[LUM#9] When the pain persists
Scientists atthe Montpellier Institute of Neuroscience have uncovered the mechanisms responsible for the onset and persistence of chronic neuropathic pain.After nine years of research, a drug candidate is currently being tested and could become the very first specific treatment for this type of pain.
This is the story of a symbiotic encounter between a molecule called FL and its receptor, FLT3. A romance that remained hidden until Jean Valmier, a researcher atthe Montpellier Institute of Neuroscience (INM), brought it to light. Because this story, once again, ends badly and causes what is known as “chronic neuropathic pain”—a condition affecting nearly four million people in France.
Chronic pain
“Pain is considered neuropathic when it results from nerve damage,” explains the researcher. “It can be caused by surgery, an injury, treatment, or an infection.” Shingles is one such example. The pain becomes chronic “when it lasts longer than three months and can persist even after the underlying cause—such as shingles—has been treated, ” the researcher explains.
No medication can cure this "pain-related condition." Morphine, a powerful analgesic, causes too many serious side effects to be prescribed long-term. The same goes for other so-called “repurposed” drugs—medications originally designed to treat other conditions such as epilepsy or depression but which can relieve pain. Moreover, as Jean Valmier points out , “when they work, they only reduce the pain by half, and half of a pain is still a pain.” This is a huge public health issue. There is demand from patients who are suffering, from doctors who are desperate because they can’t do much, and of course from the pharmaceutical industry because if they had a drug like that, it would be a blockbuster, as they say.”
The mechanism is running wild
This situation can be explained by the lack of understanding that previously surrounded the mechanism of this pain. We know that when a nerve is damaged, blood cells rush to the site of the injury and release molecules capable of activating the sensory neurons that generate pain. This is a normal mechanism. “ But sometimes the mechanism goes haywire,” explains the researcher, “and the molecules they release hyper-activate the sensory neurons. Instead of sending normal signals, these neurons generate a large number of electrical discharges.” These discharges are sent to the central nervous system , which may then malfunction by developing persistent hyperexcitability and, consequently, chronic pain.
And this is where we find our two inseparable partners, who had remained so discreet until then. Nine years after the first experiments began, Jean Valmier succeeded in demonstrating “that the FLT3 receptor on the neuron is activated by a ligand, the FL molecule secreted by blood cells; and it is their interaction that triggers a chain reaction in the sensory system, leading to chronic pain. If I inhibit this receptor, the pain disappears.” With the concept proven, the challenge remained to find a way to block this FLT3 receptor without side effects for the patient.
Five million molecules screened
To this end, Jean Valmier turned to Didier Rognan, a chemist and director of the Laboratory for Therapeutic Innovation (LIT) in Strasbourg. The chemist used computer modeling to “screen” or sort through more than five million molecules based on their physicochemical properties before selecting about sixty of them and sending them to Jean Valmier. “I checked whether the molecules prevented the ligand (FL) from binding to the receptor, and if so, I verified whether they prevented the receptor from being activated.”
The two researchers then focused on the one they would name BDT001. Acting as a sort of chaperone, this molecule prevents FL from binding to FLT3, thereby blocking its activation and, consequently, the pain. Tested on mice, BDT001 not only eliminates chronic neuropathic pain without causing side effects, but it also helps prevent potential pain in situations such as surgery. “It takes effect within three hours, and its effect lasts for 48 hours.”
To grin and bear it
Another advantage of this molecule is that “it has no effect on normal pain. It is analgesic but not anesthetic.” In other words, there is no risk of accidentally leaving your hand on a 100°C stovetop while using BDT001, if its potential use in humans were confirmed.
The discovery has already led to the filing of four patents, owned byInserm and the University of Montpellier. The two scientists, for their part, have founded the company Biodol Therapeutics to oversee testing of this molecule: “We need to demonstrate that this mechanism is just as significant in humans as it is in mice. It could take two or three years if all goes well.” Next will come trials on patient cohorts, “but it won’t be on the market anytime soon.” We’ll therefore have to be patient before our old aches and pains become nothing more than a distant memory.
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