Update on the ORATORIO Trial on Ocrelizumab for Primary Progressive MS

     ECTRIMS 2016 was the setting for the first positive results from the drug ocrelizumab for people with primary progressive MS in a multi-center, multinational drug trial called ORATORIO. Several groups presented data on the drug this year, showing consistent positive effects on walking and slowing disability progression. The most common adverse effect is reaction at injection site. (Jerome De Seze et al, poster 720; Gavin Giovannoni et al, poster 746; Jerry Wollinsky et al, poster 1278; Jerome De Seze et al, poster 1279).

 

Mouse Gene Mapping May Lead to Alternative Treatments for MS

Interferon-beta therapies (e.g. Avonex®, Betaseron®) have long been used as a treatment for multiple sclerosis, but they can be costly, painful, and sometimes ineffective. New research from Duke University on mice may point to new drug candidates that might help MS patients when interferon beta fails. The researchers studied an MS-related disease in mice and were able to map out biological mechanisms that can lead to a nonresponsive form of MS.

    “The study shows a really clear molecular mechanism that may explain why some people do not respond to interferon-beta treatment,” said Mari Shinohara, an associate professor of immunology at Duke and a senior author on the study, available online in the journal Nature Neuroscience- http://tinyurl.com/jae4wf9. “We’ve found what makes a difference in the response.”

     One challenge in treating MS is understanding the biological mechanisms that lead to damage caused by deterioration of myelin, the protective coating covering neurons. Another challenge is the recent discovery that those mechanisms may vary in each patient according to genetic and environmental factors.

    In 2012, the researchers found that interferon-beta works in mice by inhibiting an immune protein complex called the NLRP3 inflammasome. This same study, however, found that some mice missing this protein complex still got sick, and for them interferon-beta treatment was ineffective. This study was aimed at determining how the disease was triggered in those missing the protein complex.

    “We knew the second pathway bypassed the NLRP3 inflammasome,” Shinohara said. “So the question became, what is actually involved?”
The team found two genetic receptors, called CXCR2 and LTBR, were central to the development of the disease in the mice who did not respond to interferon-beta. They also found that treating the mice with a molecule that blocks these receptors improved their symptoms.

    “We found that, depending on which type of disease the mice had, we could choose the appropriate treatment,” Shinohara said.

    To compare the effects in humans the team then used data gathered as part of the MURDOCK MS study to compare the genetic profiles of MS patients who responded to interferon-beta treatment with those who didn’t.

    “We identified individuals who were not responsive to the interferon-beta treatment, and looked at their CXCR2 and LTBR” genes, said Simon Gregory, a professor of medicine and molecular genetics and microbiology at Duke and a co-author on the paper. “We found them to be upregulated,” meaning they were producing more of the receptors, he said.