Researchers uncover new pathway for popular MS drug

Scott Zamvil, MD, PhD

Researchers at UCSF and Stanford University have discovered a key mechanism responsible for the activity of a commonly prescribed drug for treating multiple sclerosis (MS), which they hope will spur better therapies for the disease.

The study was conducted on the drug glatiramer acetate (marketed as Copaxone), in mice with experimental autoimmune encephalomyelitis (EAE), the standard MS animal model. Findings appear in the August 5, 2007 online edition of the journal “Nature Medicine.”

The discovery could signal a new direction in the search for an effective therapy for MS, according to Scott Zamvil, MD, PhD, UCSF associate professor of neurology whose laboratory led the study.

Until now, he said, scientists believed this drug acted primarily on a class of white blood cells called lymphocytes, which are known to cause tissue damage in MS. This study found that, instead, the drug targets a different blood cell, called a type II monocyte. It now appears that the monocyte instructs the lymphocyte to change course. When treated with glatiramer acetate, monocytes were found to reverse paralysis in mice with EAE, an experimental disease that closely resembles multiple sclerosis.

“These results represent a major change in our understanding of how this MS drug works,” Zamvil said. “What we’ve shown, for the first time, is that the drug actually works by targeting monocytes and also that drug-activated monocytes can be transferred to an affected animal and reverse the disease.”

The next step, he said, is to assess whether they can reproduce the immunologic findings in humans.

MS is an autoimmune disease in which lymphocytes attack and damage myelin, the tissue that surrounds and protects the nerves in the brain and spinal cord. This causes a variety of symptoms, ranging from mild muscle weakness to partial or complete paralysis. The primary human symptom of the disease, which is a recurring temporary paralysis in the limbs, also occurs in mice with EAE.

Roughly 400,000 Americans acknowledge having MS, which may affect 2.5 million people worldwide, according to the National Multiple Sclerosis Society. Another 200 people are diagnosed nationwide each week, the society said.

Zamvil said about one-third of the U.S. patients who are currently being treated for MS receive glatiramer acetate, which reduces inflammation and tissue damage. How that occurs was not understood.

The UCSF-Stanford team observed that when the drug was administered daily, as it is in MS treatment, monocytes underwent a molecular switch. Before treatment, the monocytes secreted toxic cytokines, which are chemicals that promote lymphocytes to cause tissue damage. After treatment with glatiramer acetate, the monocytes switched to instead secrete protective cytokines that reduce inflammation and tissue damage.

When the researchers transferred the activated monocytes into mice with EAE, they were able to reverse both paralysis and tissue damage by causing the mice’s native lymphocytes to switch from secreting detrimental cytokines to secreting protective ones.

These findings provide an incentive to develop an “adoptive immunotherapy” for MS, that is, a therapy based on injecting drug-induced type II monocytes into patients, rather than the drug itself, Zamvil said. However, it is unclear whether this approach would be more effective.

Although Zamvil emphasized that the new findings will not alter current patient care, they could lead to important changes in the future.

“Our work in mice does not make glatiramer acetate a better drug,” he said.

Rather, the study’s significance is in developing a new entry point to targeting MS, noted Martin Weber, MD, the paper’s lead author and a post-doctoral fellow in Zamvil’s lab.

“The importance is that we have created a new approach to studying how a drug’s activity on monocytes influences other parts of the immune system,” Weber said. “This should facilitate development of better drugs for treating MS and possibly other autoimmune diseases, such as rheumatoid arthritis or type I diabetes.”

Several biotechnology and pharmaceutical companies have been looking for ways to improve on Copaxone. The new data could shift their focus from the lymphocytes to the monocytes, giving them a new target for drug development, he said. It could also provide important insights into combining glatiramer acetate with other drugs currently approved for MS therapy.

This work was supported by the National Institutes of Health, National Multiple Sclerosis Society, Dana Foundation, Maisin Foundation and Teva Neuroscience Inc., the maker of Copaxone.

Co-authors on the study include Lawrence Steinman, professor of neurology and director of the Stanford University Program in Immunology, and members of his laboratory, including Sawsan Youssef and Shannon Dunn.

Additional co-authors are Thomas Prod’homme, Cynthia Rundle, Linda Lee and Juan Patarroyo, all of UCSF; Raymond Sobel of Stanford University; and Olaf Stüve, formerly a postdoctoral fellow in the Zamvil lab and now at the Veterans Affairs North Texas Health Care System.

UCSF is a leading university that advances health worldwide by conducting advanced biomedical research, educating graduate students in the life sciences and health professions, and providing complex patient care. For more information on UCSF, visit www.ucsf.edu.

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