July 7, 1998 A drug currently undergoing phase III clinical trials for certain types of cancer may have potential benefit for the treatment of multiple sclerosis (MS), report researchers from The Rockefeller University, Albert Einstein College of Medicine (AECOM), British Biotechnology Pharmaceuticals Ltd. and Harvard Medical School. These findings, published in the July Annals of Neurology, offer a new avenue for treatment of this disease.
"We have shown that a class of drugs called matrix metalloproteinase inhibitors (MMPIs) are effective in treating a mouse model of multiple sclerosis," says Wolfgang Liedtke, M.D., lead author of the paper. "MMPIs have been shown to be safe for people in human trials as a cancer therapy, and we think that people with MS may benefit." Leidtke, now a research associate at Rockefeller, did the work in the laboratory of senior author and MS pioneer Cedric S. Raine, Ph.D., D.Sc., F.R.C.Path., a professor of neurology, neuroscience and pathology at AECOM.
Multiple sclerosis is an unpredictable disease of the central nervous system (CNS) that affects an estimated 250,000 to 350,000 people in the United States, with an annual estimated cost of more than $2.5 billion. Severity of the disease varies, however, in severely affected cases, MS can render a person unable to see, speak or walk. MS most often strikes between the ages of 20 and 40 and more often in women than in men.
In people with MS, the body's immune system launches an attack against its own tissues, specifically a fatty substance called myelin that surrounds nerve fibers in the brain, spinal cord and optic nerves, where it acts as an insulator. Myelin allows for the speedy conduction of nerve impulses that convey information in the CNS. When myelin is damaged, the nerve fibers are no longer insulated and nerve impulses cannot be conducted efficiently. The location and extent of damaged myelin in the CNS determines the type, severity and duration of symptoms in MS.
Scientists do not know what causes MS, but the disease is characterized clinically by recurrent episodes of paralysis at all levels of the CNS. Research has shown that inflammation, loss of myelin and scar tissue that replaces injured nerve fibers in the CNS underlie these symptoms. Patchy inflammation in the white matter of the CNS historically is called plaque. In the inflammatory milieu of the plaque, the nerve fibers are stripped of their myelin.
In the study, the researchers used inbred mice that were immunized to develop a disease called chronic-relapsing EAE, which has many similarities to its human counterpart, MS, including relapses and recurrences of inflammatory destruction of myelin in optic nerves, brain and spinal cord. MMPI, when given to mice with chronic-relapsing EAE, significantly ameliorated the disease course and decreased the number of relapses. Analysis of spinal cord tissue from treated mice showed a striking reduction of scarring and a strong inhibition of myelin destruction.
The scientists also looked at the levels of three substances, called cytokines, playing a role in the autoimmune process damaging the CNS in MS: tumor necrosis factor-a (TNF-a), Fas-ligand (FasL) and interleukin-4 (IL-4). TNF-a and FasL are toxic to CNS myelin and to the myelin-producing brain cells called oligodendrocytes, which are a prime target of the immune attack in MS. IL-4 is considered to be a beneficial cytokine. MMPI treatment downregulated TNF-a and FasL and, surprisingly, increased the expression of IL-4 on specialized brain cells called glial cells.
To add impact to the conclusion of the mouse experiments for the treatment of MS, the authors used immune system cells called myelin autoaggressive T cells, which many scientists think play a role in MS. Liedtke and co-workers found that MMPI, when administered to such cultured human T cells, decreased the amount of TNF-a that was shed by the cells.
"With the combined impact of MMPI on human myelin autoaggressive T cells and on a powerful animal model for MS, we are looking at MMPIs as promising candidates for human clinical trials in MS, which have already been initiated," says Liedtke.
Liedtke's and Raine's co-authors on the paper are Barbara Cannella, Ph.D., and Richard J. Mazzaccaro, Ph.D., of AECOM; John M. Clements, Ph.D., Karen M. Miller, Ph.D., and Andrew J. Gearing, Ph.D., of British Biotechnology Pharmaceuticals Ltd.; and Kai W. Wucherpfennig, M.D., Ph.D., of Harvard Medical School.
The study was supported by grants to Raine from the U.S. Department of Health and Human Services, from the National Multiple Sclerosis Society (NMSS) and from the Gladstein Foundation. Liedtke was supported by a Feodor Lynen Fellowship award of the Alexander von Humboldt Foundation (Bonn, Germany) and Wucherpfennig was supported by a Harry Weaver Neuroscience Scholarship award of the NMSS.
Rockefeller began in 1901 as The Rockefeller Institute for Medical Research, the first U.S. biomedical research center. Rockefeller faculty members have made significant achievements, including the discovery that DNA is the carrier of genetic information and the launching of the scientific field of modern cell biology. The university has ties to 19 Nobel laureates, including the president, Torsten N. Wiesel, M.D., who received the prize in 1981. The university recently created six centers to foster collaborations among scientists to pursue investigations of Alzheimer's disease, of biochemistry and structural biology, of human genetics, of immunology and immune diseases, of sensory neurosciences and of the links between physics and biology.
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