Despite inhaled glucocorticoids (“steroids”) and meaningful new biologic and small-molecule agents, the large and increasing asthmatic population has immense unmet needs and disease burden. The IL4/13-induced transcription factor STAT6 is central to allergic inflammation. My group was supported by the AAF in cloning a novel STAT6-interacting protein and creating a line of mice lacking expression of this protein. Originally called Collaborator of Stat6 (CoASt6), this polypeptide was intriguing from the outset because its sequence had a region similar to the catalytic domain of the known mammalian poly(ADP-ribosyl) polymerase (PARP), PARP1. It was my hope and prediction that the similarities and differences of primary structure meant a catalytic function would be selectively targetable by small molecules that spare conventional PARPs. We showed that CoASt6, renamed PARP14 or ARTD8 after identification of a family of ADP-ribosyltransferases, is enzymatically active and important for recall allergic lung inflammation and Th2 responses in vivo. Surprisingly, induction of Th17 cells depended on PARP14 and its catalytic activity. Until late last year, however, there was no selective inhibitor. Now, a small biopharmaceutical start-up focused on cancer has developed and started very early testing of PARP14-selective small molecules. At present, asthma is not in their plan but they are willing to share proprietary molecules with me and reconsider. In this Extension Award application, I request AAF support for experiments that would be the first work testing if selective PARP14 inhibition can reduce disease in preclinical mouse models of asthma-relevant eosinophil-pattern (Th2-driven) and neutrophil-pattern (Th17 driven) lung inflammation.

IL-17A signaling is emerging as a potential therapeutic target for treating steroid-resistant severe asthma. IL-17A signals through IL-17R (composed of IL-17RA and IL-17RC subunits) to transmit signals into cells. We have identified that a natural compound, cyanidin, exhibit robust antagonist activity against IL-17RA in in vitro biochemical assay and IL-17A-induced gene expression in cultured cells. Moreover, cyanidin also shows encouraging efficacy in several preclinical mouse models IL-17-dependent airway inflammation and hyperreactivity. While cyanidin is not orally available, it is technically possible to deliver the compound as a dry powder to achieve local pharmacological activity in the airway. In this proposal, we will design, develop, and optimize new formulations of cyanidin tailored and optimized with the necessary characteristics for inhalation aerosol delivery to the lungs with high local regional deposition in the lung. We will perform comprehensive in vitro and in vivo tests to determine the toxicity and efficacy of the cyanidin formulation in both acute and chronic models of house dust mite (HDM)-induced asthma.