73 percent of Tovaxin-treated patients showed stabilization or improvement in MS disability, including 16.5 percent with a sustained improvement of at least one full point on a standard disability scale.

Tovaxin possesses a unique dual mechanism of action that combats the demyelination of the nerve fibers in the central nervous system, the underlying cause of MS. Clinical results have demonstrated that Tovaxin produces the following therapeutic effects:

• Anti-idiotypic effect – The vaccine induces an immune response that depletes the circulating pathogenic MRTCs that attack the myelin sheath of nerve fibers and cause the symptoms of MS.
• Anti-ergotypic effect – Tovaxin also works to rebalance a patient’s overall immune system by causing a shift from pathogenic inflammatory T-cells to anti-inflammatory T-cells.

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

The new treatment,  named GIFT15  puts MS into remission by suppressing the immune response. This means it might also be effective against other autoimmune disorders like Crohn’s disease, lupus and arthritis, the researchers said, and could theoretically also control immune responses in organ transplant patients. Moreover, unlike earlier immune-supppressing therapies which rely on chemical pharamaceuticals, this approach is a personalized form of cellular therapy which utilizes the body’s own cells to suppress immunity in a much more targeted way.

GIFT15 was discovered by a team led by Dr. Jacques Galipeau of the JGH Lady Davis Institute and McGill’s Faculty of Medicine. The results were published August 9 in the prestigious journal Nature Medicine.

GIFT15 is composed of two proteins, GSM-CSF and interleukin-15, fused together artificially in the lab. Under normal circumstances, the individual proteins usually act to stimulate the immune system, but in their fused form, the equation reverses itself.

“GIFT15 can take your normal, run-of-the-mill B-cells and convert them … into these super-powerful B-regulatory cells,” study team leader Dr. Jacques Galipeau, of the Jewish General Hospital Lady Davis Institute for Medical Research and McGill University in Montreal, said in a university news release.

He and his colleagues took normal B-cells from mice and sprinkled GIFT15 on the B-cells. “And when we gave them back intravenously to mice ill with multiple sclerosis, the disease went away,” Galipeau said.

The treatment was fully effective with a single dose, and no significant side effects were seen in the mice, the researchers reported.

Their findings were published online Aug. 9 in Nature Medicine.

Sources:

• http://health.msn.com/health-topics/neurological-cognitive-health/articlepage.aspx?cp-documentid=100243178
• http://www.medpagetoday.com/Neurology/MultipleSclerosis/15492
• http://www.calgaryherald.com/health/Canadian+research+shows+reversal+mice/1881887/story.html
• http://www.eurekalert.org/pub_releases/2009-08/mu-mrs081109.php

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.

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.

Dr. Aris from BioVista was kind enough to return my email where I asked for a layman’s description of MOG-induced Experimental Allergic Encephalomyelitis (EAE).

Although no animal model thus far establishes all facets of human MS, Experimental Allergic Encephalomyelitis (EAE) induced in rodents represents the model most studied for the disease. The origin of the model is traced to the development of the rabies vaccine. Encephalomyelopathy was caused in a small percentage of humans who received the rabies vaccine. Historically is has been thought that Th1 cells played a predominant role in the pathology of the disease. However, recent evidence suggests that a proinflammatory cascade of Th17 cells, IL-6 and TGF-b in the central nervous system plays a critical role in the pathogenesis of EAE and MS.
Initially rodent brain homogenates were used as antigens for immunization. Today, myelin related proteins or peptides are used for the induction of the disease. Among the most commonly employed are MBP (a major constituent of myelin), PLP (proteolipid protein only found in myelin) and MOG (myelin oligodendrocyte glycoprotein). Sections of PLP, such as 139-151, are encephalitogenic to certain mouse strains. The choice of the peptide together with the animal strain and way of induction will determine the type of disease one wants to mimic. MOG-induced EAE is a chronic disease and is the closest murine analog of Progressive Multiple Sclerosis.

Thank you Dr. Aris!

Helen Yates, Chief Executive of the Multiple Sclerosis Resource Centre (MSRC) said: “We truly hope that the research leads to a treatment for this very worrying and potentially life threatening condition. It is important that people affected by MS that are undergoing treatment with Tysabri have as much reassurance as possible about the potential side effects and the ability to treat them should they arise.”

As reported by The Irish Times: A possible treatment for a potentially fatal side effect of multiple sclerosis therapy, Tysabri, and other immuno-modulating drugs is currently under investigation.

Biogen Idec, Elan’s partner in the development and sale of Tysabri, is testing the efficacy of a malaria pill developed during the Vietnam war in treating progressive multifocal leukoencephalopathy (PML), the brain infection that has been tied to use of Tysabri, according to Al Sandrock, Biogen’s head of neurology research.

Tysabri was pulled from the market in 2005 after three PML cases were reported. It was reintroduced a year later when US regulators said the medication’s effectiveness, twice that of other MS drugs, outweighed its risks.

However, the threat of PML has affected sales of the treatment which, although a successful drug in commercial terms, is well short of the figures initially expected.

The companies have reported five new PML cases since July 2008, reigniting concerns of patients who believe a safer Tysabri would be their best treatment option, said John Richert of the US National Multiple Sclerosis Society.

Tysabri, a laboratory-engineered antibody, is designed to suppress the immune attack that leads to MS.

PML occurs when a common germ, called JC virus, mutates, evades the body’s immune defences and penetrates the brain, causing irreversible damage.

Biogen has been seeking a PML treatment since 2005, screening about 2,000 compounds known to fight brain infections.

The drug showing the most promise in laboratory tests was the commonly used malaria pill mefloquine.

A clinical trial is now testing mefloquine in 40 patients with PML from any cause, whether drug-related or from HIV.

The goal is to see whether mefloquine, sold by Roche Holding under the name Lariam, can treat PML when it occurs. The trial is expected to be completed by the end of the year.

Source: MecidalNews

The experimental drug fampridine (4-aminopyridine) improves walking ability in some individuals with multiple sclerosis (MS). That is the conclusion of a multi-center Phase 3 clinical trial, the results of which were published February 26 in the journal The Lancet.

“This study indicates that fampridine could represent an important new way to treat multiple sclerosis and perhaps become the first drug to improve certain symptoms of the disease,” said neurologist Andrew Goodman, M.D., chief of the Multiple Sclerosis Center at the University of Rochester Medical Center (URMC) and lead author of the study. “The data suggest that, for a sub-set of MS patients, nervous system function is partially restored while taking the drug.”

The study evaluated a sustained-release formulation of the drug, Fampridine-SR, which is being developed by Acorda Therapeutics, Inc. The company, which funded the study, submitted a new drug application to the U.S. Food and Drug Administration earlier this month. Goodman has been a consultant and advisor to Acorda for its fampridine studies in MS.

Multiple sclerosis is a disease of the central nervous system and is the most common cause of neurological disability in young adults. Worldwide it is estimated that more than a million people are affected by MS which is typically characterized by recurrent relapses followed by periods of remission early in its course. The symptoms of the disease vary from person to person, but commonly consist of muscle weakness, gait difficulties, numbness or tingling in arms and legs, difficulty with coordination and balance, blurred vision, and slurred speech. Over time, the effects of the disease tend to become more permanent and debilitating.

While the precise cause is unknown, it is understood that the immune system in individuals with MS attacks myelin, a fatty tissue in the central nervous system that wraps the fibers – or axons – that connect nerve cells. Similar to the insulation on an electrical wire, myelin allows for the efficient conduction of nerve impulses. When myelin is lost or damaged in the disease, signals between nerve cells are delayed, disrupted, or even blocked.

It is believed that fampridine improves the transmission of signals in the central nervous system of some MS patients by blocking potassium ion channels. These channels serve as gates on the surface of cells and regulate the normal electrical activity. In laboratory experiments involving nerve fibers with myelin that was damaged in a manner that mimics MS, scientists found that blocking these channels results in a recovery of signal conduction.

In the Phase 3 study just published, the effects of Fampridine-SR were tested in 301 adult MS patients at 33 locations in the U.S. and Canada over a 14-week period. Three quarters of the participants took the drug and the rest were given a placebo.

Typically, MS drugs have been evaluated based on the ability to prevent relapses. Because the goal of this study was to assess changes in function, the researchers instead sought to evaluate participants’ mobility and muscle strength – as opposed to the disease process. In prior studies, Goodman and his URMC colleague, the late Steven Schwid, M.D., had validated new methods to measure changes in gait, or walking speed over distance. Employing these methods in The Lancet study, they found that 34.8% of those receiving the drug experienced an improvement (an average of about 25% increase) in the speed they could walk 25 feet compared to only 8.3% in the placebo group.

“During the course of the disease, many MS patients experience a decline in mobility and this disability has a major impact in terms of quality of life,” said Goodman. “As a clinician, I can say that improvement in walking speed could have important psychological value; it may give individuals the potential to regain some of the independence that they may have lost in their daily lives.”

From: BioResearchOnline

“These latest data show the rapid onset and sustainability of laquinimod efficacy in MS patients,” said Giancarlo Comi, M.D., University Vita-Salute San Raffaele, Scientific Institute San Raffaele, Milan, Italy, principal investigator of the study. “Just as exciting is the fact that, with increased number of patients exposed to laquinimod, we found no new risks or safety issues. This reinforces earlier results demonstrating the laquinimod safety profile. The MS community looks forward to future data as we continue enrolling patients in the laquinimod Phase III clinical program.”

These new data from the extension study build upon the initial 36-week, Phase IIb study results published in The Lancet*, which demonstrated that once-daily, oral 0.6mg laquinimod significantly reduced MRI disease activity by a median of 60 percent, compared to placebo, and was well tolerated.

From MedicalNewsToday

Treatment with laquinimod reduces development of active MRI lesions in relapsing MS

Oral laquinimod for multiple sclerosis granted fast track status by FDA