Mar. 17, 2006 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 a 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 MS.
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 MS, 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. In fact, a 2002 study of mice with EAE by the UCSF-Stanford team (Nature, Nov. 7, 2002), has led to the establishment of a fourteen-center, placebo-controlled trial, led by UCSF scientists, to determine if Lipitor prevents conversion to definite multiple sclerosis in individuals who have had a first attack, known as a "clinically isolated syndrome." 1.
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 Stüve, MD, who conducted much of his work while a UCSF postdoctoral fellow in the Zamvil lab. "As such, the therapy represents a potential new strategy for treating multiple sclerosis." Stüve is now an assistant professor of neurology at UT Southwestern Medical Center at Dallas and is affiliated with the VA North Texas Health Care System.
More broadly, notes co-lead author Sawsan Youssef, PhD, a postdoctoral fellow in the laboratory of co-senior author Lawrence Steinman, MD, professor of neurology and Director of the Program in Immunology at Stanford University, the results demonstrate that the EAE mouse model can be used to evaluate the effectiveness of various drug combinations, with an eye toward developing new strategies for treating MS.
"There is still much to learn," says co-lead author Martin S. Weber, MD, a UCSF postdoctoral fellow in the Zamvil lab, "but this is an exciting advance."
"The treatment of a complex disease like multiple sclerosis will certainly involve regimens that combine more than one drug," says Steinman. "For this approach to work we need to find drugs with complementary modes of action. Statins and glatiramer work by entirely different mechanisms, and their effects are additive. Moreover, their toxicities are modest when used alone, and they are expected to continue to show only modest side effects when used together. Finally, in an age where the costs of medical treatments are receiving more and more scrutiny, adding a relatively inexpensive drug like a statin to an already expensive regimen is likely to make consumers and health care insurers even more enthusiastic about combination therapies."
The finding is the latest step in elucidating the potential of Lipitor to treat MS. It follows a study of mouse EAE published by the same team last month (The Journal of Experimental Medicine, Feb. 20, 2006) that suggests a mechanism by which Lipitor may suppress the production of pro-inflammatory cytokines associated with central nervous system autoimmune disease. Study findings indicated that the drug's effects on the immune system occur independently of its cholesterol-reducing effects. And it builds on the team's 2002 paper that showed Lipitor significantly improved, prevented relapses or reversed paralysis in mice with two different forms of EAE, most notably preventing animals who were experiencing their first attack from progressing to the fully established disease.
Multiple sclerosis is an auto, or "self," immune disease, in which one of the immune system's key cells, the T helper (Th) cell, or CD4+ T cell, orchestrates an inflammatory attack against the central nervous system. The primary target of the attack is the myelin sheath, which coats the brain's nerve fibers, or communication wires, through which nerve cells, or neurons, communicate.
The damage to the sheath, known as demyelination, disrupts the ability of neurons to transmit signals swiftly to one another. The destruction causes fatigue, imbalance, visual loss, disrupts various motor skills and, more subtly, diminishes some cognitive abilities. In later phases of the more progressive forms of the disease, non-inflammatory toxic molecules damage some of the brain's glial tissue and kill nerve cells.
Three types of drugs are currently approved to treat multiple sclerosis. Copaxone and the beta interferons are used to treat relapsing-remitting disease, which, in half of these patients, progresses to a "secondary progressive," or chronic, form, and Novatrone, a cancer chemotherapy, is used to treat this progressive form. The drugs are effective to varying degrees in roughly a third of patients and are often limited by side effects or toxicities. A fourth type of drug, Tysabri, was removed from the market in 2004 due to severe toxicity in patients also given beta interferon, though the Food and Drug Administration is now reviewing the drug, for possible reintroduction. Statins, by contrast, are relatively well tolerated and generally safe.
Use of statins is associated with a low risk of liver toxicity, and, less frequently, with a potentially more serious medical complication that results from muscle damage. For this reason, and because the drug has not been tested in multiple sclerosis, the researchers strongly urge patients and their physicians to wait for the results of the clinical trials before considering therapy with statins for multiple sclerosis.
Other co-authors of the study were Stefan Nessler, Department of Neurology, Heinrich Heine University, Dusseldorf, Germany; Hans-Christian von Budingen, University Hospital Zurich, Zurich, Switzerland; Bernhard Hemmer, Department of Neurology, Heinrich Heine University, Dusseldorf, Germany; Thomas Prod'homme, Department of Neurology and Program in Immunology, UCSF; Raymond Sobel, Department of Pathology, Stanford University.
The study was funded by the NIH, National Multiple Sclerosis Society and the Maisin Foundation, as well as Teva Neuroscience.
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