Mike's Place - MSNews

GENETIC STUDY SUPPORTS VITAMIN D AS AN ENVIRONMENTAL FACTOR IN MS SUSCEPTIBILITY

Fri, 06 Feb 2009 21:16:33 GMT

Medical Update Memo February 5, 2009 Summary Researchers funded by the MS Society of Canada have found evidence of an interaction between vitamin D and a common genetic variant which may alter the risk of developing multiple sclerosis. The research, published in the Feb 5 edition of the open access journal PLoS Genetics, suggests that vitamin D deficiency during pregnancy and the early years may increase the risk of a child developing the disease. Details The causes of MS are unclear, but it has become evident that both environmental and genetic factors play a role. Studies have shown that MS is more common in areas of less sunshine, such as Canada and Northern Europe. It has also been shown that fewer people with MS are born in November and more in May, supporting a gestational risk effect of diminished sunlight. These findings suggest a possible link between deficiency in vitamin D, which is produced in the body through the action of sunlight, and increased risk of developing the disease. The most striking illustration of this is the geographical distribution in populations matched for ethnicity. This has further advanced the proposal that sunshine, and in particular, a deficiency in vitamin D, is an environmental factor influencing the risk for developing MS. Circumstantial evidence supporting this comes from studies showing the involvement of vitamin D in immune and nervous system function. Now, in a study funded by the MS Society of Canada, the UK MS Society, the Wellcome Trust and the Medical Research Council, researchers at the University of Oxford have shown that there is a direct relationship between DRB1*1501 and vitamin D with a receptor (a DNA sequence responsive to vitamin D) largely restricted to chromosomes bearing the DRB1*1501 variant. "We found that vitamin D affects the expression of this particular genetic variant – in other words, it affects the ability of the variant to do its normal job," explains Dr Julian Knight from the Wellcome Trust Centre for Human Genetics, University of Oxford. "This effect only appears to occur in people carrying the DRB1*1501 variant associated with MS”. "We have known for a long time that genes and environment determine MS risk," says Professor George Ebers, University of Oxford. "Here we show that the main environmental risk candidate – vitamin D – and the main gene region are directly linked and interact." Professor Ebers and colleagues believe that vitamin D deficiency in mothers or even in a previous generation may lead to altered expression of DRB1*1501 in offspring. In the current paper, researchers show that vitamin D binds to a receptor on the DRB1*1501 variant. They hypothesise that this may affect the ability of the thymus, a key component of the immune system, to perform its regular tasks. The thymus produces an army of T cells, which act like soldiers to identify invading pathogens, such as bacteria and viruses, and then attack and destroy them. There are millions of different T cells, each designed to recognise a specific pathogen, but the sheer number of T cells presents a risk that one type might mistakenly identify one of the body's own cells or proteins as an invader and attack it with "friendly fire". Ordinarily, the thymus will regulate the T cells and delete those that pose the greatest risk of attacking the body's own cells and proteins. However, the researchers believe that in people who carry the variant, a lack of vitamin D during early life might impair the ability of the thymus to delete these T cells, which then go on to attack the body, leading to a loss of myelin on the nerve fibres. "Our study suggests the possibility that taking vitamin D supplements during pregnancy and the early years may reduce the risk of a child developing MS," says Dr Sreeram Ramagopalan, first author of the study. "Vitamin D is a safe and relatively cheap supplement with substantial potential health benefits. There is accumulating evidence it can reduce the risk of developing cancer and offer protection from other autoimmune diseases." “This research represents an important development in our understanding of the cause of MS ” says Dr. Paul O’Connor, national scientific and medical advisor for the Multiple Sclerosis Society of Canada. "The evidence implicating vitamin D as a key factor in MS continues to mount," says Dr. O’Connor. “Vitamin D insufficiency is emerging as a key factor of MS in children, and in adults. This finding links important work in two streams of research, namely genetics and epidemiology, and illustrates the important role the MS Society plays in solving what is a very complex disease.” Dr. O’Connor cautions that the study does not provide guidelines on vitamin D dosage and that any decisions on treatment or supplementation should be made in consultation with a trained physician. National Research and Programs

New Biogen drug seeks to repair Multiple Sclerosis damage

Tue, 27 Jan 2009 22:34:43 GMT

Reversing the damage done by multiple sclerosis would be a dream come true for patients of the debilitating disease, and there is some promising research working toward that goal. The condition is thought to occur when the body literally attacks itself and current therapies only seek to slow or stop that situation. But Biogen Idec Inc. (BIIB) is developing a drug that may repair the damage to the nervous system from the disease, a prospect that could also aid victims of other neurological conditions. "This is the first entry into our clinical pipeline, or really in anyone else's pipeline that we are aware of, for a truly restorative therapy for MS," said Ken Rhodes, vice president of discovery neurobiology at Biogen. Though the Cambridge, Mass., biotech company is hopeful for the drug's development, it is yet to be tested in humans and, assuming success, it wouldn't be available to patients for many years. Much remains unknown about multiple sclerosis, but it is thought to be an autoimmune disease that occurs when the body attacks myelin, the protective insulation surrounding the nerve fibers called axons in the central nervous system. The myelin damage can distort or block messages carried by the axons and result in a wide variety of symptoms such as vision problems, limb numbness and paralysis. Though the cause is a mystery, MS is thought to develop from some degree of genetic predisposition working in combination with environmental triggers earlier in the life. It is more common in women and tends to develop between the ages of 20 and 50, according to the National Multiple Sclerosis Society. Current treatments for the disease all involve trying to alter the immune system's ability to attack the nervous systems, notes John Richert, executive vice president of research and clinical programs for the MS Society. A popular group of drugs are the beta-interferons, which reduce disease flare ups and are similar to proteins that play a role in the immune system. Those are Biogen's Avonex, Bayer AG's (BAY.XE) Betaseron, and Rebif, marketed by Pfizer Inc. (PFE) and Germany's Merck KGaA (MRK.XE). Teva Pharmaceuticals Industries Inc. (TEVA) makes Copaxone, which seems to fight the nerve-attacking immune cells by acting as a myelin decoy. Biogen and partner Elan Plc (ELN) also sell Tysabri, which prevents those immune cells leaving the blood stream so that they can't get to the brain or spinal cord. Early Success The focus of much of Biogen's current discovery research in MS is focused on restorative therapy, but its most advanced program is led by biologist Sha Mi, who joined the company in 2000 and studied why the axons in MS lesions weren't generating new myelin. Research found that cells called oligodendrocytes were being prevented from undergoing the needed differentiation for them to build new myelin. Furthermore, Mi found that the so-called LINGO molecule was inhibiting that differentiation and that using an antibody to block LINGO's function could allow myelin to regenerate. "When we block LINGO function, we can see robust oligodendrocyte differentiation, and they interact with the axon for remylination," said Mi. The antibody has been shown to be effective in mouse models that are accepted as being useful for mimicking the properties of MS. The antibody helped the mice grow new myelin, and it also helped with the integrity of the nerve fibers, in comparison to untreated mice, thus aiding nerve function. More myelin growth occurred closer to the site of the antibody application, also suggesting its responsibility for the effects. The research showed that the antibody didn't prevent the loss of myelin in an animal model, but it did reduce the effects of disease progression. Though the development is clearly exciting, the antibody is only in toxicity studies that are expected to be completed later this year. Biogen expects to file an Investigational New Drug application with Food and Drug Administration in the fourth quarter and begin human studies starting shortly thereafter. Rhodes noted that the next goal is to conduct proof-of-concept studies to determine if the drug inhibits LINGO function in humans with the same positive effects. Hopeful Future The possibility of repairing damage done by MS and reducing symptoms of the disease would be revolutionary for MS patients, but Dr. Richert believes that currently used therapies are likely to continue as the best treatment for new patients who may not have a lot of nerve damage. Regeneration would be used on patients who already have neurological deficits, he said, as well as those whose disease continues to progress regardless of treatment. In order to provide the best benefit, Dr. Rhodes said that the anti-LINGO antibody would likely be used in combination with one of the more traditional immunosupressive approaches. "As you dampen the immune response, you treat with anti-LINGO to try and actually facilitate recovery and repair," he said. If successful, the antibody could have a future in treating other neurological disease such as Parkinson's, or even help repair damage done to the spinal cord. Biogen has a number of programs to explore the antibody's use in other diseases but is cautious on any of those prospects. "The preclinical data supporting the utility of those indications isn't as well developed yet as it is with MS," Dr. Rhodes said. Source: CNN Money.com © 2009 BigCharts.com Inc. (14/01/09)

Hope for cure of early stage multiple sclerosis

Fri, 24 Oct 2008 01:20:59 GMT

London (IANS): Human trials of a new medicine have been found to control multiple sclerosis (MS) and even reverse the damage caused by the disease, a study has revealed for the first time. The medicine, alemtuzumab, will undergo further trials before appearing in the market around five years from now, according to the study published in The New England Journal of Medicine. Scientists, however, said the medicine works effectively only on patients with early stages of MS where the nerve damage is in the beginning phase. It also has some potentially serious side-effects, which will be examined in future trials. Multiple sclerosis is a disease of the central nervous system marked by numbness, weakness, loss of muscle coordination, and problems with vision, speech and bladder control. MS is an autoimmune disease in which the body's immune system attacks myelin, a key substance that insulates nerves and helps in the transmission of nerve signals. The study was conducted by a team of neuro-scientists led by Alistair Compston, head of neurology, University of Cambridge. Alasdair Coles, a member of the study team, said: "It is our view that alemtuzumab offers the most effective treatment for relapsing-remitting multiple sclerosis described to date. The ability of an MS drug to promote brain repair is unprecedented. We are witnessing a drug which, if given early enough, might effectively stop the advancement of the disease and also restore lost function by promoting repair of damaged brain tissue." According to The Times, when people with early-stage MS were treated with alemtuzumab, their condition improved significantly more than those on beta interferon, the best treatment available now. The drug reduced the number of MS attacks by 74 percent, and the progression of disability by 71 percent, when compared with beta interferon. Patients on alemtuzumab also showed recovery of brain function, so that they were less disabled at the end of the three-year study than at the beginning, while those on beta interferon continued to decline. Almost every patient taking alemtuzumab improved, whereas about half of MS patients show no response to beta interferon.

Cancer Drug Shows Promise in MS

Fri, 15 Feb 2008 00:19:52 GMT

http://www.reuters.com/article/healthNews/idUSKUA47354420080214?feedType=RSS&feedName=healthNews&sp=true By Gene Emery BOSTON (Reuters) - Two infusions of the cancer drug Rituxan given 2 weeks apart slowed the progression of multiple sclerosis for nearly 1 year, researchers reported on Wednesday. And Rituxan appears to be twice as effective as first-line treatments for MS, which reduce the number of relapses by about one third, the researchers said. "It's quite remarkable that the effect was sustained for 48 weeks with just a single course of therapy," said Dr. Stephen Hauser of the University of California at San Francisco, who worked on the study published in The New England Journal of Medicine. Multiple sclerosis, which affects as many as 350,000 people in the United States and 2 million worldwide, is apparently caused when the immune system attacks and breaks down the insulation surrounding cells that make up the brain and spinal cord. MS symptoms may include blurred vision, loss of balance, poor coordination, extreme fatigue, paralysis and blindness. There is no cure. Although no head-to-head comparison has been done, Hauser said Rituxan appears to work better than existing therapies. His team tested patients with the relapsing-remitting form of the disease, in which symptoms wax and wane over many years, making it difficult to gauge whether a treatment is really working. They make up about half the patients with MS. To assess the progress of the Rituxan treatments, they used magnetic resonance imaging, or MRI, scans to see damage to the nervous system. "What was so surprising here is that the effect on MS inflammatory measures was so fast," Hauser said. The number of lesions they could see dropped immediately after the two treatments. Within 12 weeks, there were almost no old or new lesions, while the number of lesions on volunteers who received placebo shots tended to stay the same or increase in number. But the drug was not as good at preventing relapses. After 48 weeks, 20 percent of the 69 Rituxan recipients had suffered a relapse. That was still much better than the 35 patients who got placebo infusions and had a relapse rate of 40 percent. CONCERN VOICED Rituxan, known generically as rituximab, is made by the biotechnology companies Genentech Inc. and Biogen Idec Inc., which sponsored the study. It is approved for non-Hodgkin's lymphoma and rheumatoid arthritis and sold by Roche AG as MabThera outside the United States, Japan and Canada. Hauser expressed concern that, based on the new results, doctors may begin using the drug on their MS patients even though it has not been approved for that use. "This trial was not designed to assess long-term safety or to detect uncommon adverse events," the researchers wrote. "It would be a tragedy if the drug were to get dinged because of a side effect in a patient that shouldn't have received the drug," he said. The research has also given doctors a better idea of what causes MS, according to Hauser. Rituxan is a monoclonal antibody, a genetically engineered immune system protein, that attacks immune cells called B cells. "This study has taught us that B cells are absolutely essential to the genesis of inflammatory attacks in multiple sclerosis," Hauser said.

Antibody Repairs Myelin Sheath in Multiple Sclerosis

Mon, 31 Dec 2007 21:42:22 GMT

http://www.virtualmedicalcentre.com/news.asp?artid=10835 Abstract Mayo Clinic researchers have found that a human antibody administered in a single low dose in laboratory mouse models can repair myelin, the insulating covering of nerves that when damaged can lead to multiple sclerosis and other disorders of the central nervous system. 9 Dec 2007 The study was presented on Oct. 9 at the American Neurological Association meeting in Washington, D.C. "The repair of chronic spinal cord injury is seldom modelled in laboratory studies, but it is an important reality for the treatment of humans. The concept of using natural human antibodies to treat disease of this kind has not yet been tested in humans, but these research findings are very promising," says Moses Rodriguez, M.D., a Mayo Clinic neurologist and the study's corresponding author. "The findings could eventually lead to new treatments that could limit permanent disability," states Arthur Warrington, Ph.D., a Mayo Clinic scientist and study author. Myelin repair normally occurs spontaneously, but in multiple sclerosis and other disorders of the central nervous system, the myelin repair process occurs very slowly or fails altogether. Researchers are trying to determine how to speed up the myelin healing process, which they hope will eventually lead to new treatments for patients. The antibody, which was genetically engineered from a single cell, binds to myelin and the surface of cells in the brain and spinal cord, then it triggers the cells to begin the repair process called remyelination. This antibody is the first known reagent designed to induce repair by acting within the central nervous system at the damage sites on cells responsible for myelin synthesis. The study uses laboratory mouse models of chronic progressive multiple sclerosis in humans. The severity of the disease and also success of the treatment were largely defined by how naturally active the mice were, particularly during the night because mice are nocturnal and are especially active at this time. They received a single dose of the antibody. A minimum of 25 mcg/kg was needed to trigger remyelination, which is equivalent to about 2 mg in the average adult, considered a very low dose. The myelin repair plateaued after five weeks in the mice models. In addition, when combined with daily methylprednisolone, (an immune modulating steroid) the antibody still promotes remyelination in mouse models. This is an important fact because the first multiple sclerosis patients treated with the antibody will have been treated first with methylprednisolone. As a naturally occurring protein of the immune system, antibodies do not appear to carry any side effects, nor are they toxic - even when administered at 4,000 times the minimal effective dose - though the concept has not yet been tested in humans, the researchers say. In summary, this antibody: * Promotes remyelination with a single dose as low as 25 mcg/kg in mice models * The remyelination plateaus at five weeks after a single dose * Converts a model of chronic immune mediated demyelination to one that repairs with the speed of a toxin induced model of demyelination In terms of replicating the findings in humans, the researchers have already produced the antibody through genetic engineering and conducted preliminary toxicology experiments in mice showing that 1,000 times the therapeutic dose is not toxic. The study continues to be explored in animal models and eventually, in clinical trials. In short, the critical finding is that when combined with methylprednisolone, the antibody still effectively promotes remyelination and does not make the mice worse, Dr. Warrington states. The study was funded by the National Institutes of Health, the National Multiple Sclerosis Society, Multiple Sclerosis Society of Canada, the Hilton Foundation and Mr. and Mrs. Eugene Applebaum. (Source: Meeting of the American Neurological Association, October 2007 : Amy Reyes : Mayo Clinic : December 2007)

Hope for MS

Mon, 26 Nov 2007 18:02:01 GMT

http://news14.com/content/headlines/589868/hope-for-ms/Default.aspx 11/25/2007 05:55 AM By: Ivanhoe Newswire Rich Elliott is now part of a small group of people in the United States testing a new drug for MS. PORTLAND, Ore. -- 400,000 people in this country suffer from multiple sclerosis, or MS, and there’s still no cure. Now, a new drug is showing promise. Rich Elliott is having fun with his daughter. But it’s hard work just staying on his feet. "It’s difficult to walk and stay upright without falling," Elliott said. At 36, Elliott is fighting a daily battle with MS. He is now part of a small group of people in the United States testing a new drug. At this point, he’d settle for anything that keeps the debilitating symptoms from getting worse. "I’d know that this is as bad as it’s gonna get, and I could handle that," Elliott continued. Researchers say current MS therapies affect more than just the bad cells. They can also harm good cells that protect the body’s nervous system. "It’s like having a sledge hammer to kill a fly," said Arthur Vandenbark, Ph.D., Neurologist at O.H.S.U./V.A. Medical Center in Portland, Ore. Dr. Vandenbark and his team designed RTL-1000 to zero-in on the bad cells that cause MS. It works by binding to those cells’ receptors and inactivating them. Pictures from an animal study show MS before RTL and after. The MS cells simply disappear. "I think we can potentially reduce the symptoms a lot, maybe completely, in early stage patients," Dr. Vandenbark said. Researchers hope RTL will reverse damage already caused by MS, even for patients whose disease has progressed. For Elliott, it’s hard to imagine. "If I could walk on my own again without assistance, have a normal day, be able to use your fingers, to get it back would be incredible," Elliott said. He’s hopeful the new medication could hold the key. If RTL-1000 is proven effective in the fight against MS, scientists hope this kind of therapy may also be used to treat other auto-immune diseases, such as diabetes and rheumatoid arthritis. MS is about three-times more likely to occur in women than in men.

An Article for People With Progressive MS

Thu, 15 Nov 2007 04:11:31 GMT

A good article for people with Progressive MS. http://www.unitedspinal.org/publications/msqr/2007/11/14/living-with-multiple-sclerosis-disease-progression/ Some highlights:

Research into what is happening to the central nervous system in multiple sclerosis (MS) gives hope that the disease can be slowed and eventually cured or prevented.
persons with MS understand that until there is a cure, they will have to accept and make the best of what is, in fact, a disabling disease
Quality of life studies show that persons with chronic diseases, including MS, continually redefine their quality of life

Old drug offers new MS hope

Wed, 14 Nov 2007 15:45:05 GMT

Last Updated: 4:01pm GMT 13/11/2007 http://www.telegraph.co.uk/earth/main.jhtml?view=DETAILS&grid=&xml=/earth/2007/11/13/scims113.xml Trials of the drug are to start next year, reports Roger Highfield Tens of thousands of people who suffer the degenerative disease multiple sclerosis receive new hope of more effective treatments after the discovery that an old fashioned drug could be effective. Multiple Sclerosis is the most common disabling neurological disease among young adults and affects around 85,000 people in the UK. It is thought to be an auto immune disease, where the body's own protective immune system turns on itself so that inflammation strips the insulation from nerve cells, so they degenerate, causing weakness, fatigue, brain damage and dependency. advertisement A diuretic drug, amiloride, which has been used for four decades to treat high blood pressure and heart failure has now been found to reduce the degeneration of nerve tissue and symptoms of multiple sclerosis in mice and a team in Oxford is preparing to test the drug on patients next year. The discovery was made by a team led by Professor Lars Fugger of the Medical Research Council Human Immunology Unit and Department of Clinical Neurology at Oxford University and is published in Nature Medicine. Prof Fugger said that, because the side effects of the drug are already well understood, years of expensive effort have been saved in the effort to turn this fundamental understanding into a new treatment. "This drug [amiloride] is already licensed for another purpose. Looking for new ways to use established drugs is usually cheaper than starting the discovery process from scratch, we've had a really positive result." He stressed that clinical trials in people, to test the drug's full potential "are crucial" before it is given as a treatment for the disease. And the drug will not counter the underlying disease process, only help nerve cells to survive for longer. The drug affects the way that charged atoms - ions - move into nerve cells, through special proteins, called channels, in the membranes of nerves. Prof Fugger's team found that the damage of MS was caused by surges of charged sodium and calcium atoms into the axon, the long stem of the nerve that carries signals. "We found that this damage was reduced in mice given amiloride. The drug appears to work by blocking the action of the channel that lets sodium and calcium molecules into the cell." Overall this suggests that drugs targeted at one particular kind of channel (Acid-sensing ion channel 1), such as amiloride, could help reduce the level of nerve damage caused by multiple sclerosis. "We are in the process of setting up the clinical trial and hope to start next year," said Prof Fugger. "It is too early to say how many patients will be enrolled." The team is also interested to find out whether any MS patients in the past have used amiloride, to see if there is any evidence of an effect. "We are trying to find out by get access to various data bases. "However, one should be aware that most MS patients are younger than the patients who are treated for hypertension. Accordingly, it might be a challenge to find an overlapping group that is sufficiently large to allow us to draw any conclusion."

MS Breakthrough in Italy

Sun, 11 Nov 2007 04:23:50 GMT

http://www.italymag.co.uk/2007/news-from-italy/general/italians-in-ms-breakthrough/

New Genetic Risk Factors For Multiple Sclerosis Disease

Fri, 09 Nov 2007 03:23:25 GMT

November 8th, 2007 http://google-sina.com/2007/11/08/new-genetic-risk-factors-for-multiple-sclerosis-disease/ Multiple Sclerosis Study has revealed two genes that influence the risk of getting multiple sclerosis (MS) — data sought since the discovery of the only other known MS susceptibility gene decades ago. The findings could shed new light on what causes MS — a puzzling mix of genes, environment and immunity — and on potential treatments for at least 350,000 Americans who have the disease. "These studies describe the first genes conclusively linked to MS in more than 20 years," said Ursula Utz, Ph.D., a program director at the National Institute of Neurological Disorders and Stroke (NINDS), a part of NIH. "This breakthrough was made possible through persistence, an elegant search strategy, and genomic data and techniques that were not available until recently." Both studies involved scanning DNA samples from more than 20,000 MS patients and unaffected individuals in the U.S. and Europe, and looking for single nucleotide polymorphisms (SNPs), which are single-letter variations in a gene’s DNA code. Published simultaneously today in the New England Journal of Medicine and Nature Genetics, the studies demonstrate an association between MS and SNPs in two genes that encode interleukin receptors, proteins that serve as antennae on the surface of immune cells. Both studies were supported by NINDS and the National Multiple Sclerosis Society. The Nature Genetics study received additional support from the National Institute of General Medical Sciences (NIGMS). The NEJM study was also supported by the National Institute of Allergy and Infectious Diseases (NIAID), the National Center for Research Resources (NCRR) and the Penates Foundation. They were conducted by overlapping teams of scientists that used different gene-hunting strategies. One team, which scanned the entire human genome for MS risk factors, was co-led by David Hafler, M.D., Professor of Neurology at Harvard Medical School and Brigham and Women’s Hospital in Boston, Stephen Hauser, M.D., Professor and Chair of Neurology at the University of California in San Francisco, and Alastair Compston, FRCP, Ph.D., Head of the Department of Clinical Neurosciences at the University of Cambridge, U.K. The other team, which focused their search on a set of genes they considered potential risk factors for MS, was co-led by Jonathan Haines, Ph.D., Director of the Center for Human Genetics Research at Vanderbilt University Medical Center in Nashville, Tenn. and Margaret A. Pericak-Vance, Ph.D., Director of the Miami Institute for Human Genomics at the University of Miami. Drs. Hauser, Compston, Haines and Pericak-Vance participated in both studies. MS typically causes limb weakness, vision loss and problems with coordination, and is the most common disabling neurological disorder of young adults. It’s an autoimmune disease, occurring when the body’s immune system mistakenly attacks a protective sheath around axons — the delicate cables that nerve cells use to connect with each other. Various immunosuppressant drugs can reduce symptoms and slow the disease’s course, but most MS patients become increasingly disabled with time. The trigger for MS is unclear, though there’s strong evidence for an interplay between genetic susceptibility and some type of environmental factor. Having a relative, especially an identical twin, with MS increases one’s risk of developing the disease. In the mid-1970s, researchers discovered that human leukocyte antigens (HLA) account for some of this genetic susceptibility. HLAs are proteins displayed on all the body’s cells to help the immune system distinguish self from non-self. A variant of the HLA-DRB1 gene, now widely accepted as the strongest genetic risk factor for MS, increases the likelihood of getting the disease up to four-fold. Still, HLA does not fully explain the genetic basis of MS; scientists have long realized that other genes must play a role that has been difficult to detect. Some studies have pointed to other HLA genes, but neither of the two genes reported today belong to that category. Both genes encode receptors on the surface of T cells — the immune system’s mobile infantry — that enable the cells to respond to regulatory, secreted proteins called interleukins. "These are the first non-HLA genes to be unequivocally associated with MS," said Dr. Pericak-Vance. "They give us a new way of looking at the biology of the disease, and could be targets for therapeutic development." Both studies searched for a link between MS and SNPs that were previously identified by the HapMap, an NIH-supported project to catalog genetic differences in human populations. In the genome-wide association study, the first of its kind in MS, the researchers used gene chip technology to scan more than 500,000 SNPs. In total, they analyzed more than 13,000 DNA samples, many of them collected and stored by the Center for Genetic Studies at the National Institute of Mental Health (NIMH) and the U.K.’s Wellcome Trust Case Control Consortium. In the candidate gene study, the researchers scanned DNA samples from four large groups in the U.S, U.K. and Belgium, totaling more than 10,000 people. Both studies revealed an association between MS and a single SNP in the gene interleukin 7 receptor-alpha (IL7R-alpha). The genome-wide scan also found two SNPs in the gene for interleukin 2 receptor-alpha (IL2R-alpha) associated with the disease. Both receptors are known to influence the way that T cells patrol the body for pathogens. IL2R-alpha has previously been implicated in other autoimmune diseases, including type 1 diabetes. Each of the SNPs associated with MS appears to increase the risk of developing the disease by about 20 to 30 percent. Although that number might seem small, "it’s the size of effect we expect to see for genes outside of HLA," said Dr. Haines. Multiple genetic variations, each carrying a small risk of MS, could combine with one another and with environmental factors to create a large risk, he said. The researchers who conducted the candidate gene search also think they know how variation in the IL7R-alpha gene affects the IL7R-alpha protein. They found evidence that the MS-associated variant causes a reduction in the amount of the IL7R-alpha protein at the T cell surface. Less is known about how variation in IL2R-alpha might contribute to MS, but that protein is already being viewed as useful therapeutic target. In a 2004 study by NINDS scientists, 10 MS patients who were unresponsive to currently approved therapies showed improvement when treated with an antibody that blocks IL2R-alpha, developed to prevent rejection of organ transplants. Finally, the genome-wide scan identified nearly a dozen other genes that could represent risk factors for MS. Some of the associations were relatively weak and some of the genes’ functions are unclear. "A major effort to understand the full complement of genes involved in MS will be necessary to completely understand the disease," said Dr. Hafler, adding that all of the data from the genome scan will be made publicly available for future investigations.

Apitope vaccine stops MS in its tracks!

Wed, 07 Nov 2007 04:53:07 GMT

http://www.outsourcing-pharma.com/news/ng.asp?n=81147-apitope-multiple-sclerosis-ms-autoimmune-diabetes-diagnose By Mike Nagle 06/11/2007 - UK biopharmaceutical firm Apitope has developed a vaccine that could halt multiple sclerosis in its relentless march to destroy nerve cells. The drug, called ATX-MS-1467, has now been tested in humans for the first time - in six Secondary Progressive Multiple Sclerosis (SPMS) patients in a Phase I/IIa trial - and the results so far are encouraging. No safety issues have been unearthed and one patient also showed good clinical improvement in their symptoms. The immune system attacks proteins it sees as dangerous and helps protect us from a myriad of pathogens. Occassionally these attacks can be devastating if it mistakenly sees proteins in our own body as dangerous and sets about destroying them. This autoimmune reaction leads to numerous diseases, such as Type I diabetes. In the case of MS, the immune system wipes out the myelin sheath around nerve cells - an insulating layer that allows the cells to effectively conduct electrical signals. This causes the nerves to die and the symptoms of MS to appear, including visual problems, weakness, difficulties with balance and speech, severe fatigue, pain, impaired mobility and often disability. According to the MS International Federation, around 2.5 million people suffer from the incurable, progressive disease. Current therapies aim to reduce the inflammation around the nerve cells to offset further damage or, alternatively, to suppress the immune system. However, these broad approaches also suffer from significant side-effects such as an increased susceptibility to infections and a greater risk of cancer. Apitope has taken a different approach with their peptide based vaccine that seeks to retune the immune system so it no longer overreacts to proteins in the myelin sheath. One of these proteins in called myelin basic protein (MBP). This protein is chopped up inside a cell into different peptide strips. Some of these strips or epitopes then bind to a protein called major histocompatability complex (MHC) class II and are carried to the surface of the cell where they are presented to the immune system. Dr Keith Martin, CEO of Apitope, explained to DrugResearcher.com that if certain danger signals are present, then the MBP peptide epitopes can 'switch on' T cells and cause an inflammatory response that damages the myelin. However, and this is where the Apitope vaccine comes in, if the epitope is presented to the immune system in the absence of these danger signals, a different subset of T cells are switched on (called regulatory T cells) and instead of causing damage, these can suppress the immune system reaction to the epitope in question and thus make it more 'tolerant' to myelin. They do this through producing interleukin-10 (IL-10), an anti-inflammatory cytokine. One key part of this is to ensure the vaccine is only injected at sites where there are no danger signals. So, the clinicians doing the trial inject the drug in the periphery of the body and the regulatory T cells produced can then travel to the central nervous system (CNS) and begin to retune the immune system there. One problem remained however. Not all fragments of MBP are capable of causing the immune system to become tolerant to the protein. For example, the MBP peptide made up of amino acids 89 to 101 can induce an immune response both in terms of priming for T cell reactivity and inducing autoimmune encephalomyelitis (EAE) - the commonly used animal model for MS. However, the same peptide does not induce tolerance. So which peptides do and which don't? After much research, David Wraith, a Professor of Experimental Pathology at the University of Bristol, found the answer. He discovered that only peptide fragments that are the right size and shape to be presented to the immune system without further processing can go on to induce tolerance. The discovery led to the spin out of the company and also gave it its name and the name of this class of potential drug - Antigen Processing Independent epiTOPES or Apitopes. Prof. Wraith became the chief scientific officer at Apitope. First, the team use bioinformatics to design peptides that will bind to MHC strongly and, crucially, ones that can also adopt the right shape to bind. "If the peptide isn't the right shape, then it won't trigger a response," said Martin. "If they are in the right conformation, they won't require processing [and therefore will induce immune system tolerance]." He added that in the case of MS, Apitope identified five different peptide epitopes that looked like they would work and then proceeded to test them in a number of in vitro assays. After that process, four remained and these are what make up ATX-MS-1467. The advantage to having four is that there are different subtypes of MHC class II molecules and these four can bind to different ones, such that the "vast majority" of MS patients will be theoretically responsive to the drug. The initial signs are that the vaccine is effective. Given that the myelin sheath also contains other proteins that are thought to induce the immune system to attack, such as myelin oligodendrocyte glycoprotein (MOG), and proteolipid protein (PLP), this is perhaps surprising at first. So how does a vaccine based only on MBP peptides also prevent these other proteins from sending the immune system into overdrive? The answer is 'bystander suppression'. The epitopes for a given protein antigen (in this case MBP) can also induce tolerance to other epitopes from the same antigen, and even epitopes from other antigens, such as MOG and PLP. "Essentially, the activity of the mixture is greater than the sum of its parts," explained Martin. Indeed, one patient on the trial has shown "remarkable improvement in her eyesight", explained Prof. Wraith. "Since the optic nerve is acutely sensitive to inflammation and optic neuritis is often one of the first symptoms of MS, this early indication of efficacy is very encouraging. It suggests that treatment with ATX-MS-1467 can suppress the inflammation associated with MS," he continued. The next step is to continue to monitor the six patients who have completed dosing in the Phase I/IIa trial so that a three month safety follow-up can be conducted. If the drug gets the all clear, Apitope will then continue with a Phase IIb proof-of-concept trial. If that proves successful, the firm will then look to partner the programme with a larger pharma company, although Martin said the company would be willing to partner earlier if the opportunity arose. Way before this drug makes it anywhere near the market though, Apitope hope to begin generating revenues thanks to a MS diagnostic test they have developed. Martin said that early diagnosis in MS is crucial as treatments that seek to slow down or halt the progression of the disease are obviously best given before the disease has had the chance to do too much damage. Even with existing treatments, there is evidence to suggest patients would have much better outcomes if they were diagnosed earlier he said. Unfortunately, the current process of diagnosing the disease can take a while, leaving patients untreated while the disease damages their nerves. Apitope have developed a blood test that can diagnose the disease much more quickly. The test is still undergoing regulatory tests but Martin said that Apitope hopes it will be available to doctors by the end of 2009. The same test also has the potential to be extended as a tool for other autoimmune diseases such as rheumatoid arthritis and lupus. Apitope's approach is also applicable to other immune hypersensitivity reactions and the firm has a programme to identify apitopes to prevent Factor VIII inhibitor formation, which can cause haemophilia. Martin said that he is confident the company will gain orphan drug status for this programme from the US Food and Drug Administration (FDA), although they haven't applied for it yet. This is important as the faster regulatory process for orphan drugs means that, if necessary, Apitope could bring that drug to market without a partner. Scientists at Apitope are also conducting preclinical tests on Type I diabetes and allergy peptides. The MS project remains the most advanced however, and it is this research that will make or break Apitope's approach to peptide induced tolerance. A great number of people with autoimmune diseases will be waiting with baited breath.

Safer Gene Therapy? Hope For Parkinson's, Alzheimer's, and MS

Sun, 28 Oct 2007 16:13:41 GMT

http://www.sciencedaily.com/releases/2007/10/071026095210.htm ScienceDaily (Oct. 27, 2007) — Researchers at the Board of Governors Gene Therapeutics Research Institute at Cedars-Sinai Medical Center have shown for the first time that it is possible to sustain therapeutic gene expression in the central nervous system for up to a year, even in the presence of an anti-viral immune response mechanism that is normally present in humans. The researchers demonstrated in an animal model that the delivery system for the gene, a novel gutted adenoviral vector called HC-Adv, is completely invisible to the immune system. Vectors previously used to deliver genes carried minute amounts of viral proteins that were detected by the immune system, triggering an immune response that rendered the therapeutic gene inactive after a period of weeks. According to the researchers, this delivery system is safer and more effective than what is currently available, and should therefore advance clinical gene therapy trials for people suffering from central nervous system disorders such as Parkinson's, Alzheimer's, and Multiple Sclerosis.

New Test Gene Could Help Treat Multiple Sclerosis

Wed, 24 Oct 2007 03:43:49 GMT

http://abclocal.go.com/kgo/story?section=drive_to_discover&id=5721124 Oct. 22, 2007 - KGO - Multiple sclerosis or MS is a frustrating disease to treat. There are drugs to help symptoms, but none that targets the cause. But a new genetic discovery may be the biggest step forward in decades to help researchers determine the cause of ms and to develop treatments for it. Janek Pawlik adores spending time with his son, but he isn't as care-free as most dads. "I can't do things other fathers can do, like I don't give him piggybacks," said multiple sclerosis patient Janek Pawlik. Janek has multiple sclerosis. His immune system attacks his nervous system and makes simple things -- like walking -- difficult. "It changes how you perceive yourself and the things you think you can have. You get scared of living and scared of dying at the same time," said Pawlik. MS Affects 300,000 Americans. Researchers have spent decades trying to pinpoint what causes it. "We've all been very frustrated by how slow a process it's been," said Professor of human genetics Jonathan Haines Ph.D. For the first time in 30 years, researchers have discovered another gene involved in MS. It's called IL7R, and people with a variation of this gene have a 30-percent increase risk of developing MS. "It's very exciting to us to actually make this breakthrough," said Haines. Here's how they did it: Researchers took blood samples from thousands of patients with and without MS. Robots separated out the DNA and made hundreds of copies of it. Computer software helped researchers determine which groups had which genes. "What it does is open up a whole new avenue for research to try to identify new targets," said Haines. Patients could be tested for the gene and put on treatments earlier. Also - therapies could eventually be designed to target the genetic defect. Janek's excited about the research. "It may not benefit me ever, but maybe my son or the next generation," said Pawlik. A discovery that could eventually lead to better understanding of this debilitating disease. Testing for the gene could be a simple blood or saliva test. This is just the second gene ever discovered that contributes to MS. While researchers say this discovery proves ms is indeed a genetic disease, they believe environmental factors also play a significant role.

SCIENTIST have discovered the "Holy Grail" of Multiple Sclerosis treatment.

Wed, 10 Oct 2007 16:27:32 GMT

Hopes rise of breakthrough in fight against MS Researchers have succeeded in repairing the nerve damage that causes the disease, which affects the central nervous system, leading to muscle weakness. A team of American scientists made the breakthrough in experiments with laboratory mice. Dr Arthur Warrington, from the Mayo Clinic in Rochester, Minnesota, said: "The findings could lead to new treatments that could limit permanent disability." advertisement MS is caused by "friendly fire" from the body's immune system, which destroys myelin, the fatty insulation around nerve fibres in the brain and spinal cord. The damage disrupts nerve messages, leading to symptoms ranging from blurred vision and numbness to complete paralysis. Around 85,000 people in the UK, including former Clyde 1 DJ Tiger Tim, suffer from the condition for which there is currently no cure. Treatment involves calming the immune system and reducing damaging inflammation, but nothing yet exists that can restore lost myelin. Finding a way to repair myelin is the "Holy Grail" of MS research. The scientists used a human antibody to re-grow myelin in mice with multiple sclerosis. They found that one low dose of the antibody was enough to trigger the repair mechanism. The antibody targets the sites of damage and activates cells responsible for synthesising myelin. Patient trials are planned following further animal studies. Publication date 09/10/07

Scientists in Scotland on the way to discovering the cause of long term disability in MS

Thu, 04 Oct 2007 17:23:40 GMT

Scientists in Scotland may be on the way to discovering the cause of long term disability in people with multiple sclerosis (MS). New research carried out at the University of Aberdeen in Scotland, led by Professor Chris Linington, showed that some people with MS have specific antibodies (a type of immune molecule) which attack nerve fibres. The newly identified antibodies recognise and attack a protein called neurofascin-186 which makes up part of the nerve fibre. Higher levels of these antibodies were discovered in a small study of people with MS who have a particularly degenerative type of MS. Researchers are now planning a larger study and if further research showed the antibody to be responsible, it may be possible to remove these antibodies from the blood of people with MS to slow disease progression. Professor Linington said 'I am particularly encouraged because there are already treatments available for other antibody mediated conditions. These type of therapies could be very rapidly translated and applied to MS if we confirm our findings' Millions of nerve fibres are responsible for transmitting messages from our brain to the rest of our body and these nerves are covered in a protective coating called myelin which wraps in bundles around nerve fibres. The gaps which exist between these bundles are very important to allow transmission of nerve impulses along nerve fibres. The neurofascin antibodies can attack the nerve fibres between these gaps in the myelin. In a rat model of MS the attacking antibodies interrupted nerve impulse transmission and worsened disease symptoms by damaging nerve fibres. Dr Laura Bell, research communications officer at the MS Society, said: 'Nerve fibre loss is thought to be the primary cause of long term disability in MS though little is known about what causes that loss. This early research provides potential insight into the process and I look forward to seeing the results of the next stage of the study.' Multiple Sclerosis Society Article URL: http://www.medicalnewstoday.com/articles/84164.php