Blackshear, Perry (NIEHS)
Tristetraprolin (TTP) is the prototype member of a small family of RNA binding proteins that bind to specific types of AU-rich elements in the 3'UTRs of target mRNAs and promote their rapid turnover. One of the targets destabilized by TTP is Tumor necrosis factor alpha (TNF). TNF has long been a target of anti-inflammatory drug development, in which recombinant protein molecules based on TNF antibodies or TNF receptors have been used to bind directly to TNF and inactivate it. These therapies are very expensive because of their recombinant origin, require frequent injections because they are proteins, run the risk of producing antibodies to themselves, and have other problems. This invention describes using the newly discovered endogenous anti-inflammatory protein, TTP, for possible therapeutic development. The inventors generated a novel genetic knock-in mouse line called the TTP?ARE mice, where the entire AU rich region (ARE) in the 3'UTR of TTP mRNA was deleted from the mouse genome. These mice were almost completely protected from the development of collagen antibody-induced arthritis, a standard model of immune-mediated arthritis that involves many of the cytokine systems. This finding supports the concept that general increases in “whole body” TTP might have beneficial consequences in certain inflammatory diseases if they could be achieved therapeutically.
- The invention can primarily be used for developing screens for compounds that stimulate the accumulation of TTP in cells and tissues of the body, without disqualifying side effects.
- This discovery can eventually lead to the development of small molecule drugs suitable for oral use, which would elevate TTP in cells and tissues of the body and achieve anti-inflammatory effects. Compare to the currently available biologics that have the same effect, the small molecule drug would be much less expensive and without disqualifying side effects. Furthermore, a potential TTP elevating agent would be expected to have beneficial effects by acting to reduce TNF production, as well as production of other cytokines shown to be important in the pathogenesis of inflammatory diseases, such as Il23 and Il17, whose mRNAs are both targets of TTP.