In a mouse model of MS, researchers found that the protein, CXCR4, is essential for repairing myelin, a protective sheath that covers nerve cell branches. MS and other disorders damage myelin, and this damage is linked to loss of the branches inside the myelin.

“In MS patients, myelin repair occurs inconsistently for reasons that aren’t clear,” says senior author Robyn Klein, MD, PhD, associate professor of medicine and of neurobiology. “Understanding the nature of that problem is a priority because when myelin isn’t repaired, the chances that an MS flare-up will inflict lasting harm seem to increase.”

The findings appear online in The Proceedings of the National Academy of Sciences.

Mouse models typically mimic MS symptoms by causing chronic immune cell infiltration in the brain, but, according to Klein, the ongoing immune damage caused by the cells makes it difficult for researchers to focus on what the brain does to repair myelin.

For the study, Klein and first author and postdoctoral fellow Jigisha Patel, PhD, used a non-inflammatory model that involves giving mice food containing cuprizone, a compound that causes the death of cells that form myelin in the central nervous system. After six weeks, these cells, known as oligodendrocytes, are dead, and the corpus callosum, a structure that connects the left and right hemispheres of the brain, has lost its myelin. If cuprizone is then removed from the mouse diet, new cells migrate to the area that restore the myelin by becoming mature oligodendrocytes.

Klein’s investigations began with the processes triggered by dying oligodendrocytes while mice are still on the cuprizone diet. The dying cells activate other support cells in the brain, causing them to express inflammatory factors.

Klein showed that levels of a receptor for inflammatory factors, CXCR4, peaked at six weeks. If researchers continued feeding the mice cuprizone for 12 weeks, levels of the inflammatory factor and its receptor dropped significantly. At 12 weeks the mice were also unable to restore myelin, suggesting a potential connection between myelin repair and CXCR4.

“This was a surprise, because the main thing CXCR4 has been known for is its role in forming the brain, not healing the brain,” Klein says. “But we did know that injury increases the number of brain cells that make CXCR4, so it wasn’t an unreasonable place to look.”

Klein showed that the cells destined to become oligodendrocytes and repair myelin damage, known as neural precursor cells, have high levels of the CXCR4. The cells come up to the corpus callosum from an area below the ventricles, a noncellular area filled with cerebrospinal fluid.

When scientists blocked CXCR4 from becoming activated or reduced cells’ ability to make it, the mice were unable to restore myelin. Neural precursor cells stayed in the ventricle and grew in number but did not move to the corpus callosum to begin repairs.

“Apparently the neural precursor cells have to stop proliferating before they can migrate, and CXCR4 plays a role in this change,” Klein says. “CXCR4 also seems to be essential to the cells’ ability to develop into mature oligodendrocytes and form myelin.”

Klein plans to see if she can restore myelin repair in genetically engineered mouse models of MS with a genetically altered lentivirus that increases levels of an inflammatory factor that activates CXCR4. She also will work with Washington University colleagues to study the new model with advanced imaging techniques in an attempt to further clarify the relationship between loss of nerve cell branches and myelin damage in MS.

“We do not yet know if this myelin repair pathway is somehow damaged or impaired in MS patients,” Klein says. “But I like the idea of turning on something that the brain already knows how to make by itself, allowing it to heal itself with its own molecules.”

Funding from the National Institutes of Health and the National Institute of Neurological Disorders and Stroke supported this research.

Italian Dr. Paolo Zamboni has put forward the idea that many types of MS are actually caused by a blockage of the pathways that remove excess iron from the brain – and by simply clearing out a couple of major veins to reopen the blood flow, the root cause of the disease can be eliminated.

Dr. Zamboni’s revelations came as part of a very personal mission – to cure his wife as she began a downward spiral after diagnosis. Reading everything he could on the subject, Dr. Zamboni found a number of century-old sources citing excess iron as a possible cause of MS. It happened to dovetail with some research he had been doing previously on how a buildup of iron can damage blood vessels in the legs – could it be that a buildup of iron was somehow damaging blood vessels in the brain?

He immediately took to the ultrasound machine to see if the idea had any merit – and made a staggering discovery. More than 90% of people with MS have some sort of malformation or blockage in the veins that drain blood from the brain. Including, as it turned out, his wife.

He formed a hypothesis on how this could lead to MS: iron builds up in the brain, blocking and damaging these crucial blood vessels. As the vessels rupture, they allow both the iron itself, and immune cells from the bloodstream, to cross the blood-brain barrier into the cerebro-spinal fluid. Once the immune cells have direct access to the immune system, they begin to attack the myelin sheathing of the cerebral nerves – Multiple Sclerosis develops.

He named the problem Chronic Cerebro-Spinal Venous Insufficiency, or CCSVI.

Zamboni immediately scheduled his wife for a simple operation to unblock the veins – a catheter was threaded up through blood vessels in the groin area, all the way up to the effected area, and then a small balloon was inflated to clear out the blockage. It’s a standard and relatively risk-free operation – and the results were immediate. In the three years since the surgery, Dr. Zamboni’s wife has not had an attack.

Widening out his study, Dr. Zamboni then tried the same operation on a group of 65 MS-sufferers, identifying blood drainage blockages in the brain and unblocking them – and more than 73% of the patients are completely free of the symptoms of MS, two years after the operation.

In some cases, a balloon is not enough to fully open the vein channel, which collapses either as soon as the balloon is removed, or sometime later. In these cases, a metal stent can easily be used, which remains in place holding the vein open permanently.

Sources and links:

http://www.gizmag.com/ccsvi-multiple-sclerosis-ms-cure-zamboni/13447/

http://www.theglobeandmail.com/news/national/researchers-labour-of-love-leads-to-ms-breakthrough/article1372414/

http://www.northumberlandtoday.com/ArticleDisplay.aspx?e=2193676

The team carried out tests on mice and found those with higher levels of galanin, a protein within brain nerve cells, were resistant to MS.

Researchers at Bristol University say it may take ten years before the discovery leads to a new generation of drugs, they believe the results are “very encouraging”. A spokesman for the Multiple Sclerosis Society Scotland welcomed the development yesterday.

Professor David Wynick, who led the Bristol team, said mice that were given increased levels of the neuropeptide – or protein – galanin had proved resistant to the disease.

He said: “The levels of galanin are much higher in the brains of patients with MS.

“We weren’t sure why that was, so we used an animal model of MS and showed that, if we increase the levels of this protein in the brains of mice, they are completely resistant to the development of the disease.

http://news.bbc.co.uk/2/hi/uk_news/england/bristol/somerset/8217972.stm

http://news.scotsman.com/scotland/39DIY-repair39-protein-may-.5583578.jp

Professor Lawrence Stienman, a neurologist, believes the drug, which costs a fraction of the price of normal treatment for the degenerative disease, could slow down the relentless march of the condition by blocking the way it attacks the central nervous system.

The research could offer new hope to the 100,000 or so sufferers of the condition which leads to debilitating attacks, including balance problems, bladder complaints and memory loss.

The renin-angiotensin-aldosterone system (RAAS) is a system of messengers and receptors that regulates blood pressure. The angiotensin-converting enzyme (ACE) produces angiotensin II, which increases blood pressure. This effect is mediated mainly via the angiotensin 1 receptor (AT1R). Medications that inhibit the ACE enzyme or block the AT1R receptor are used by millions to lower blood pressure. Scientific trials and clinical observations have increased the suspicion that RAAS also plays a decisive role in immunological processes.

Inflammation and paralysis reversed

In their tests, the Heidelberg researchers first showed that the RAAS was actually elevated in MS foci in the brains of deceased MS patients. They then treated mice that had an autoimmune disease of the nervous system similar to MS with ACE inhibitors and AT1R blockers. The results were astonishing – the drugs suppressed specific immune cells that were instrumental in promoting inflammation. In addition, they increased anti-inflammatory immune cells that reversed existing neuroinflammation and subsequent paralysis.

Clinical studies to follow soon

Since the animal model the researches employed is an established model that is frequently used for drug development in MS, the researchers hope that the results are transferable to humans. Clinical trials analyzing the efficacy of ACE inhibitors in MS patients are currently being planned. “The use of this blood pressure medication is an attractive strategy for treating autoimmune diseases. The drugs are already used by millions of people, are cheap, and have few side effects,” explains Professor Lawrence Steinman, partner of the Heidelberg researchers at Stanford University.

Sources:

http://www.eurekalert.org/pub_releases/2009-08/uhh-bpm081809.php

http://www.telegraph.co.uk/science/6043212/Blood-pressure-pill-could-help-treat-multiple-sclerosis-claims-scientist.html

http://www.dailymail.co.uk/health/article-1207217/The-2p-blood-pressure-pill-holds-multiple-sclerosis-bay.html

Using a method known as autologous non-myeloablative haemopoietic stem cell transplantation, Burt and his colleagues essentially eliminated misbehaving immune cells and replaced them with healthy ones (made from stem cells) in 21 patients (11 women and 10 men) with relapsing-remitting MS, a common form of the disease in which symptoms come and go.

The way they did this: patients were given drugs that prompted their bone marrow to release immune stem cells (which have the ability to morph into any type of immune cell) into the blood; they then extracted the cells from the blood and gave patients drugs that wiped out their overactive immune systems. The researchers then injected the patients with their stem cells that had been removed earlier; the stem cells quickly divided, giving rise to a fresh batch of normal immune cells in the patients.

The idea behind the therapy, Burt says, is to “regenerate a new immune system” that recognizes healthy tissue and does not destroy the protein sheaths.

After an average follow up time 37 months, 17 of the patients (80 percent) scored better on a standard test used to gauge their vision, muscle strength, motor coordination, and other aspects of neurological function than they had before the trial. The other four patients did not improve, but they also didn’t get any worse, Burt notes.

The next critical step is to figure out how the stem cell therapy stacks up against existing treatments for MS, such as tysabri and novantrone. These meds slow the disease by blocking or suppressing overactive immune systems, but they do not improve symptoms. Burt says he’s currently conducting another clinical trial with 110 MS patients in which he is comparing the safety and effectiveness of the stem cell therapy and MS drugs.

Australian and New Zealand researchers have accelerated research into Multiple Sclerosis by discovering two new locations of genes which will help to unravel the causes of MS and other autoimmune disease.
Their findings will be published today in the journal Nature Genetics.

“For decades the cause of MS has remained a mystery. This discovery reveals important new insights into the genetic susceptibility to the disease, “says Professor Trevor Kilpatrick, Director for Neurosciences at the University of Melbourne, who with Dr Justin Rubio of Florey Neurosciences Institutes coordinated the international study.

“The newly discovered gene locations in chromosomes 12 and 20, offer very promising targets which indicate susceptibility to MS,” says Professor Kilpatrick.

“They also reveal a link between genetic susceptibility to MS and other autoimmune diseases including Type 1 diabetes, Rheumatoid Arthritis and Graves’ Disease and the also the potential involvement of Vitamin D metabolism in the risk of developing these diseases.”

“These results are like the key in the door – leading us to where to look for MS susceptibility,” explains Professor Trevor Kilpatrick.

The research was conducted by members of the ANZgene consortium, more than 40 investigators from 11 institutions in Australia and New Zealand.

The three year study utilized the MS Research Australia (MSRA) Gene Bank and involved scanning the DNA of 1,618 people with MS and 3,413 people without MS (controls).

Using a genome-wide association scan (GWAS), researchers scanned the entire human genome in broad brushstrokes; looking at genetic landmarks in the genome and then progressively narrowing down their search to individual genes.

Dr Justin Rubio who coordinated the GWAS says these genetic discoveries are a major advance for the field.

“We expect that within one to two years we will be able to fine map these new regions and identify the genetic changes that underpin these findings,” says Dr Rubio.

“Our next steps include studying how changes in these target genes might influence the development of MS. This work could provide insight into the development of novel therapeutics,” says Dr Rubio.

MS affects some 2.5 million people worldwide and almost 20,000 in Australia. It is a devastating autoimmune disease as it occurs at the prime of life and mostly in young Caucasian women.

“This Australasian team is competing on a global scale to unravel the complex genetics of MS. This is a significant discovery” says Professor Jim Wiley, Chairman of the ANZGene consortium.

Mr Jeremy Wright, Executive Director of MS Research Australia, says: “We are thrilled to have been funding this study with the Australian Research Council and helping in its coordination. It is central to our mission of accelerating MS research to identify susceptibility in individuals so that we can potentially prevent the onset of the disease, and develop better ways to treat it”.

Researchers at the University of Illinois-Chicago College of Medicine say they conducted a small, double-blind clinical trial involving patients with relapsing remitting multiple sclerosis. The patients were assigned to take pioglitazone — a type 2 diabetes drug commercially known as Actos — or a placebo. Patients continued their normal course of therapy during the trial.

The scientists said patients taking pioglitazone showed significantly less loss of gray matter during the course of the one-year trial than patients taking placebo. Of the 21 patients who finished the study, patients taking pioglitazone had no adverse reactions.

“This is very encouraging,” said Professor Douglas Feinstein. “Gray matter in the brain is the part that is rich in neurons. These preliminary results suggest the drug has important effects on neuronal survival.”

The scientists also tested pioglitazone in an animal model of MS and found the drug “can significantly reduce the clinical signs in mice with an MS-type disease,” said Feinstein.

“More importantly, when mice who are already ill are treated with pioglitazone, the clinical signs of the disease go away,” he said.

The study is reported in the online edition of the Journal of Neuroimmunology.

“While obviously no conclusions in terms of therapeutic efficacy can be drawn from these reports, this first clinical use of fat stem cells for treatment of MS supports further investigations into this very simple and easily-implementable treatment methodology,” said Dr Boris Minev, from the University of California.

Here are some of the links:
BBC
Bloomberg.com
Independent.co.uk
Telegraph.co.uk

In a cell biology lab at UC Riverside, researchers look at the four screens of a flow cytometer, a sophisticated instrument that searches for fluorescent labeled reactions inside cells.

Some cell activities will fluoresce green, red, yellow or some other color based on how the study is set up.

The computer-driven machine uses a laser to scan 5,000 cells per second in the search for understanding the relationship between neurons, the electricity-carrying cells of the nervous system, and the microglia, the cells that support the neurons, said Monica Carson, associate professor of biomedical sciences at UCR and director of UCR’s Center for Glial-Neuronal Interactions.

In multiple sclerosis patients, why do some microglia turn on the nervous system and attack the myelin sheath that protects neurons and speeds the conduction of electrical impulses?

When scientists understand this relationship, they can develop drugs to turn off the hostile behavior of microglia and other soldiers attacking the immune system, preventing the advance of multiple sclerosis, Carson said.

While Carson and researchers are looking for the ultimate understanding and ultimate cure for MS, others are fighting the battle with current knowledge and an arsenal of medicines that have been around for about 20 years.

Dr. Richard Shubin, who is program medical director of Casa Colina’s Multiple Sclerosis Center in Pomona, meets with patients at the center.

Shubin, a neurologist, also has a private practice in Arcadia and through his Pasadena-based research office, Neurotherapuetics, is engaged in trial studies for the three new medicines with MS fighting potential.

In three to five years, doctors will have a new arsenal of medications in the battle against the harmful effects of multiple sclerosis, Shubin said.

Included in this list is a group of drugs that can be taken in pill form, where all frontline drugs currently authorized are delivered either intravenously or via injections.

Most patients with MS now have treatment with one of four frontline drugs of roughly equal efficiency, Shubin said.

Three of them are in the interferon family of drugs, meaning they belong to a group that tweaks the immune system to turn off the characteristic MS trait of attacking the cells that make the myelin sheath.

Another drug, called Tysabri, is stronger than the interferon drugs but can have a serious side effect, leading to a viral infection of the brain called progressive multifocal leukoencephalopathy (PML), which is caused by activation of the JC virus, a bug carried by most people that is harmless except in immune system compromised individuals.

PML is most frequently seen in people with AIDS. Oddly, Shubin said, patients who have developed PML after treatment with Tysabri do not develop the other diseases characteristic of AIDS patients.

Because of this side effect, Shubin said Tysabri is not given to MS patients unless the other medications have not been successful in controlling the progression of symptoms.

Shubin said he believes that one of the new drugs with the most promise is FTY-720, or Fingloimod, a daily pill that is in the third phase of clinical study in multiple sites around the world.

In addition to the Pasadena site, the drug is being tested in other locations throughout North America, South America, Australia and Europe, Shubin said.

“For years patients have been asking for an oral medicine. So that development of pills will help improve quality of life and improve compliance,” he said.

If the trial delivers the expected results, the manufacturer will be able to apply for approvals from multiple countries around the world at the same time, Shubin said.

Campath is another one of the drugs in clinical trials. While it appears to be twice as effective as the interferons, it has potentially severe side effects, Shubin said.

“There is a tradeoff with greater potency. They work better but there are more side effects. Some people are calling this a neutron bomb because of its potency. It’s probably the most potent of the new drugs, but also potentially the most toxic.”

In earlier trials, some patients on Campath have developed Goodpasture’s syndrome, a condition leading to the rapid destruction of the kidneys and hemorrhaging of the lungs, he said.

Laquininod, a once-a-day pill, is another drug Shubin is working with under clinical trials.

“This may be the winner in terms of lack of side effects,” Shubin said.

There are several others in various phases of clinical trials as well.

Shubin said that when people are diagnosed with MS, their path is frequently a gradual worsening to the point that they are forced into a wheelchair after 15 years.

That time frame may be lengthened somewhat with medications, he said.

For some, however, the disease progresses much more rapidly and doctors are willing to use more aggressive medicines on them.

Although MS can strike at any age, the most common years for diagnosis are between 20 and 40. Women are three times more likely than men to have the disease.

This disease strikes different parts of the nervous system “without rhyme or reason,” Shubin said.

It can affect vision, the ability to think, bowel and bladder functions, coordination, walking, speech, cause numbness or burning sensations, or involuntary contractions. A commonly shared effect of the disease is fatigue.

“Imagine starting out every day feeling you were just getting over the flu,” he said.

Patients may have long periods of stability before their symptoms flare up. Some patients Shubin sees may visit him only once a year.

When MS patients experience a flare-up, they may rebound to life just as it was before the onslaught of symptoms. But as time goes on, patients don’t spring back.

Too much damage to the nervous system has occurred, Shubin said. Now, each flare-up will leave them in worse shape than before.

It’s the mystery of what causes those flare-ups that has Carson and her researchers running their tests. The next batch of cells analyzed by the flow cytometer could bring us a little closer to those answers.