MP72-15 GENE EXPRESSION IN THE BLOOD OF INTERSTITIAL CYSTITIS PATIENTS AND CONTROLS DISTINGUISHES PATHWAYS ASSOCIATED WITH INTERSTITIAL CYSTITIS AND PREDICTS CLINICAL RESPONSE TO CYCLOSPORINE THERAPY

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INTRODUCTION AND OBJECTIVES: Interstitial cystitis (IC) is a heterogeneous condition with urinary and systemic symptoms.Clinically relevant phenotyping has been a challenge, but some patients, especially those with Hunner's Ulcers, have evidence for immune activation.We hypothesize that gene expression signatures can be used as a biomarker to phenotype patients with IC and predict response to specific therapies.METHODS: As part of a clinical trial of oral cyclosporine A (CyA), blood was collected from 26 IC patients prior to treatment and after 3 months of CyA at 3 mg/kg/d as well as from 20 asymptomatic controls.A training set of 6 controls and 6 IC patients including those who did or did not respond to CyA was initially run.RNA was isolated from whole blood (Tempus tubes) and analyzed using Illumina HT-12 v4 BeadChip arrays.PANTHER pathway analysis and DAVID functional classification were used for annotation and grouping of differently expressed genes.RESULTS: Using the criteria of fold-changes less than 0.5 or greater than 2 and p<.05, we found 155 unique genes that were differently expressed in the blood of IC patients vs controls representing 55 pathways including inflammation mediated by chemokines and cytokines, T cell activation, integrin signaling, angiogenesis, and apoptosis.Comparing patients who subsequently had significant clinical improvement with CyA therapy to those who didn't improve, there were 37 genes with at least two fold differential expression.Using DAVID functional annotation clustering, these genes represented responses in inflammation, wound healing, and innate immunity.Finally, following CyA therapy, interleukin signaling changed in all patients but other pathways that changed were distinct between responders and non-responders.In CyA responders, the altered gene expression pathways were related to matrix remodeling (plasminogen activating cascade) and pain modulation (cannabinoid and dopamine receptor signaling).CONCLUSIONS: Gene expression signatures in whole blood distinguished between IC patients and controls as well as between patients who would subsequently improve with CyA therapy.Pathways altered following CyA therapy in the responders could serve as potential targets for new drug development.

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