Scientists Report Cancer Fighting Drug As Possible Treatment For
Multiple Sclerosis
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.