Stanford Report Online

Stanford Report, October 4, 2000
Designer protein therapy for multiple sclerosis shows promise


People with multiple sclerosis may find new hope in the clinical trial of an innovative treatment developed by Lawrence Steinman, MD, professor of neurology and neurological sciences, of pediatrics, and, by courtesy, of genetics. A phase II clinical trial of the treatment, the results of which are published in the October issue of Nature Medicine, revealed that certain dosages of a small designer protein can alter patients' immune cells so that they no longer attack patients' own nervous systems. Although the trial was halted because of allergic reactions in a minority of patients, Steinman said the reactions were much less significant than feared, and he plans to repeat the trial soon.

Multiple sclerosis (MS) is a chronic neurological disorder in which the body's immune cells attack myelin, a sheath that helps signals travel farther and faster along the nerve cell. Currently no accepted cure for MS exists, and people with the disorder experience a progressive loss of the communication between the brain and other parts of the body.

The experimental treatment is based on a discovery made by Steinman and his colleagues in 1990. At that time scientists knew that T cells, the immune cells responsible for attacking the body's foreign invaders, can act in one of two modes. T cells either take part in attacking tissues and microbes (an inflammatory response), which can lead to autoimmune diseases like multiple sclerosis, juvenile diabetes and rheumatoid arthritis; or the cells take part in allergic reactions, causing disorders like asthma and food allergy. Steinman's research team discovered a receptor that can switch T cell activity from an inflammatory mode to an allergic one.

Steinman also discovered the specific protein sequence that would flip this switch in only those T cells that attack myelin in multiple sclerosis. The idea that changing T cell behavior might stop the progression of multiple sclerosis got a boost in 1994 when he found that a short, designer protein called a peptide could halt the progression of MS in an animal model. Stanford patented the technology for creating the tailored peptide and licensed it to Neurocrine Biosciences, a company that Steinman co-founded.

By 1999, Steinman had high hopes that the peptide would perform as well in people with multiple sclerosis as it had in the animal model, and he started a multicenter clinical trial of the therapy. The trial at 14 research centers in the United States, Europe and Canada included 144 patients and was a double-blind trial, in which neither those administering the therapy nor the patients knew whether they were receiving the actual therapy or a placebo. Stanford was not one of the treatment sites because of Steinman's potential conflict of interest.

Steinman's hopes, and those of patients in the clinical trial, were strained by two developments during the trial. The first was that about 10 percent of the people involved in the trial got a mild allergic reaction ­ a reddening of the skin where the peptide was injected. "There was a fear that the therapy might be causing a similar allergic reaction in the brain, which could itself cause damage to myelin," Steinman said. As a result of those concerns, a safety board ordered that the clinical trial be stopped.

Another worry arose when a group of scientists at the National Institutes of Health (NIH) independently tested the peptide on a few patients in a separate, uncontrolled trial. The NIH scientists reported that the therapy actually made inflammation in the brain worse in at least one person with multiple sclerosis.

When Steinman's group started analyzing their own data, however, they were pleasantly surprised. "When we broke the code (on the results) we were delighted that there were no signs of an allergic reaction in the brain and no worsening of inflammation," Steinman said. Furthermore, at the lowest dose the therapy did indeed lessen inflammation in the brain.

Nature Medicine published the paper reporting the NIH scientists' results alongside Steinman's, but Steinman is not dissuaded by the NIH researchers' data. "What they did was an uncontrolled trial with only a few patients, so it's hard to know what they really found," Steinman said. "In every trial of drugs for MS, there are some patients who get worse."

Steinman and the NIH scientists will hold a public discussion of the clinical results of peptides in the treatment of MS on October 31. NIH will sponsor the discussion, "Altered Peptide Ligands as Treatment for Multiple Sclerosis," and the public is invited to attend.

Now that he has addressed the safety questions that halted the recent clinical trial, Steinman hopes to adjust the dosage of the peptide so that it switches off the attacks on myelin but doesn't cause an allergic reaction in the skin. "If we can't stop the reaction we may just have to accept the reddening of the skin as a minor side effect, just as we accept that chemotherapy for cancer causes hair to fall out," Steinman said.

If the clinical trials are successful, it would still be another five years or so before this MS treatment might receive approval by the Food and Drug Administration, Steinman cautioned.

The clinical trials were co-sponsored by Neurocrine and another company, Novartis Pharmaceuticals.