Interfering with inflammation

US scientists have developed a method to selectively shut off genes linked to inflammation all around the body. Writing in this week's Nature, University of Massachusetts researcher Michael Czech and his colleagues describe how they have produced gene-silencing particles which are orally active and can block the production of inflammatory signals linked to diseases including rheumatoid arthritis and septic shock. Surprisingly, part of the key to the breakthrough was baker's yeast cells, which coat themselves with a sugary layer of a chemical called beta-1,3-D-glucan which is itself recognised and picked up by inflammatory cells called macrophages. The team found that by treating yeast cells with acid and solvent solutions they were able to dissolve away all but this outer layer, which remained like hollow husks, each about one five hundreth of a millimetre across.

These they then could then refill with short segments of genetic material called interfering RNA molecules. These are the genetic mirror images of certain cellular genes and when they enter cells they shut off their target gene by binding to the gene product and causing it to be broken down. In this case the researchers used interfering RNA molecules directed against two inflammatory genes called tnf-alpha and map4k4. When they fed the particles to mice, macrophages lining the animals' digestive tracts recognised the beta-1,3-D-glucan on the surface and picked them up. Once inside, rather like the Trojan Horse, the particles then discharged their gene silencing contents, shutting of the target genes in these cells.

The researchers think that it may be possible to use the same technique to treat certain inflammatory disorders, such as rheumatoid arthritis which is triggered by the body attacking its own tissues. Blocking the production of the signals thought to drive the process should help to control it. The team tested the potential for doing this by exposing treated mice to the substance LPS (lipopolysaccharide), which usually produces a profound inflammatory reaction. Compared with control animals, which succumbed rapidly, nearly half of the treated animals were protected. This approach could, therefore, pave the way for the development of orally-active targeted ways to shut off genes linked to certain disease conditions.