An Irish research team is testing a drug used mainly for cosmetic treatments to block otherwise untreatable chronic pain
A DEADLY poison holds great potential to help patients who suffer from chronic pain. A research team based in Dublin is developing the idea and will also begin producing the substance for use in human trials.
Most people know about the poison botulinum toxin A under the brand name Botox. Millions around the world use it to reduce wrinkles by temporarily paralysing the underlying muscles.
Less well known is the fact that there are at least 100 different medical applications where the toxin can contribute, says Prof Oliver Dolly. The Dublin City University professor of neurotherapeutics has been working with the toxin for more than 20 years and has developed a number of clinical uses for the substance.
Originally from Dublin, he returned here six years ago after 27 years at Imperial College London to take up a Science Foundation Ireland Research Professorship. He is the director of DCU’s International Centre for Neurotherapeutics and has developed ways to use the toxin to clinical advantage.
He currently has human trials under way to assess the toxin’s ability to control muscle spasm, particularly in children with cerebral palsy. He is also studying its use to block symptoms associated with MS and Parkinson’s disease.
His most recent work however relates to chronic pain. “This is a big area because millions of people suffer worldwide from chronic pain that is resistant to drugs,” he says.
Dolly became interested in botulinum toxin A because of its ability to affect skeletal muscles, something originally discovered in the 1950s.
He wanted to study the biochemistry of how the toxin can interfere with the nervous system by blocking neurotransmitters. These are essential biochemicals released at the junctions of nerves to support the transfer of signals between muscles and the brain.
“The toxin gets internalised by the nerve and works within the nerve,” Dolly explains. This is why accidental poisoning with the toxin can kill so quickly, but also why it holds such potential for the control of pain.
“It proved to be a very good substance for blocking neurotransmitters,” he says. And once it gets into the nerves it stays, something that allows cosmetic Botox injections to last for months.
Early on the toxin was used to relax eye muscles to treat misalignment, but patients who received the treatment benefited in another way. “People who had the [treatment] came back and said ‘my migraine or my tension headache is better’,” Dolly says.
This encouraged him to look at pain control. “We found in the lab we could block the release of pain mediators,” he says, the sensory neurons responsible for pain signalling. “If you could put the toxin into the sensory neurons you could block the pain.”
While toxin A could do this, his group discovered that botulinum toxin E did a better job. “We found type E gave a much better block for pain reduction than type A,” he says. But while type A persisted in the nerve, type E tended to break down too quickly.
His group decided to take the best of both, engineering a modified toxin that had both persistence and effectiveness. “We used protein engineering technologies to improve the toxin. We can now achieve long-term control using this new composite toxin,” he says.
He will soon publish these findings in the Journal of Biological Chemistry, but work is already under way to build a facility on campus able to produce the engineered toxin for human trials. Dolly believes these could happen quickly given the long term experience of using botulinum toxins in humans.
He has received significant support for his research from Science Foundation Ireland, from the US government and also from health care company Allergan.
