Immune system misinterprets threats and attacks body's own cells and tissue

Many chronic diseases are the result of the body's immune system mistakenly perceiving that the body is under attack from foreign bodies. A counterattack is then launched - an inflammatory response meant to vanquish the intruder. In reality, the immune system has misinterpreted the threat and is actually attacking the body's own cells and tissue.

Unless this situation is rectified, an inflammation can become chronic and eventually lead to psoriasis, rheumatoid arthritis or a number of other inflammatory conditions. Professor Berit Johansen and her research colleagues at the Norwegian University of Science and Technology (NTNU) in Trondheim have discovered one of the culprits in this process - the enzyme phospholipase A2 (PLA2).

"This is the enzyme that triggers the inflammatory response," explains Professor Johansen. "We are currently conducting research on various molecules that we believe could arrest PLA2 activity, thus stopping the inflammatory response."

Professor Johansen and her colleagues have received funding from the Research Council of Norway's programmes Functional Genomics (FUGE) and User-driven Research-based Innovation (BIA).

Scientists in Denmark, France, Germany and Scotland have been involved in the research. "Relatively few scientists in Norway are working on this kind of research, so we have assembled international expertise. And we will continue working with many of the same experts in the future."

Clinical trials in one year

Professor Johansen's research on PLA2 provided the starting point for Avexxin, a company established in 2005. In roughly one year, the company plans to begin the first clinical trials of a medicine for psoriasis. Parallel to these, the researchers will also continue testing other molecules that can hopefully put a stop to rheumatoid arthritis and kidney inflammation.

Despite the common objective for all three diseases - to trip up the PLA2 enzyme - different means are needed to accomplish this. Since the enzyme functions differently in different cells and tissue types, combating the inflammation requires a variety of molecules.

Mikael Ørum, President and CEO of Avexxin, explains that the company could have chosen to target a number of other inflammatory diseases, but that rheumatoid arthritis and kidney inflammation are each distinctive in their own way.

"Rheumatoid arthritis is a very common disease," says Mr Ørum, "so an effective medication would benefit many people. Kidney inflammation, on the other hand, is rare, but no treatment exists for it. Patients have to undergo frequent dialysis and intensive care - so medication to treat this would be a major advance."

Avoiding side effects

Mr Ørum estimates that a psoriasis medicine could be available on the market in five to six years. For the other two diseases, the researchers must still narrow down their choice to the single most highly effective molecule from among the candidates. Their results have been promising so far.

Bringing a new medicine to market is a lengthy, involved process. In this case, the researchers must first mix the PLA2 enzyme with the candidate molecule in a test tube to observe whether the molecule succeeds in neutralising the enzyme activity. If so, the same sort of testing is performed on human cells in the laboratory.

"It's important that the molecule only affects the PLA2 enzyme and no others," points out Professor Johansen. "Too broad an impact could lead to side effects."

The final phase before testing a medicine on humans involves a number of trials on animal models for the disease. The medicine being developed for rheumatoid arthritis has now reached this phase, while the molecules targeting kidney inflammation are not as far along yet. The research on both of these diseases has received funding under the National Programme for Research in Functional Genomics in Norway (FUGE), one of the Research Council's Large-scale Programmes.

Earlier-stage treatment

Various enzymes play a role in transforming a cell from healthy to dysfunctional. According to Professor Johansen, the PLA2 enzyme works its mischief at an earlier stage than the enzymes targeted by current medicines, which may entail great benefits for patients.

"Medicines targeted at a point too far along in the disease progression have major side effects," explains Professor Johansen. "This means that a patient must be very ill for the treatment to be worth suffering through its side effects. Our goal is to develop more effective medicines that work at an earlier stage and have fewer side effects."

Current medicines on the market, as well as those the professor and her colleagues are developing, can only treat the symptom, i.e. the inflammation. Since the causes of chronic inflammatory diseases are not yet known, it is impossible to get to the root of these and eradicate them for good.

Pharmaceuticals very interested

Based on their findings so far, Professor Johansen and her research colleagues believe they can someday develop medicines targeting this same enzyme to treat a variety of chronic inflammatory diseases.

"No one else is using these molecules in research on chronic inflammatory diseases," states Mr Ørum, "which gives us exclusivity in the market - and the pharmaceutical companies have shown great interest. When we reach the third phase of clinical trials, in which the medicine is tested on a large number of patients, we will consider selling the license to one of these companies."

http://www.forskningsradet.no/en/Newsarticle/When_the_body_attacks_itself/1253965256723