Playing “LEGO” with Botulinum Toxin: A Potential Alternative to Opioids?

A new study shows that modifying the toxin using a LEGO-like “protein stapling” technique can ease pain in mice. Image credit: Danny Kosmayer/123RF Stock Photo.

You may know it by its brand name, Botox. But botulinum toxin, which is made by the bacterium Clostridium botulinum, does more than just get rid of wrinkles.

In a new study, researchers from University College London (UCL), UK; the University of Sheffield, UK; and the Hospital for Sick Children, Toronto, Canada, have used an innovative “protein stapling” technique to modify the botulinum toxin so that it safely relieves pain in mice. A single spinal injection eased pain for five months, without the paralysis or toxic effects of the natural toxin.

Tony Yaksh, a pain researcher at the University of California San Diego, US, who was not involved with the study, calls it a “truly exciting advance.”

“This ability to produce a long lasting, but reversible block of [electrical signal] transmission in the pain pathway after a single treatment could be a major step in reducing the persistent need for medications like opiates, which can have quite adverse side effects,” he says.

The research was published July 18, 2018 in the journal Science Translational Medicine.

Protein stapling: A form of LEGO assembly
Even a small amount of botulinum toxin can cause paralysis, and even death, as it disrupts communication between nerve cells and muscles. Past studies suggested that the toxin might also dampen the activity of nociceptors. These are the nerve cells that detect harmful stimuli in the environment and relay information about those threats into the spinal cord. When this information reaches the brain, it can culminate in an experience of pain.

However, botulinum’s toxicity made it difficult for researchers to fully investigate its potential as a pain reliever.

But Bazbek Davletov, one of the leaders of the new research at the University of Sheffield, wondered if there might be a way to tinker with the botulinum toxin so it could dampen the activity of nerve cells in the spine that relay information from the nociceptors to the brain, but without side effects.

“Botulinum toxin is a very dangerous substance—one of the most toxic toxins known to man,” he says. “But it could have some utility in alleviating pain if you can create a functional molecule that is not paralytic.”

Previously, using a technique called “protein stapling,” Davletov and Stephen Hunt, who co-led the study at UCL, re-engineered the toxin so it could attach to specific proteins on two different kinds of nerve cells in the spinal cord. “It’s a molecular LEGO system, in a sense,” Davletov said.

Specifically, for one of the modified botulinum molecules, called SP-BOT, they attached the toxin to substance P (SP), a molecule that attaches to a protein on a specific population of spinal nerve cells.

For the other botulinum molecule, called DERM-BOT, they attached the toxin to dermorphin (DERM), which attaches to a protein on a different population of spinal nerve cells and that has been shown to relieve pain.

With this protein stapling technique, the researchers had engineered two different botulinum molecules that could quiet two different kinds of spinal neurons that each transmit information coming from the nociceptors.

Easing pain
The stage was now set to test whether SP-BOT and DERM-BOT could relieve pain. So the researchers injected SP-BOT or DERM-BOT into the spines of mice with experimental pain—either pain caused by inflammation (inflammatory pain), or pain resulting from nerve injury (neuropathic pain).

After receiving injections of SP-BOT, the mice experienced substantial pain relief, without effects on movement, in as little as three days after injection. The scientists also saw that SP-BOT worked as they predicted, by silencing the activity of nerve cells in the spinal cord. What’s more, it did so without killing the cells.

DERM-BOT showed similar effects. Here, too, DERM-BOT eased inflammatory pain and neuropathic pain without causing cell death. And, they saw that DERM-BOT was just as effective as morphine in relieving pain.

“These new botulinum molecules bind to spinal neurons without toxicity,” says Davletov. “We removed the toxicity by targeting the botulinum molecules specifically to those neurons instead of muscles. And we saw that we could block chronic pain and continue to block it for months at a time.”

What comes next?
Davletov and his colleagues are buoyed by the success of their BOT molecules, but say there is much work left to do before this approach could be tested in people.

They plan to follow up their study by testing the molecules in companion dogs that suffer from age-related chronic pain. Yaksh is also interested to see whether the modified botulinum toxin molecules will have similar pain-reliving effects in other animals. If so, this could offer the possibility that people with chronic pain could use lower doses of opioids, or not need them at all.

“Even if this is just something that just reduces the opioid requirement, it would be quite significant,” Yaksh says. And, “it could be a very significant therapeutic alternative for patients who suffer from chronic pain without all of the issues of tolerance and addiction.”

To read about the research in more detail, see the related IASP Pain Research Forum news story here.

Kayt Sukel is a freelance writer based outside Houston, Texas.