New Evidence Suggests Statins Could Prove Useful in Treating MS
Multiple Sclerosis Treatment
Scientists at the University of California, San Francisco and Stanford University Medical Center are reporting compelling new evidence that the cholesterol-lowering drug atorvastatin could prove an effective therapy for preventing the progression of, and reversing the severity of, multiple sclerosis (MS).
In the March 16 on-line edition of The Journal of Clinical Investigation, they report the results of an animal study that looked at the use of the drug (marketed as Lipitor) in combination with Glatiramer acetate (marketed as Copaxone), a drug already approved for treating multiple sclerosis.
The findings demonstrate, they say, that the drugs worked synergistically, preventing or diminishing paralysis in mice with experimental autoimmune encephalomyelitis (EAE), a model disease that closely resembles multiple sclerosis. Multiple sclerosis causes a variety of neurological symptoms including loss of motor control, visual loss or imbalance. A primary symptom is temporary, recurring paralysis in the limbs, as occurs in the mice.
Copaxone is known to boost the immune system's anti-inflammatory response, countering the release of pro-inflammatory cytokines, or chemicals, unleashed when the immune system inadvertently turns against the brain's nervous tissue in MS. The drug is approved for treatment of relapsing-remitting multiple sclerosis, the most common form of the disease, but is effective in only a third of cases.
Lipitor is also known to have immunomodulatory properties, and recent evidence in mice and initial clinical trials suggest that it, and possibly other statins, may be effective in treating T-cell-mediated, autoimmune diseases, such as rheumatoid arthritis, as well as other inflammatory conditions.
A clinical trial now underway seeks to determine if Lipitor prevents conversion to definite multiple sclerosis in individuals who have had a first attack, known as a "clinically isolated syndrome." Led by UCSF scientists, this placebo-controlled trial is enrolling participants at 14 medical centers across the country. It is based on a study (Nature, Nov. 7, 2002) of mice with EAE by the same UCSF-Stanford team.
In the current study, however, the researchers took a different tack. Because Lipitor and Copaxone work through different mechanisms, the team set out to investigate whether Lipitor could augment Copaxone's efficacy in mice with EAE. Because both drugs are fully effective in preventing or reversing the disease in the animals, they were administered at precisely determined suboptimal doses.
The results were dramatic, according to the researchers. In the first step of the study, 10 mice were given the combination therapy prior to their immunization with the protein that induces EAE (MBP, or myelin basic protein). Of these, only three developed paralysis, and their symptoms were very mild. In addition, the central nervous system tissue of these animals had substantially fewer destructive inflammatory lesions. Fewer pro-inflammatory cytokines were produced, while more of the beneficial, anti-inflammatory cytokines were produced. In contrast, all of the EAE "control" mice - those that received either no drug or suboptimal doses of Lipitor or Copaxone - developed the full-blown disease.
In the second, and more provocative step of the study, involving 10 mice with established EAE, the combination therapy dramatically lessened the clinical and histological signs of the disease. The animals were essentially free of paralysis, they had reduced inflammation in the central nervous system, and decreased destruction of the myelin sheath, which insulates the nerves and is the target of destruction in MS. In contrast, there was no reversal of the disease in mice that received either no drug or suboptimal doses of Lipitor or Copaxone.
The findings in the mice demonstrate, says co-senior and corresponding author Scott Zamvil, MD, PhD, UCSF associate professor of neurology, that agents with different mechanisms of immune modulation can combine in a synergistic manner for the treatment of central nervous system autoimmunity, and provide a rationale for testing the combination therapy in multiple sclerosis. "We hope," he says, "that the combination will prove beneficial in MS treatment."
"The combined effect of these two drugs is very impressive," says co-lead author Olaf St