SEEKING SOLUTIONS

SCIENCE FOUNDATION IRELAND:New treatments for diseases such as MS and cerebral palsy could be in the pipeline from DCU-based ICNT, which is researching these conditions in conjunction with Allergan

NEW, MORE effective treatments for conditions such as multiple sclerosis (MS), cerebral palsy and even migraines could be in the pipeline, thanks to the work of the International Centre for Neurotherapeutics (ICNT).

Headed up by molecular neurobiologist Prof J Oliver Dolly, Science Foundation Ireland (SFI) research professor of neurotherapeutics, the centre is researching a number of treatments for common conditions, the symptoms of which may be alleviated through the use of therapeutic treatments the centre is developing.

Prof Dolly has a long history in neuroscience. He did his initial degree in NUIG, before leaving for the UK to complete his PhD. Following that, he obtained a scholarship from the American Muscular Dystrophy Association to work in the US.

"At that stage, I was quite keen to work with human diseases," he explains. "While working in the lab of Prof Eric Barnard FRS, he asked if I would like to work on the nervous system. That was the beginning, the rest is history."

Prof Dolly now works in the field of neuroscience. He spent 27 years at Imperial College in London, where he directed the Centre for Neurobiochemistry, before the chance to return to Ireland arose in the guise of a research professorship by SFI.

It was at DCU that he established the International Centre for Neurotherapeutics. In addition to funding from the SFI, the centre is also working with several industrial contacts to help build up a body of research, and has received support from Allergan and the US government.

Under the deal, Allergan provides funding for the centre and in return will get first refusal on the research that is produced by ICNT, which could prove to be lucrative for the firm if the drug treatments are successful in clinical trials.

The basic research is on the normalisation of communication within the nervous system and, more specifically, how messages are carried and synaptic transmission. Prof Dolly's main research includes identifying the proteins and mechanisms responsible for quantal release of transmitters and the development of therapeutics to selectively control this process. He is also researching the molecular characterisation of neuronal voltage-sensitive K+ channels in normal and diseased states, with the ultimate goal of developing inhibitors that are capable of controlling nerve cell excitability and synaptic transmission.

The research being carried out at the institute could have far-reaching effects for sufferers of conditions from cerebral palsy and multiple sclerosis, to migraines and tension headaches. In years to come, there may even be localised, effective treatments for back pain, rather than the current method of swallowing a pill that can affect your entire system.

Some breakthroughs are down to the use of a drug more commonly known for its use as a cosmetic treatment - botox.

While most people are familiar with botox as a treatment for wrinkles and facial lines, the botulinum neurotoxin can also be used as a powerful therapeutic to help treat a whole series of diseases that can occur when the transmitters are abnormally high and not performing at their optimum level.

The toxin can be used to combat human dystonias and movement disorders, as well as autonomic neuronal abnormalities of secretory glands, such as excessive sweating, and hyper-salivation.

Prof Dolly explains that the successive release of transmitters cause the muscles to become "over excited", manifesting itself as spasming, twitching or other involuntary muscle movements. Using the botulinum therapy, these conditions can be alleviated to a certain degree.

"One of the most exciting things is in the treatment of conditions such as cerebral palsy in children," says Prof Dolly.

With this condition, children are often unable to walk properly as the calf muscle is in spasm causing the tendon and muscle to grow abnormally. The use of botulinum neurotoxins can cause the muscle to relax, allowing the tendons and muscle to grow normally.

"In the past this would have required repeated surgery," he says. However, it is important to treat the condition early, to allow the muscles and tendons to grow.

Aside from treating musculoskeletal conditions, the toxin also has applications treating so-called "smooth" muscles, such as the bladder. Overactive bladder, a condition that can cause considerable pain and can affect those living with spina bifida, spinal cord injuries and multiple sclerosis, could be treated by injecting directly into the muscle of the bladder wall.

The centre's research is also studying what Prof Dolly describes as "hypo-excitable" conditions. "This is where you need to boost the activity of nerves to get the nerves up to normal," he explains. "When the axons in the nerves lose their insulating sheets, you get the appearance of channels in the membrane."

It is these potassium channels that counteract the normal messages sent by the nerves, resulting in conditions such as multiple sclerosis.While isolating the root cause of MS is proving a challenge, researchers are finding new and better ways of treating the manifestations of the condition.

While in London, he examined autopsy samples of patients who died from MS. "We found a unique potassium channel that we couldn't find in the normal human brain," he says. "If it is responsible for the symptoms, we could develop drugs to block the potassium channel. However, that's easier said than done."

Several years of work has gone into this area of research, isolating the major subtypes of potassium channels in the brain, each made up of four subunits.

It is the distinct combination of subunits that gives the channel its characteristics. Researchers can then test the different drugs available to researchers to see which is the most effective.

Although Prof Dolly is optimistic that the research will ultimately yield a treatment that will benefit MS sufferers, it will still be some years before the drugs make it to market, as they must go through the standard process of demonstrating lab success before clinical trials begin.

Other research projects are more advanced. The second and third generation of the botulinum toxin drugs are already in the pipeline, having been proven to work on animals.

However, it has not been without its challenges. "It's very difficult to grow - it's anaerobic for a start, which means it won't grow where there is oxygen. It also forms spores which are very dangerous. We simplified the process and came up with a patent to make it in e-coli," he said.

"We're making a drug that is a fraction the size of the original. This means less protein is being injected into the patient, it's more potent and has fewer side effects."

If the drugs are commercialised, they will have significant payback for the university. "The royalties would be enormous," says Prof Dolly. It would be a lucrative partnership for both the university and Allergan's Irish operation - the current botox drugs are worth about $1 billion (about €650 million) in sales - and could pave the way for further projects.

To speed up the process, the centre has invested in a GMP facility - Good Manufacturing Process. This facility, which has yet to be built, will produce the first analytical batches of the drug for human use, proving its worth to the company before Allergan makes a significant investment in new facilities to manufacture the drug.

Prof Dolly hopes Irish researchers can lead the way in producing drugs, instead of playing a support role to large pharmaceutical companies.

"In a nutshell, in my scientific career I want to produce at least one Irish drug," he says. "The funding agencies are putting a lot of money into this. If we can do that, it would be tremendous."