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Atorvastatin
therapy in early multiple sclerosis
Principal Investigator: Scott Zamvil,
University of California San Francisco
Abstract | Investigators
| News | Background
| Resources
Abstract
Multiple sclerosis (MS), the most common central
nervous system (CNS) demyelinating disease, is thought
to be mediated in part by CNS autoantigen-specific MHC
class II-restricted Th1 cells. With development of treatments
that reduce the risk of relapse and development of sustained
disability, earlier treatment is encouraged. However,
currently approved immunomodulatory therapies are partially
effective, administered parenterally and associated with
significant side effects and potential toxicities. In
contrast, HMG CoA reductase inhibitors "statins"
are administered orally, are well tolerated and have few
toxicities. Recent studies in experimental autoimmune
encephalomyelitis (EAE), a model for MS, have indicated
that atorvastatin has immunomodulatory activity that may
be beneficial in MS treatment. Atorvstatin promoted the
differentiation of Th0 cells into Th2 cells that in adoptive
transfer protected recipient mice from EAE induction.
Thus, induction of regulatory T cells is one mechanism
for statin-mediated immune tolerance. Atorvastatin treatment
after the first attack of chronic relapsing remitting
EAE reversed paralysis. Atorvastatin inhibited IFN-gamma-inducible
expression of MHC class II molecules and CD40, CD80 and
CD86 costimulatory molecules on nonprofessional APC. Statins
also inhibit CNS APC (microglia and astrocytes) from producing
nitric oxide synthetase (iNOS) and TNF-alpha, suggesting
that they may also have a neuroprotective role that could
be beneficial in MS.
A clinically isolated syndrome (CIS) refers to the
first clinical attack attributed to CNS demyelination
that precedes the clinical diagnosis of MS. The primary
goals of this proposal are to: 1) determine whether
atorvastatin treatment will reduce the risk of conversion
to MS in patients that have experienced a CIS and are
at high risk to develop MS, and (2) determine if atorvastatin
treatment causes immune deviation. Nine MS centers that
are highly experienced in MS clinical research will
participate in this randomized double-masked, placebo-controlled
phase II trial. One hundred and twenty six patients
(63 in each arm) will be enrolled. These patients will
have had a CIS within one month of enrollment and at
least two T2 bright lesions of the screening brain MRI.
Patients will be treated for one year with the approved
80 mg dose or placebo. The primary endpoint will be
conversion to MS by clinical or MRI events according
to MacDonald's criteria. Immune function will be assessed
by several different parameters including CNS autoantigen-specific
proliferation, Th1 and Th1 cytokines by ELISA, T cell
differentiation/activation markers and expression of
MHC class II and costimulatory molecules on APC by FACS.
Substudies will involve evaluation of MHC class II transactivator
expression and analysis of markers for oxidative injury.
Our proposed studies involve collaboration with ITN
microarray, real-time PCR and ELISPOT Core Facilities.
This study is highly relevant to immune tolerance. The
results from this clinical trial may be relevant to
treatment other organ-specific Th1-mediated autoimmune
diseases, including insulin-dependent diabetes mellitus
and rheumatoid arthritis.
 Participating
Investigators
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Scott Zamvil,
University of California San Francisco, CA |
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Daniel Pelletier, University
of California, San Francisco, CA |
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Dennis Bourdette, Oregon
Health Sciences University, Portland, OR |
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Marco A. Rizzo, Yale
University, New Haven, CT |
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Anne Cross, Washington
University School of Medicine, St Louis, MO |
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Timothy Vollmer, Barrow
Neurological Institute, Pheonix, AZ |
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Mariko Kita, Virginia
Mason MS Center, Seattle, WA |
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Jeff Cohen, Cleveland
Clinic, Clevelane, OH |
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Leslie Weiner, University
of Southern California, Los Angeles, CA |
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Michael K. Racke, Medical
Center at Dallas, TX |
News
& Recent Developments
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You Want
Statins With That? - Newsweek [go ] |
Background
Articles
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Statins
as potential therapeutic agents in neuroinflammatory
disorders - Curr Opin Neurol [Abstract] |
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The HMG-CoA
reductase inhibitor, atorvastatin, promotes a Th2
bias and reverses paralysis in central nervous system
autoimmune disease - Nature [Abstract]
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Resources
& Interesting Links
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Lipitor
information from Pfizer [go] |
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