Scientists Uncover Drug Targets for Arthritis and Inflammatory Kidney Disease using New Techniques in Genetics

Scientists at the Medical Research Council Clinical Sciences Centre (MRC-CSC) and Imperial College London have discovered new drug targets to treat inflammatory disease.

Using a new 'systems genetics' approach, the scientists identified a large network of genes that work together in cells to control processes involved in inflammatory disease. By targeting one specific molecule involved in this network, Kcnn4, the researchers showed that they can significantly reduce the symptoms of arthritis and kidney inflammation.

Kcnn4 has previously been shown to be involved in immune system responses. Drugs to block the Kcnn4 molecule are currently in phase III clinical trials to target diseases involving the immune system going wrong, such as inflammatory bowel disease and asthma. This study identifies two new potential uses for these drugs in preventing debilitating inflammatory diseases.

Kcnn4 is a molecule that is found on the surface of cells called macrophages (a type of infection-fighting cell). The research, published in scientific journal Cell Reports, has shown for the first time that Kcnn4 works by controlling the formation of giant cells - multiple macrophages fused together into one single big cell. The resulting giant cells contribute to various inflammatory diseases. The authors have shown that by using drugs to block the action of the Kcnn4 molecule, the cells do not fuse together and therefore inflammatory symptoms are reduced.

In bones, these giant macrophage cells eat away at bone tissue and reabsorb the nutrients into the body. In normal circumstances, the bone is constantly being built up again so remains unharmed by this process. However, these cells can lead to bones losing density in arthritis patients with inflamed joints. In collaboration with researchers at Yale University, the authors showed in mice that targeting Kcnn4 with drugs to stop the giant cells forming alleviates the symptoms of arthritis by preventing bone erosion and inflammation.
Similarly, these giant cells contribute to an inflammatory kidney disease called glomerulonephritis, a common cause of kidney failure caused by inflammation within the glomerulus, the filtering unit of the kidney. Administering drugs that stop the action of the Kcnn4 molecule relieved this disease in rats by preventing the formation of giant cells in the glomerulus.

The authors confirmed that the same network of genes that controls the formation of giant cells in rodents is also present in humans. Further studies would be required to prove that targeting Kcnn4 with drugs could ease inflammatory disease in humans. Since Kcnn4 is present in both rodents and humans, the scientists are hopeful of a similar effect on inflammatory conditions in humans.

Dr Enrico Petretto, Head of Integrative Genomics and Medicine Group at the MRC-CSC and Senior Lecturer at Imperial College London, says: "This study shows how our new 'systems genetics' approach has great potential to discover new genes that can be targeted to treat disease. Similar to what happens in social networks, Kcnn4 interacts with other genes inside a cell, forming a complex 'gene network'. We discovered another 183 genes which could also prove to be promising drug targets for inflammatory disease. This study represents an important step towards understanding of the complex interactions in inflammatory disease."

Dr Jacques Behmoaras, Head of Molecular and Cellular Immunogenetics Group at the Centre of Complement and Inflammation Research, Imperial College London, says: "We have shown that Kcnn4 is a promising drug target for kidney inflammation. The fusion of macrophages giving rise to giant cells is still a poorly understood phenomenon. This work is fundamental to understand how genetic differences between individuals can affect the ability of their macrophages to fuse. Such information could be crucial to understand the genetic basis of inflammatory diseases."

Professor David Lomas, Chair of the Population and Systems Medicine Board at the MRC, says: "Life expectancy is increasing and more people are living to ages at which they experience common chronic and degenerative diseases. Chronic inflammation is linked to many age-related diseases such as cardiovascular disease and arthritis. Arthritis is a huge problem in the UK - 20% of people over 45 years old have reported symptoms to their GP. This study shows that learning more about the fundamental mechanisms of inflammatory disease can help to identify new targets for therapies or open up opportunities to use existing drugs for different diseases."