This Is MS Multiple Sclerosis Community: Knowledge & Support

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.

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, ....

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?

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

... 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. ....

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.

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.