have MS but could not find it in most people with MS. People with other inflammatory/autoimmune diseases such as rheumatoid arthritis or lupus erythematosus did express the Sp3 messenger RNA and were therefore more like the healthy subjects than like people with MS. Therefore, it appears that the abnormal turning off of the Sp3 gene is relatively specific for MS. Thus, we know that the Sp3 gene is inherited by everyone but its transcription (I.e. its ability to produce Sp3messenger RNA and subsequently Sp3 protein) is stopped.

What is the function of the Sp3 protein? It, itself, is a transcription factor. That is, it is involved in turning on or off other genes in the body. Among the genes that it helps control the expression of are several immune-related genes that you may have heard of and which appear to play a role in immune function in MS: T cell receptors, tumor necrosis factor alpha (TNF-alpha, which is found in areas of inflammation in MS nervous system tissue and which is known to cause damage to myelin-producing cells in tissue culture), and transforming growth factor beta (TGF-beta, which helps calm down abnormally active immune responses). So, it is possible that the abnormal turning off of the Sp3 gene may lead to a cascade of abnormal events in the immune system that could potentially contribute to the inflammation and demyelination in the nervous system.

The most important issue, from our standpoint, is the question: “What is turning off Sp3 gene expression in MS immune cells?” The most intriguing potential answer is: “a virus.” Dr. Richert’s lab is currently searching for whatever is present in MS immune cells that is absent from healthy immune cells and which is capable or turning off the Sp3 gene. Although it is still quite speculative as to whether this will lead to important answers in MS, this work has the potential for identifying an environmental agent that may trigger the disease process in MS and may also lead to methods for turning the Sp3 gene back on so that normal transcription of the genes it controls can again be sustained.

This reseach is supported by the National Multiple Sclerosis Society, The Conrad Hilton Foundation, and by gifts from individuals to Dr. Richert’s Laboratory and to the Georgetown University MS Center. ....


To me, this holds more promise than what Serono is telling us. But that is just my personal opinion.

Deb
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Re: Good news - Major milestone in identifying ms genes

Postby NHE » Fri Mar 18, 2005 5:04 am

bromley wrote:Would be grateful if those with the relevant knowledge could translate into what this might mean

Researchers at SGI used the Affymetrix GeneChip technology to scan over 100,000 SNPs (single nucleotide polymorphisms) to identify the genes involved in MS, comparing the genetic profile of cases and controls. The next step is to continue this endeavour, applying next generation GeneChip technology to scan over 500,000 SNPs and thus complete the MS Whole Genome Scan during 2006.

I'm new to GeneChip technology, though in a nutshell, I believe that Serono examined the genetic differences, i.e., "single nucleotide polymorphisms" or DNA sequence variations, in MS patients compared to non-MS patients and found 80 genes of interest in MS patients. Moreover, in addition to studying sequence variations, GeneChips can also be used to examine differential gene expression, i.e., up or down regulation of particular genes.

Some overviews of GeneChips can be found at here and here.

Essentially, probes for genes of known interest are bound to a chip and then samples from the study participants are applied to the chip. The analysis looks at the differential binding to the probes on the chip.

JFH wrote:Haven't the studies on twins (mono and di) shown conclusively that there is a genetic component? No references to hand but I'm sure I've seen that somewhere.

I believe that a genetically identical twin of someone with MS has a higher risk factor for MS. This risk factor is followed by a lower risk factor for siblings of someone with MS which in turn is still higher than those in the general population. I don't remember the exact numbers that have been cited for the risk factors but the trend should be correct. My understanding is that there's a genetic predisposition combined with an unknown environmental influence. Many have suspected that the environmental influence might be related to vitamin D while others have looked for an MS pathogen (referring to molecular mimicry which may train the immune system against oligodendrocyte myelin). I don't see any reason why the environmental influence couldn't be a combination of these or other additional factors. For an example of the genetic predisposition, please refer to this post discussing recent work with interferon-gamma gene polymorphisms.

NHE
Last edited by NHE on Fri Mar 18, 2005 5:21 am, edited 1 time in total.
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Postby OddDuck » Fri Mar 18, 2005 5:18 am

Thanks, NHE!

As we get going here, this is an example of the "complexity" I was referring to above. We could go on forever, practically.

So, bottom line? It "sounds" like something majorly concrete has suddenly been "discovered" regarding MS. But, has it really? As far as suddenly being able to come up with a new treatment for MS based off of this new discovery?

Again, to me, it is a "vague" announcement from Serono. Promising, of course, but "vague" as far as what it really means for MS sufferers.

Researchers all have their theories regarding which genes are involved. Corporations just issue press releases more often, is all. (I hope I'm not sounding negative, because I'm not. I just don't believe this indicates anything extremely exciting as far as "treatment" for MS goes. Not really.)

They have narrowed down which chromosomes are believed to be involved in MS for years now. And there is still disagreement, too.

And in theory, what might be the BEST treatment for genetic mutations such as may be going on in MS? Especially if there are so many genetic mutations involved? I'm afraid that if/when we follow that path, we will find it leads us right back to stem cell.

Deb
Last edited by OddDuck on Fri Mar 18, 2005 5:21 am, edited 1 time in total.
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Postby bromley » Fri Mar 18, 2005 5:20 am

Deb,

My posting was aimed at cheering people up after a disastrous month in terms of new tretments. But (having v.little knowledge of genetics) - I think you're right about the Serono information.

I have recently visited the MSIF website which provides profiles of other poor souls with this disease. What is surprising is that they come from all parts of the world - one of Jewish origin from South Africa, Chile, Mexico etc etc. One is a Japanese woman who talks about the increase in ms cases in Japan (funny because some of my initial reading suggested that it was almost unknown in the far east). I also read recently that neurological problems (including ms) are also more common in India than previously thought. MS among black Africans might appear rare but those who reside in non-African countries seem to be just as prone (accepted that some may be of mixed race) - Montel Williams, Richard Pryor.

What I'm saying (in a very unscientific way) is that basic observation points to more than genetics - Kurtze's theory is that ms comes from Sweden and you just have to follow the Vikings.

Families can point to more ms cases which might suggest a genetic susceptibility - but may also point to a stack of other things (viruses, environmental issues, diet etc etc).

I'm not really adding much but like you cannot see how these apparent findings on genetics will lead anywhere quickly.

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Postby OddDuck » Fri Mar 18, 2005 5:25 am

I'm sorry, bromley. :(

I do think people should be cheered up (that's why I keep saying I'm really not trying to be "negative"), because any little advancement in MS research is great! I just hate to see expectations to be raised too high.

There ARE other treatments being tested, just not being "published" in press releases. It just takes more "digging".

Perhaps I can find some others that are going on more quietly in the background that sound more promising in the short run and near future (like someone else just recently did) (?)

Deb

EDIT: 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.

http://www.jneuroinflammation.com/content/1/1/3

SECOND EDIT: Ok, it is called "Actos" in the U.S., and is currently prescribed for diabetes. http://www.actos.com/ You do need to be careful combining this drug with others, as it is strong, and there are some indications of cardiac effects, BUT you are informed of this particular risk (which appears to be fairly small, particularly if you currently do not suffer from heart problems and you are not combining this drug with other drugs which have possible side effects on the heart. It is particularly warned not to combine Actos with insulin.) Oh, and as with most strong drugs, liver enzymes need to be monitored closely.

For MS, though, it REALLY looks promising. And folks, it is HERE already!! On the market!
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Postby bromley » Fri Mar 18, 2005 6:04 am

Deb,

This is from the UK MS Society website. Professor John F. Kurtzke's aim in terms of his research:

Continuing study of the epidemiology of MS, to include evidence for or against the possibility that MS in fact began in south central Sweden, with a slow spread throughout Europe accounting for the oft-quoted "north-south gradient" - which gradient indeed is lessening markedly; and whether there was a similar introduction and spread in the United States.


Is it me or does this lack any real sense of why this disease should be being researched. Surely it's to help relieve suffering than some academic interest!

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Postby OddDuck » Fri Mar 18, 2005 6:08 am

bromley,

Ok..........I'm confused. I think you and I are talking about two different things here.

There is lots of research going on regarding MS in different ethnic groups.

I'm not sure what you are asking. :?: I guess I mean, in the long run, does it matter exactly where it "originated", i.e. which culture or ethnicity? I mean, maybe, but...........

Deb

EDIT: Well, I will say this. Treatment of the same diseases in different ethnic groups does tend to require different strategies. I myself believe this is why there is such study regarding this area.
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Postby rasnet6 » Fri Mar 18, 2005 7:36 am

Hi Deb,

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!!

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diabetes drug for MS??

Postby Trudy » Fri Mar 18, 2005 7:48 am

Ok, since I am not a scientist, I am confused. Why would medication that treats type 2 diabetes (Actos) work for MS?? What does this tell us about MS? Mind you, this isn't the first I have heard about this. The neurologist I see was all excited about both statins and this drug (I think) last year. Too bad--no diabetes, no problem with cholesterol here. Just MS. Small mercies??! But seriously, what is it about the diabetes drug that might prove beneficial in the case of MS??

Thanks,
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Postby raven » Fri Mar 18, 2005 8:00 am

Diabetes is also an autoimmune condition, so are arthritis and Crohn's disease. Therefore you often see crossover between medications for these conditions.

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