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.
Continue Reading from the paragraph that reads, Precisely How….
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