IL-23 and IL-17A mrna-targeted oligonucleotide therapeutics in autoimmune uveitis - the pro-inflammatory cytokines IL-23 and IL-17A play critical roles in autoimmune uveitis (AU)

Current AU treatments include immunosuppressants, including systemic corticosteroids, accompanied by many challenging toxicities. As a novel cytokine gene expression control mechanism, we found that the microrna (mirna) MIR466L-3P cooperates with the mrna- stabilizing protein HUR to augment IL-17A mrna and protein levels. To exploit this unusual mirna-mediated enhancing mechanism as a potential therapeutic target, targetsite therapeutics and yale university have collaboratively generated a target site blocker (TSB) oligonucleotide that specifically blocks MIR466L-3P binding to the IL-17A 3'UTR, leading to transcript decay and decreased IL-17A protein levels both in vitro and in vivo. This includes our preliminary TSB efficacy data in the RAT autoimmune uveitis model. The mrna levels of IL23, a cytokine upstream of IL-17A, are also augmented in MIR466L-overexpressing cells. This phase i sbir will provide proof-of-concept that MIR466L - cytokine mrna interaction-specific TSB oligos, either singly or in combination, will be a novel effective treatment for AU. We will do so by: (1) designing, validating and evaluating specificity of a MIR466L - IL-23 3'UTR TSB; (2) optimizing the IL-17A mrna-specific TSB for the foundational (RAT) model; and (3) assessing the efficacy of the IL-17A and IL-23 tsbs, singly and in combination, in the RAT AU model, by clinical scoring, histopathology and aqueous humor levels of the tsbs and relevant cytokines. The achievable milestone for this phase i sbir project is >50% reduction in clinical and histopathologic AU parameters, thereby offering therapeutic benefit of this novel approach in autoimmune uveitis.