Inflammatory diseases represent increasing health care cost to American people. For many chronic inflammatory diseases (asthma, rheumatoid arthritis, bowel inflammatory diseases, etc.), there are no effective treatment. With the increase in the aging population of American society, this problem becomes aggravating. Targeted degradation of important factors (cytokines, cytokine receptors and intracellular mediators) participating in the inflammation signaling is a cost-effective strategy to develop an anti-inflammatory therapeutic measure. PKR is emerging as an important mediator for inflammatory process by transducing signaling activation of NF-kappa B or p38 to activate gene transcription of a number of inflammatory cytokines. Therefore, disruption of PKR activity is a particular attractive means of treating inflammatory diseases. The advantage of selecting PKR as a target also resides in that PKR is nonessential protein for cell survival compared with other targets (TNF-alpha, NF-kappa B, p38, etc.) which are vital for cell survival. Disruption of their activities may lead to undesirable and unexpected side effects. RBI is developing a novel class of chimerical oligonucleotides for use in antisense therapeutic strategies. This chimeras are comprised of an antisense component, which directs the compound to the complementary PKR sequences, and an activator moiety, 2',5'-oligoadenylate (2-5A) that serves to activate a cellular enzyme, ribonuclease L (RNase L), which cleaves the target RNA. Preliminary results demonstrated that 2-5A anti-PKR chimera can efficiently degrade PKR and inhibit PKR activation. The goal of this proposal is to progress this compound toward commercialization by obtaining a lead chimera compound with affinity to both human and murine PKR mRNA, and investigating the anti-inflammatory activity of the lead compound. If successful, the 2-5A anti-PKR compound will have a potential application to the treatment of chronic inflammatory diseases including rheumatoid arthritis, Crohn's diseases etc.
