Gene flaw 'explains why drugs failed to treat MS'

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Gene flaw 'explains why drugs failed to treat MS'

Postby MSUK » Mon Jul 09, 2012 12:51 am


Scientists have identified why a once-promising class of drugs do not help people with multiple sclerosis.

An Oxford University team say an genetic variant linked to MS means the drugs which work for patients with other autoimmune diseases will not work for them.

The team, writing in Nature, say the drugs can actually make symptoms worse.

Experts say the work shows how a person's genetic make-up could affect how they responded to treatment.

The drugs, called anti-TNFs, work for patients with rheumatoid arthritis and inflammatory bowel disease, but they have not done so for patients with MS and researchers were unsure why.... Read More - ... ageid/1347
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Re: Gene flaw 'explains why drugs failed to treat MS'

Postby jimmylegs » Tue Jul 10, 2012 5:04 am

Rare variants in the CYP27B1 gene are associated with multiple sclerosis ... 8/abstract
Multiple sclerosis (MS) is a complex neurological disease. Genetic linkage analysis and genotyping of candidate genes in families with 4 or more affected individuals more heavily loaded for susceptibility genes has not fully explained familial disease clustering.
We performed whole exome sequencing to further understand the heightened prevalence of MS in these families.
Forty-three individuals with MS (1 from each family) were sequenced to find rare variants in candidate MS susceptibility genes. On average, >58,000 variants were identified in each individual. A rare variant in the CYP27B1 gene causing complete loss of gene function was identified in 1 individual. Homozygosity for this mutation results in vitamin D-dependent rickets I (VDDR1), whereas heterozygosity results in lower calcitriol levels. This variant showed significant heterozygous association in 3,046 parent-affected child trios (p = 1 × 10−5). Further genotyping in >12,500 individuals showed that other rare loss of function CYP27B1 variants also conferred significant risk of MS, Peto odds ratio = 4.7 (95% confidence interval, 2.3–9.4; p = 5 × 10−7). Four known VDDR1 mutations were identified, all overtransmitted. Heterozygous parents transmitted these alleles to MS offspring 35 of 35× (p = 3 × 10−9).
A causative role for CYP27B1 in MS is supported; the mutations identified are known to alter function having been shown in vivo to result in rickets when 2 copies are present. CYP27B1 encodes the vitamin D-activating 1-alpha hydroxylase enzyme, and thus a role for vitamin D in MS pathogenesis is strongly implicated.
odd sx? no dx? check w/ dietitian
99% don't meet these. meds/lifestyle can affect levels
status can be low in ms & other cond'ns
'but my results are normal'. typical panels don't test all
deficits occur in 'normal' range
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Re: Gene flaw 'explains why drugs failed to treat MS'

Postby Leonard » Wed Jul 11, 2012 1:47 am

I am not convinved by this study.
I think that MS is a complex two stage disease with different underlying mechanisms, see e.g. general-discussion-f1/topic15188.html
Making this differentiation is essential when studying possible treatment options or drugs.
If the study design is wrong or based on the wrong presumptions, you will never find the right answer...

From the press release: "There are many genes associated with MS, but we know little about the role they play or the influence they have on the condition."
I think there are many genes, molecular and cellular pathways and interactions with the immune system that have not been understood so far.
And I am sure that is true for many many diseases, not just for MS....
It is a bit like the search for the Higgs boson and the uncertainties surrounding this research see e.g. ...

This gene study reported here is a continuation of the old line of thinking, about fancy genetic deficiencies and the like.
But that model is broken; I think the goal is unattainable..

I think the answer is much simpler:
- many years of ccsvi causes weakening of endothelium and lymphatic system; early treatment by angioplasty could be useful as a pre-emptive measure;
- the first peak in the MS onset graph is caused by Cpn or EBV blocking receptors; may be treated by a good dose of anti-biotics;
- in the second peak, it is a deficiency in the glucose metabolism that causes the immune system reaction. In stead of studying all these very advanced drugs, there may be much simpler and more effective solutions such as Metformin, that -incidently - also work via the gut flora. Or a gut flora transplant. Or a diet. see e.g. general-discussion-f1/topic15188-330.html

There are some postings on this thread under this link on how the fancy genetic research is now quickly being replaced by research into the health and workings of nuclear receptors..

Has Metformin ever been studied for MS? I know for Alzheimer, the drug is under study in Berlin and apparently gives promising results. Why not study it for MS? The prevalence of diabetes in MS would at the very least suggest to be a good reason to have a closer look...
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Re: Gene flaw 'explains why drugs failed to treat MS'

Postby NHE » Wed Jul 11, 2012 1:54 pm

Here's a write-up from Nature...

Genome study highlights risk factor for multiple sclerosis ... is-1.10967

Discovery of genetic variant could help to improve clinical trials of potential therapies.

Ewen Callaway, 09 July 2012

    Like diabetes, most forms of cancer and other common diseases, there is no single gene that causes the autoimmune condition multiple sclerosis (MS). Dozens of genetic variations act in concert with environmental factors to cause the debilitating neurological disease.

    Yet a single genetic variant may explain why drugs that treat other autoimmune diseases tend to make MS symptoms worse, and could identify other MS patients who might benefit from the therapies. Researchers say that the findings, which are published online in Nature1, also highlight how genome-wide association studies (GWAS) can yield useful medical insights.

    GWAS compare thousands of people who have a particular disease, detailing hundreds of thousands of genetic variations between them. The goal is to identify variations that are more common in people with the condition than in healthy people. Most such studies uncover scores of genetic variants associated with the disease in question, each increasing a person’s chances of developing the condition by a small percentage.

    Such is the case for a DNA letter in the gene that encodes the protein called tumour necrosis factor receptor 1 (TNFR1). The protein senses a potent immune molecule called tumour necrosis factor (TNF) that destroys cancerous cells but that is also implicated in autoimmune disease. People of European ancestry who have two ‘A’s at that particular spot on the genome are 12% more likely to develop MS than those with two ‘G’s at that spot.

    Lars Fugger, a neurologist at the University of Oxford, UK, and his team discovered that the variant A shortens the TNF receptor 1 protein. Normally, the protein sits within a cell’s membrane, where it can sense TNF molecules circulating outside the cell and convey their instructions to that cell. The protein starts a cascade that can lead to inflammation and cell death. But the shortened form of the protein never makes it into the membrane, Fugger’s team found. Instead it is probably shunted outside the cell, where it can bind TNF molecules, stopping them from signalling to cells.

    Biologic drugs that block TNF from signalling to cells have revolutionized treatment for autoimmune conditions such as rheumatoid arthritis over the past decade, says Fugger. Yet despite achieving some encouraging results in animal models of MS, drugs that block the activity of TNF tend not work in patients with MS. In fact, they usually make symptoms worse, and they may even have caused the disease in people predisposed to it, says Fugger. He thinks the variation his team studied could explain why.

    Fugger says it is unclear how TNF influences MS, but in patients with the gene variant, the TNF-blocking drugs could be providing a double-whammy by suppressing TNF signalling further. The normal receptor prevents mice from developing symptoms of a model of MS2.

    It is not clear whether TNF-blocking drugs might help MS patients who don't have the TNF variant, says Fugger, but taking a closer look at the genetics of the patients who received the treatment as part of clinical trials in the 1990s could provide the answer.

    Alastair Compston, a neurologist at the University of Cambridge, UK, who led a consortium that last year identified dozens of genetic risk factors for MS in nearly 10,000 MS patients3, says there is overwhelming genetic evidence that TNF is somehow involved in the condition. “Therefore the potential for manipulating it therapeutically is real,” he says.

    Fugger hopes that his team’s study will also help to dispel the notion that genome-wide association studies will never offer much that can be used in patient care (see 'Human genetics: Hit or miss'). If doctors had known that TNF-blocking drugs mimic the effects of a major risk factor for the disease, they might have designed their clinical trials differently, he says. “The idea is you can use GWAS studies to decide which drugs should be used and which should not be used,” Fugger says.
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