We’re Taking the First Steps Toward a Cure for Narcolepsy
This has been a long-term project for Masashi Yanagisawa, who was in the race with Mignot to link the orexins with narcolepsy 20 years ago. But designing and synthesizing a compound that will make it through the gut intact, that has what it takes to find its way from blood to brain, and that boasts the perfect configuration to activate one or both of the orexin receptors is “a very, very high challenge” he says, one that is “significantly” greater than finding a compound to interfere with the receptor as Belsomra does.
Earlier this year, Yanagisawa and his colleagues published data on the most potent such compound to date, a small molecule called YNT-185. Injections of this molecule into narcoleptic mice significantly improves their wakefulness and cataplexy and reduces the abundance of the REM stage of sleep in which most dreaming occurs (one of the characteristics of narcolepsy). This, says Yanagisawa, is a “proof of concept”. Although the affinity of YNT-185 (how strongly it binds to the orexin receptor) is not great enough to warrant a clinical trial, Yanagisawa’s team has already hit upon several other potential candidates. “The best one is almost 1,000 times stronger than YNT-185,” he says.
While the symptoms of narcolepsy can vary wildly from one person to the next, the underlying pathology—the absence of orexins—is still the same. “If this compound works, it’ll work for all those patients,” he says. “In that sense, it’s a relatively simple clinical trial compared to many other disorders.”
A still more futuristic avenue involves stem cells. Sergiu Paşca has the office next to Emmanuel Mignot at Stanford and in 2015, he and his colleagues developed a way to take induced pluripotent stem cells (fashioned from skin cells) and direct them towards a new life as brain cells. “You can use this system to derive various brain regions and like a Lego game, assemble them to form circuits in a dish,” he says.
Recently, his lab has developed methods to do something similar for people with narcolepsy, starting with a skin cell and ending up with a fully functional orexin neuron. In theory, it should be possible to transplant this into the brains of people with narcolepsy and restore some of the function. This is, however, not something to be taken lightly. For a start, the cells themselves are unlikely to be exactly the same as orexin cells, inserting a needle into the brain is not a risk-free exercise, and there’s always the possibility that the immune system might make another assault on the transplanted cells.
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