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Scripps scientists probe new MS drug’s mechanism of action
LA JOLLA, Calif.— A team of scientists at the Scripps Research Institute recently published a study describing an unexpected biological mechanism acting within the central nervous system (CNS) that could enhance the potential of Gilenya, a multiple sclerosis (MS) drug approved in September 2010 by the U.S. Food and Drug Administration (FDA).
The study, published in December by the Proceedings of the National Academy of Sciences (PNAS), suggests that Gilenya offers even more benefits than previously realized and could represent the first MS therapy with direct CNS activities.
"That would be a first for any therapeutic for the treatment of MS," says Dr. Jerold Chun, a professor in Scripps' Department of Molecular Biology. "This is especially important because our work suggests that we are potentially able to alter the course of the neurological impairment of the disease."
Novartis' Gilenya (fingolimod, or FTY720) is a first-line treatment for relapsing forms of MS, the most common forms of the disease. In clinical trials, Gilenya reduced relapses by 52 percent at one year compared with interferon beta-1a IM, a commonly prescribed treatment, and had a high safety and tolerability profile.
Gilenya has been hailed as a prospective blockbuster drug (with some analysts predicting more than $5 billion in sales by 2014) but the way the drug works is not completely understood. Most researchers believe that like other primary MS therapies, Gilenya acts on a patient's malfunctioning immune system to prevent the attack on the brain that causes the disease. Research has shown that when Gilenya goes through phosphorylation, it binds with molecular receptors known as S1Preceptors (S1PRs) found on the surfaces of immune system cells.
That is where Chun's lab, which was the first group to discover the family of receptors that includes S1PRs, comes in. The lab, a member of Scripps' Dorris Neuroscience Center, developed a mouse model of MS that responds to Gilenya in a similar manner as humans to get a better idea of how people will respond to treatment.
Chun and his colleagues found that the binding with S1PRs causes the cell to internalize the receptor and ultimately destroy it, and hypothesized that this receptor destruction pathway gives Gilenya its positive MS results.
But Chun's group suspected that Gilenya might also have important effects within the CNS, and genetically altered mice so they lacked S1P1 only within the CNS. S1P1 in immune system cells remained intact. Knocking out these S1PRs decreased the severity of MS, but as the scientists administered Gilenya to the mice, it had very no effect, while it continued to affect the immune system.
"What the data argue is that you need these receptors on these astrocytes in order to allow the drug to function, but if you take them away, the drug does not appear to function as it should," Chun explains. "That points us to the central nervous system rather than the immune system, and is a major factor for how this drug actually works."
Next, Chun's lab will explore the possibility that Gilenya's brain locus of activity could offer neuroprotective benefits, meaning that it could shield nerve cells against MS-associated deterioration. If the drug does have such properties, it would open the possibility of actually preserving the nervous system, rather than simply reducing the number of MS attacks as most current MS drug treatments do.
While Chun's lab doesn't have any formal interaction with Novartis at this point, "we'd certainly like to interact," he says.
"We as a lab would like to better understand the S1P1 receptor functions in these astrocytes, and more broadly, how SiP1 receptors and related signaling pathways in the brain provide neuroprotection," Chun says. "If this indeed the way the drug works, it says you can access these neuroprotective properties, which may be helpful for other CNS disorders."
The study, "FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte S1P1 modulation, " was supported by grants from the National Institutes of Health, Novartis Pharma, NRF (Korea) and Singapore's Agency for Science, Technology and Research (A*STAR). Chun's co-authors included Ji Woong Choi, Shannon E. Gardell, Deron R. Herr, Richard Rivera, Chang-Wook Lee, Kyoko Noguchi, Siew Teng Teo, Yun C. Yung, Melissa Lu and Grace Kennedy.