Causes and potential cures for MS

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Causes and potential cures for MS

Postby MattB » Sat Dec 01, 2007 10:18 am

Although I'm new to the community I've noticed something I think is important. Both in reading posts here and looking at information elsewhere I've found that with almost every case of MS research can be done to find a potential cause or cure but that it may only apply to a few cases. What I mean is there are so many different pieces of research that seem to have valid finds with solid information that MS can't possibly be caused by all of these things. To me is seems like every single case is different and you can't generalize treatments on the whole MS population.

This being said my question is: How do you go about finding what is right for you without too much risk?
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Postby BioDocFL » Sat Dec 01, 2007 3:20 pm

MattB,

There is another post today regarding 'silenced genes'. That might help shed some light on how each case of MS might differ and provide some kind of answer to your question.
If a gene has two copies in the cell and one copy is normally silenced and the other copy is expressed, the protein created from the gene will be at a certain level. With ongoing turnover of proteins (ex. degradation or sequestering), there is a continued expression from the active gene to keep the needed level of that particular protein at a stable level.
If for some reason the silenced copy becomes active, there is now overexpression of the protein. Now there could be consequences from having overexpression of that protein. If, for an example, it is a histone acetylase, the cell could experience an inordinate amount of acetylation of histones, which could lead to opening up of other genes that had been silenced previously. Or if both copies of a gene, ex. the histone acetylase again, are silenced, there could be a reduction in the acetylation. Either way it could destabilize the whole cell and lead it to apoptosis or some altered state.
Now, let's say we recognize a set of 50 genes related to MS which normally have a particular silencing pattern, such as one copy active and the other copy silenced. We might find that different patterns of disruption in subsets of these 50 genes can lead to different 'subtypes' of MS. Say 10 of the 50 genes are disrupted in one lesion giving problems in myelin synthesis. In another patient perhaps disruption of a different 15 of the 50 genes leads to problems with aberrant triggering of apoptosis.
They both might be termed MS but in one there is a slow loss of myelin, whereas the other might be a faster, more chronic loss of key myelin-producing cells going into apoptosis.
I have frequently mentioned the inactive X chromosome before as a prime site where we could find genes pertinent in autoimmune diseases. Women have 2 X chromosomes, men have only 1 X. Most of the genes on the X are not sex-related so in women one X chromosome in each cell is inactivated (actually ~70% inactive) and only one X is active, giving a similar gene expression pattern to men. This goes along well with the female predominance of autoimmune diseases.
Now what happens if some or all of the inactive X chromosome becomes reactivated? Perhaps some cellular stress like viral activity (ex. EBV) has thrown out of balance the establishment of proper DNA and histone methylation patterns on the silenced genes so now some of the silenced copies can become active and lead to overexpression of the protein for which they code. I have given examples of polyamine synthesis before, spermine synthase and spermidine/spermine N1 acetyltransferase, both genes being at Xp22.1 on the short arm of the X chromosome. Also near that is I believe a B cell receptor gene that could be overexpressed in B cells. There was recent discussion on this board of an article about a lipase involved in myelin synthesis that might be dysregulated. I believe copies of that lipase are on the X chromosome. I have also mentioned the LINE1 pseudogenes, which are enriched on the X chromosome and some of which code for functional reverse transcriptases. Usually LINE1 sequences are silenced but there might be situations where they kick into action when silencing is removed. This could explain how reverse transcriptase activity is seen in many autoimmune cases.
So, just from the X chromosome, there are some possible gene copies that could become dysregulated and their impact might be on myelin synthesis in oligodendrocytes or auto-antibody production in B cells, or other scenarios.
How do we attack this problem if this loss of silencing is what is occurring? There is a new buzz word in medicine, especially cancer research and therapy. It is 'personalized medicine'. What we do is determine the exact type of cancer a person has before we start treating the patient. For example, breast cancer can be BRCA+ type or it can be BRCA- type (BRCA being a protein, Breast Cancer Antigen, or some name like that). There has been some reports that BRCA1 is involved in X chromosome inactivation in some manner but that is still under research for confirmation. Different drugs will work on different types of cancer. So we would do a biopsy to analyze the tumor cells to see which type of cancer it is. That helps us select between one set of drugs versus another. We can also grow the tumor cells in culture and test different drugs and concentrations on them to have a better plan for treatment. Only then do we approach the patient with a specific treatment plan, knowing that we have probably reduced or avoided ineffective attempts at eradicating their particular cancer.
I would imagine something similar for MS, a personalized approach. Once we have the realm of MS-related genes identified and know what their normal sequences and methylation patterns should be for the promoter and gene, then we could do a genetic analysis to see how a particular MS patient's genes vary, perhaps identifying the specific genes involved in their MS subset by sequencing and phenotype. Then we might know which drugs work best, a lipase inhibitor if that gene is part of their subset, or a polyamine synthesis inhibitor if polyamines are involved, or perhaps some drug-antigen combination that binds only those B cells expressing a particular auto-antibody. There are probably sets of lupus-related genes and rheumatoid arthritis-related genes, with some overlap. So, although the puzzle is complicated, we are approaching solutions not just with MS research but with cancer research and research on other diseases.
As you say, each case of MS is different. Some patients may need placement of stem cells if they have progressed too far and need to recover key areas of their CNS. Other patients may be stabilized with drugs that inhibit the activity of protein overexpression related to their subset of MS genes. And another goal would be to identify a person susceptible to MS based on their inherited subset of genes and put them on some kind of preventative treatment before they starting having symptoms. Maybe their subset of genes is susceptible to activation when EBV or CMV viral activity occurs. So we need to figure out how to eliminate those triggers.
One thing we are finding in cancer therapy is that one drug alone is not necessarily the best treatment. Often a combination therapy works to hit the tumor cells in several different signalling or biosynthetic pathways at once, while reducing the dose of any one drug in the combination can reduce the potential side-effects of that particular drug. A combination can work better, more different drugs, but with less of each drug, so less of each drug-specific side-effect. So MS treatment may need drug combination therapies. If lipase genes and polyamine synthesis genes are dysregulated in the same subset of MS-related genes for a particular type of MS, just giving lipase inhibitors may not be enough to halt the disease in the cells, since an imbalance in polyamine synthesis could still give problems in the same cells.

Wesley
Last edited by BioDocFL on Sat Dec 01, 2007 10:21 pm, edited 2 times in total.
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Postby Toyoterry » Sat Dec 01, 2007 5:46 pm

This is the kind of thing I really appreciate. Great info from someone in the frontline. Thanks for the post.
Terry
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Postby dignan » Sun Dec 02, 2007 10:18 am

Wesley, on gene silencing: are there any treatments (for any disorder, not just MS) that silence genes? Is this possible? Dumb question?
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Postby BioDocFL » Sun Dec 02, 2007 12:13 pm

Dignan,

Not a dumb question at all.

The traditional approach would be to try to counter the effect of the protein created by the gene. Typically a drug is given to inhibit the protein's activity so that, even if there is too much of the protein, its overall effect is tolerable.
Another approach could be to target other proteins in the same pathway as the problem protein, to cut off the supply of precursors in the case of enzyme proteins. Or, in the case of signalling proteins, cut off a protein further up in the signal cascade before it gets to the problem protein.
A new approach to target genes is RNA interference, RNAi. The cell creates small RNAi molecules that can interfere with gene expression, either by binding the DNA (probably in the promoter) or by binding the messenger RNA (mRNA) created by the gene. RNAi binding would block the transcription of the gene. RNAi binding the mRNA could lead to destruction of the mRNA before protein is created from it by the ribosome because the cell has systems in place to degrade double stranded RNA (ex. RNAi-mRNA duplexes). So RNAi is currently a hot topic in new approaches to silence genes.
Now, if you are asking about targeting one copy of the gene (an allele) and not interfere with the other alleles, that is more difficult. Then it would be a matter of trying to get the cells' chromatin modeling enzymes back in balance. Silenced alleles are packaged as heterochromatin (more tightly packed, methylated gene promoters and histones, histone H1 is involved, MeCP2 protein). Active alleles will be more open with less DNA methylation in promoters, less H1, less MeCP2 if any, histones are more acetylated, less methylated. Acitve chromatin is referred to as euchromatin. So if you can somehow get the chromatin maintenance enzymes and the precursors they need back to normal, perhaps the cell can stabilize itself back to normal. Vitamin D and calcium are both involved in chromatin stabilization.
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Postby dignan » Sun Dec 02, 2007 4:52 pm

Thanks Wesley. It is all interesting. I guess without knowing it, I was asking more about targeting one copy of the gene, since you were suggesting that having both copies active could be an issue with autoimmune diseases. It sounds like stabilizing the cell is not something that is possible yet from your answer, but you provided yet another reason (not that I think we need any more) for people with MS to consider taking vitamin D.

I'm also glad you touched on RNAi because it's a term I've seen and not understood it's significance.
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Postby TwistedHelix » Mon Dec 03, 2007 7:35 am

Because my brother has Huntington's disease, and it is an autosomal dominant disorder, RNA via siRNA is looking like a very promising treatment. This quote is from the Huntington's Disease Association website in 2005 which suggests possible human trials may be only three years away:
"The first clinical trials on Huntington's patients, or people with related brain disorders are likely to begin within the next five years provided there are no signs that the technique is dangerous in humans",
(complete article: http://www.hda.org.uk/research/rs035.html ).

Matt, I know what you mean about the bewildering number of published findings, each of which seems to have discovered a key element which, if interrupted, would stop MS in some people. I work on the assumption that those elements are quite " high up in the tree" of MS and would stop one branch becoming diseased, but that there are roots – perhaps more than one of them – which can stop the tree growing if only we could get at them.
Dom
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