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Science Advances: New Potential Therapeutic Strategy to Suppress Inflammation

Scientists have developed new technology with potential as a therapeutic strategy for inflammatory diseases. Short molecules of ribonucleic acid (RNA) can be targeted to reduce levels of specific proteins by interacting—or interfering—with the genetic material that encodes the protein to prevent the protein from being made. This technique, known as “RNA interference,” has potentially transformative therapeutic value. The development of a safe and effective way to deliver short interfering RNA molecules (siRNA) to specific types of cells in vivo, however, would be required before this technique could be used therapeutically. In a recent study, scientists designed a method to orally deliver siRNA to mouse macrophages, a cell type of the immune system that is important in initiating the inflammatory response. In this novel approach, layers of RNA molecules can be encapsulated within hollow, porous, tiny (micron-sized) shells of a substance called beta1,3-D-glucan, a nontoxic material made by yeast cells. The shells are recognized by proteins found primarily on the surface of macrophages, allowing for the specific uptake of the shells by macrophages. The scientists termed these shell particles “GeRPs” or glucan-encapsulated siRNA particles.

To test this system as a potential therapeutic in animals, the investigators examined the effects of feeding mice GeRPs with siRNA to a specific inflammatory protein known as MAP4K4. They detected GeRPs inside mouse macrophages in various tissues of the mouse body, including spleen, liver, and lungs, and observed a decrease in levels of MAP4K4 in these tissues. To determine whether a reduction in MAP4K4 protein levels suppresses the inflammatory response, the mice were fed GeRPs with siRNA to MAP4K. The mice were then given a toxic chemical that mimics a bacterial infection in order to stimulate the inflammatory response. When mice without the siRNA were given the chemical, their macrophages stimulated an excessive inflammatory response, which was fatal to the animals. By feeding the mice siRNA to MAP4K4, the scientists were able to halt the inflammatory response to the chemical, thus protecting the mice. This exciting result demonstrated that the orally administered siRNA was not only delivered to the correct cells—the macrophages—and carried to multiple tissues, but that the siRNA also reduced levels of MAP4K4 and thus altered the mouse inflammatory response.

Inflammatory responses triggered by macrophages are involved in many conditions, including obesity, type 2 diabetes, inflammatory bowel disease, colitis, cardiovascular disease, atherosclerosis, and rheumatoid arthritis. The GeRP technology provides a novel oral delivery system for RNA interference to reduce levels of proteins involved in inflammation. Although further development and testing of the GeRP delivery system in animal models and in humans will be required, this study reveals the exciting potential of a new therapeutic strategy to suppress inflammation associated with numerous adverse health conditions. In addition, this technology could be used to deliver siRNA, and possibly other cargo, to other types of cells in the immune system to alter their function and therefore, could be explored as a potential therapy for autoimmune diseases like type 1 diabetes. 

Aouadi M, Tesz GJ, Nicoloro SM, Wang M, Chouinard M, Soto E, Ostroff GR, and Czech M: Orally delivered siRNA targeting macrophage Map4k4 suppresses systemic inflammation. Nature 458: 1180-1184, 2009.