By Jeffrey Perkel
HealthDay Reporter
Monday, February 18, 2008; 12:00 AM
MONDAY, Feb. 18 (HealthDay News) -- A high-tech molecular fishing expedition has led researchers to two potential therapeutic targets for the treatment of multiple sclerosis.
The data implicate a pathway more typically associated with wound healing -- the blood clotting cascade -- than in the development of multiple sclerosis (MS).
"There is no coagulation component to MS," explained Patricia O'Looney, vice president of biomedical research at the National Multiple Sclerosis Society.
But coagulation factors also play a role in inflammation, whichisa component of the disease, she noted.
"If you can use this pathway and engineer some new drug therapy that will turn on the anti-inflammatory pathway, that could benefit people with MS," O'Looney concluded. "So, this perhaps reveals new therapeutic targets."
The research was published Feb. 17 in the advance online edition of Nature.
In the study, a team led by Dr. Lawrence Steinman of Stanford University School of Medicine grouped MS brain lesions from six autopsied human subjects into three classes based on histological criteria. They then probed those samples, along with samples from two healthy controls, using a technique called mass spectrometry, which essentially identifies the proteins in a tissue based on their mass.
The result was a "proteome" -- a sort of protein index of the tissues. Of the 2,574 proteins the team identified from all the samples, they found a few hundred that were unique to MS. More than half of those proteins were of unknown function, but five were known players in blood coagulation -- a pathway not previously recognized as being involved in the origin and development of the disease. All five were found in a single type of lesion, called a "chronic active plaque."
Puzzled by that observation, Steinman's team then tested whether drugs that targeted two of the five coagulation pathway members, called tissue factor and protein C inhibitor, could alleviate the symptoms of MS in a mouse model of the disease.
They seemed to have succeeded: Mice formerly paralyzed by an MS-like illness regained walking ability after the treatments, the researchers said. "They went from paralysis involving hind limbs to a much more functional score," Steinman said. The effect lasted at least two months, he added.
According to the National Multiple Sclerosis Society, MS affects at least 400,000 Americans. The disease results from loss of the insulating myelin sheath that surrounds nerve fibers, thereby disrupting nerve transmission, and causing damage to the nerve fibers themselves. Symptoms vary from patient to patient but can include blurred vision, slurred speech, loss of coordination and paralysis. Disease course can also vary, with four distinct disease forms recognized, the most common of which is relapsing remitting MS.
According to O'Looney, that variability is "the biggest challenge" of the disease.
"The symptoms may vary from person to person, the disease course will be variable, and we don't understand why there is this difference among people with MS," she said.
"And so," she added, "what is terrific about this study is that it compares the different forms of MS."
Six MS treatments have been approved for use by the US Food and Drug Administration, but there is as yet no cure for the disease, according to O'Looney. The two drugs Steinman used have been approved by the FDA for use in treating other diseases, however. Hirulog is an anti-coagulant protein fragment derived from leeches; Xigris is a recombinant form of activated protein C, for use against severe sepsis.
Those approvals should give researchers a head-start in getting these compounds into clinical testing for MS, Steinman said. "We can already jump past toxicity testing, because they are already approved," he noted.
But that doesn't mean doctors should administer these drugs to their MS patients right now, Steinman cautioned.
"It needs to be tested in clinical trials. We need evidence, and these drugs have serious potential side effects," he said. "But organized, well-run clinical trials should be done, because these drugs may be of immense potential benefit to people with MS."
Praising the study's use of donated human samples, O'Looney added that, "it's a perfect example of how we can learn so much from the use of tissue samples. We are so indebted to people with MS who leave the message that their bodies are available to researchers. So, this is the perfect example of how valuable that is. That's what drove this study."
More information
For more on multiple sclerosis, visit the National Multiple Sclerosis Society.
SOURCES: Larry Steinman, M.D., professor, neurology and neurological sciences, and chair, Interdepartmental Program in Immunology, Stanford University School of Medicine; Patricia A. O'Looney, Ph.D., vice president of biomedical research, National Multiple Sclerosis Society; Feb. 17, 2008, advance online publication,Nature
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