TARGETSITE THERAPEUTICS CORPORATION — Department of Health and Human Services SBIR Phase I: NEI

Description

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 andgt;50% reduction in clinical and histopathologic AU parameters, thereby offering therapeutic benefit of this novel approach in autoimmune uveitis.This collaborative project between a new company, TargetSite Therapeutics, and Yale University, will develop novel immune system-modifying drugs for the treatment of uveitis, an autoimmune eye disease that is one of the leading causes of blindness in the U.S. These relatively small molecules will block the expression of genes that typically drive this autoimmunity (IL-23 and IL-17) in a highly specific and non-toxic manner. As such, this should have major positive public health implications and applications.