McGill finding may lead to MS cure

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McGill finding may lead to MS cure

http://www.medicalpost.com/mpcontent/article.jsp?content=20040217_145103_3208

By nah Benady

MONTREAL – Scientists at the Research Institute of the McGill University Health Centre have identified a novel target for the development of drugs to treat and possibly even reverse multiple sclerosis (MS).

The researchers found a particular enzyme, cytosolic phospholipase A2 (cPLA2), plays a central role in the onset and progression of MS and that blocking the enzyme prevents onset and progression of the disease.

"We have identified a key enzyme that triggers MS-like disease in an animal model," said Dr. Sam (PhD) a neuroscientist at the research centres and professor of medicine at McGill University.

"We also show blocking this enzyme has a remarkable effect in preventing disease and relapses.

"This discovery suggests the cPLA2 enzyme may be an excellent target for the development of drugs to treat MS," said Dr. . MS affects about 35,000 young adults in Canada and is twice as prevalent in females.

The cPLA2 enzyme is a novel target because existing treatments either target inflammation or try to act as a decoy for immune cells. This new discovery approaches the MS problem from within the cell rather than outside it.

"There are no other molecular targets at present," said Dr. .

"So the key thing is that it opens up the field."

While Dr. described blocking the enzyme as having a strong effect on MS-type disease, he stressed that so far it had only been shown to work for the relapsing/remitting form of the illness, not the progressive, degenerative form.

He also stressed that while cPLA2 triggers the pathology, it does not cause MS.

"Infections or environmental factors cause an autoimmune response (in a susceptible individual) and the immune system starts to attack the myelin.

"But, we show this enzyme plays a central role in evoking the complex pathological changes seen in MS.

He first suspected the enzyme might play a central role in the disease from his previous research into nervous system degeneration and regeneration.

"We found this enzyme is important in calling in immune cells which then clear debris after injury. So this enzyme has a normal function in the peripheral nervous system.

"So we then asked the question: 'What if this enzyme is abnormally expressed in the brain and spinal cord? What would we predict that you could get?'

"We knew one of the metabolic products of the enzyme is arachidonic acid that produces inflammation. The other component is a detergent which, because it dissolves fat, induces myelin breakdown," he explained.

"So the answer to our question was an inflammatory disease—such as MS. So we looked at an animal model of MS, and wherever we saw the lesions, we saw cells that expressed very high levels of this enzyme cytosolic phospholipase A2."

Dr. , with his PhD student Athena Kalyvas, tested the theory on a group of mice in which they had induced MS-type disease. The mice were given an injection to induce the illness and at the same time were treated with an analogue of arachidonic acid to inhibit the enzyme.

"This analogue binds to the cPLA2 enzyme and stops it from latching on to the myelin."

They found fewer of the animals treated got the disease, compared with animals that were not treated. The ones that did get it had a milder form.

"So the onset and severity of the disease were reduced," said Dr. .

The researchers then tested the inhibitor against a placebo. They induced MS in two groups of mice and waited for the animals to get an attack. When they started to go into remission, the researchers gave one group the inhibitor, while the other group was treated with placebo.

"We found both groups remitted equally—which we expected," said Dr. .

"But the untreated group went into a second attack and then a third attack, whereas the treated group just carried on getting better and better. They did get secondary attacks, but they were very mild and then they just carried on improving.

"It is a very strong effect we see."

Break the code

He described the results as "fantastic," especially after two months of daily evaluations, all done blind. "Then we break the code and find the hypothesis has been correct."

There was also a third group of mice with the chronic form of the disease humans get called secondary, progressive MS.

"Those animals did not respond."

However, he cautioned they had only tested one protocol with one concentration of inhibitor. "We haven't done variations yet."

The researchers are now concentrating their investigations on some of the unanswered questions.

First, what are the differences in the inflammatory changes between the two forms of MS?

"We need to find out what are the genes that are turned on in the chronic form versus the genes that are turned on in the relapsing/remitting form."

Second, they will be looking to find an enzyme inhibitor more specific than the one they have used so far.

"This enzyme is part of a family and the inhibitor we used blocks all the members of this family.

"Now we are trying to identify which of these members is being expressed highly. Is it only one or two or all of them? We want to narrow it down even further so we can design drugs even more specific.

"The more specific the drug, the fewer the side-effects."

Dr. said he could not predict how long it will take for clinical trials on humans.

"If we rush it, things can fail and the whole thing gets discredited," he cautioned.

"We have to have time to sit back and think things through properly. My choice would be to identify even more specific targets first.

"But my gut feeling is this should result in treatment for patients down the line."

Their findings were published in the Feb. 5 issue of the scientific journal Neuron.

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