http://www.usc.edu/hsc/info/pr/1vol5/526/ms.html

A USC-invented vaccine for multiple sclerosis (MS) is about to enter Phase II clinical trials, backed by a combined $3.5 million in funding-including a $1.1 million award from the National Multiple Sclerosis Society that is one of its largest in recent memory, as well as $2.4 million from the National Institute of Neurological Disorders and Stroke (NINDS).

While the vaccine is unlikely to rid patients of their current MS symptoms, said Keck School of Medicine professor Leslie Weiner, chair of the Department of Neurology and co-inventor of the vaccine, results from the Phase I study on four patients indicate that it may well be able to halt the disease in its tracks.

Weiner and former faculty member Jorge Correale, now head of neurology at FLENI, a foundation and neurologic institute in Buenos Aires, Argentina, that is involved in the fight against neurological diseases, came up with the idea for the vaccine together some 6 years ago. A patent is currently pending, and the Phase II trial has an Investigational New Drug number, which means the Food and Drug Administration has looked at and approved the trial.

Multiple sclerosis is a chronic and oftentimes progressive and debilitating condition that affects some 250,000 to 350,000 Americans. According to the NINDS, physicians diagnose 200 new cases of MS each week. It seems to be an autoimmune condition, a disease in which certain white blood cells turn on the body that produces them.

The best current hypotheses say that MS is caused by the body's T-cells attacking the myelin sheaths that serve as the insulation for the conduction of electricity and coat and protect the long, delicate axons of the brain's neurons.

"This vaccine allows the patient's immune system to take control of the disease," said Weiner. "At the end of two years of vaccinations, we hope they will never need treatment again."

Weiner and his USC colleagues are currently recruiting patients for the three-year-long trial, in which 40 people with MS will receive the active vaccine and another 40 will receive a placebo.

Patients are eligible for the trial if they have what is known as secondary progressive multiple sclerosis-they had periods of both remission and relapse for some time, and now are experiencing a significant progression of the disease (though they may still be symptom-free at times). They also must be between 12 and 65 years of age and be able to walk at least 50 feet, though use of a cane or walker is acceptable.

"It's a very hard task to take sick patients and ask 40 to get a placebo and go off everything else," Weiner admitted. "But we think it's worth it because of the potential benefits of this vaccine." In addition, he noted, most of the patients in this trial will likely be treatment failures on the limited number of treatments available for MS, and so abandoning those treatments should not be detrimental.

Patients accepted into the trial will have a baseline MRI to measure the MS lesions in their brains, and then will undergo a process called leukapheresis, in which their white blood cells are removed from their body. (Since the body is continually producing white cells-and in fact will replace the ones removed within 24 hours-this does not have any long-term effect.)

To create an individualized vaccine, the research team will then expose those cells to myelin from a cow brain, which should prompt the characteristic MS response from the misguided, autoimmune T-cells. (The cow brains have been examined for any evidence of the so-called mad cow disease-bovine spongiform encephalopathy-in collaboration with Nobel laureate Stanley Prusiner of the University of California, San Francisco, and have been approved for use in the preparation of these vaccines.)

Those T-cells are then exposed to 12,000 rads of radiation, killing them and at the same time altering them subtly, so that when they are reintroduced into the body, they will be seen as foreign. That reintroduction-or vaccination-should prompt the immune system to create antibodies and reactive T-cells against the MS-causing T-cells. "We vaccinate them against their own bad T-cells, their own bad lymphocytes," Weiner explained. "After that, they should be immune to the cells they produce that attack their white matter at any time in the future, because they have a memory for the bad T-cells."

How will this help the patient? Simply put, if the body destroys the autoimmune T-cells before they can get to the myelin, this sometimes-devastating disease should be stalled in its tracks. "We don't anticipate that it will get anyone out of a wheelchair," said Weiner. "But we think we can prevent the progression of the disease. We will have made their immune systems 'normal' again, leaving the future repair of their nervous system an easier task."

Vaccines will be created for both the vaccine and placebo groups. If the trial shows that the vaccine is useful, it may be possible to then vaccinate the placebo group as well.

Weiner is optimistic about the vaccine's chances.

"We're giving them weapons to kill their self-immune responses, which you and I can do on our own. In the vaccinated patients, the good T-cells are interacting with the bad T-cells and killing them."

The patients will receive vaccinations every month for three months, and then every three months for two years at the General Clinical Research Center, an NIH-supported facility at LAC+USC Medical Center. The third year of the study will simply be follow-up, to see whether the effects of the vaccination persist over time.

The vaccine will be deemed successful if it can halt the progression of existing lesions and the appearance of new MS lesions, as measured by MRI. Weiner and his colleagues will also look at any changes in neurologic function and will be monitoring any and all side effects of the vaccine.

From a scientific point of view, Weiner noted, the study will most likely put the lid on the debate over whether myelin is indeed the immune system target in MS; scientists have long assumed that to be the case, but it has yet to be definitively proven.

An even more interesting question that the trial will address, he noted, is just how the immune system is able to get quite so out of control, spewing out the literally self-destructive T-cells at an ever-increasing rate.

"The implications of this trial are really quite interesting," said Weiner. "We've made a case that this is worth doing scientifically. Overall, I think this trial is very exciting for USC, especially since the vaccine was invented, developed and manufactured here."

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