In September, patients suffering from multiple sclerosis (MS) received the welcome news that the U.S. Food and Drug Administration (FDA) had approved a promising new drug for their condition called Gilenya. Now, a team from The Scripps Research Institute has discovered that this drug's success may involve an unexpected biological mechanism acting within the central nervous system (CNS). This difference may mean that Gilenya offers even more benefits than previously realized and would represent the first MS therapy with direct CNS activities.
The work, scheduled for advance, online publication the week of December 20, 2010 by the Proceedings of the National Academy of Sciences, also reveals potential new strategies targeting the CNS for research into better MS treatments.
"This drug could make a big difference to MS patients," says Jerold Chun, M.D., Ph.D., a professor in the Department of Molecular Biology and member of the Dorris Neuroscience Center at Scripps Research. "And these results are going to make doctors and scientists consider CNS mechanisms in MS therapies, as they follow patients being treated with Gilenya."
Beyond the Immune System?
Gilenya is the first oral MS drug available and it was approved to treat relapsing forms of MS, the most common initial presentation of the debilitating and potentially deadly disease. The understanding among biomedical researchers has been that, like all other primary MS therapies, Gilenya acts on a patient's malfunctioning immune system to prevent the attack on the brain that causes the disease.
This was a logical conclusion. Among other important effects in the immune system, researchers have well documented that after Gilenya goes through a transformation in the body called phosphorylation, it binds with molecular receptors known as S1Preceptors (S1PRs) found on the surfaces of certain cells. "Then it does something weird," says Chun.
This binding causes the cell to internalize the receptor and ultimately destroy it. In the case of immune system cells, one subtype of receptors, called "S1P1"are critical in the release of white blood cells (lymphocytes), from lymphoid organs, which in MS patients can damage nervous system cells. So the hypothesis was that this receptor destruction pathway gives the drug its positive MS results.
But the Scripps Research team suspected the drug might also have important effects within the CNS. Fifteen years ago, Chun's group was the first to discover the family of receptors that includes the S1P receptors (S1PRs). Many receptors from this family are expressed in the brain, suggesting that a drug tied to the receptors might well have important activity in the brain.
Intriguing Brain Activity
To test this hypothesis, the researchers genetically altered mice so that they lacked S1P1"only within the CNS. S1P1 in immune system cells remained intact.
"If there was purely an immunologic effect, if the CNS was just a bystander, then there should be no effect from removing those CNS receptors," says Chun.
But that's not what the researchers found.
Knocking out the nervous system S1PRs decreased the severity of a mouse disease analogous to MS (experimental autoimmune encephalomyelitis). And when the team administered Gilenya to these mice, it had very no effect, while it continued to affect the immune system.
All told, these results strongly suggested that Gilenya's main disease-fighting properties must be centered within the CNS.
"It's a surprising result especially considering the purely immunological focus of current MS therapies as well as many under development. That you can alter the course of this disease through S1PR signaling in the CNS points to new ways to treat MS," says Chun.
Precisely how Gilenya acts in the brain isn't yet clear. The researchers have narrowed the drug's key activity to a specific S1P receptor subtype (S1P1) and a kind of nerve cell known as an astrocyte. Other cell types expressing S1P1 or different S1P receptor subtypes may also be involved, however a dominant influence appears to involve S1P1 and the astrocyte. The researchers also found that the knockout mice had lower levels of inflammatory proteins called cytokines that are known to play a role in MS and EAE. "Exactly how all that happens still needs to be understood," says Chun.
Multiple Benefits
Regardless of the specifics, which the team is now exploring, the results offer some good news for MS sufferers. One initially promising MS treatment that acts on the immune system (Tysabri) was taken off the market because it caused a deadly side effect in some patients—a disease called progressive multifocal leukoencephalopathy (PML), also associated with AIDS immunosuppression. Tysabri has reentered the market with a "black box" warning of PML risk.
If Gilenya is chiefly an immunosuppressant, the fear is that it might eventually cause PML. But if the Chun team's results apply to humans as expected, then such a problem would be less likely
Another benefit of the work is that now that the team has shown that nervous system S1PRs play an important role in MS, researchers have a possible new target on which to focus when developing new treatments.
The researchers will also be exploring 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 is the case with other current MS drug treatments.
In addition to Chun, authors of the paper, titled "FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte S1P1 modulation," are Ji Woong Choi, Shannon Gardell, Deron Herr, Richard Rivera, Chang-Wook Lee, Kyoko Noguchi, Siew Teng Teo, Yun C. Yung, Melissa Lu, and Grace Kennedy. All were at Scripps Research while this work was conducted; Choi is now at the Gachon University of Medicine and Science in Korea.
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