PROJECT SUMMARY In the United States alone, approximately 3.1 million adult patients suffer from inflammatory bowel disease (IBD), a group of disorders characterized by chronic or recurring inflammation of the gastrointestinal (GI) tract. Although several therapeutics, including anti-TNF antibodies, have been approved for the treatment of IBD, many patients do not respond to current treatments or experience relapse, highlighting an urgent need for the development of more effective long-term therapies. Antigen presenting cell (APC) dysfunction drives IBD initiation by encouraging a breakdown in intestinal homeostasis and promoting pathogenic proinflammatory circuits against harmless commensal microbes. Although APCs are considered critical to IBD pathogenesis, there have been no APC-targeted therapies developed to date for the treatment of IBD. Qrono Inc is developing QR401, a first-in-class, oral, APC-specific AMPK pathway agonist for the treatment of IBD. QR401 uses custom nanoparticles to directly promote an AMPK- induced immunoregulatory APC phenotype. This work is inspired by studies demonstrating 1) that the AMPK pathway is downregulated by intestinal APCs in IBD patients and 2) that activation of the AMPK pathway via oral or systemic administration of AMPK pathway agonists can successfully alleviate disease severity in preclinical mouse studies. While AMPK has long been a target of interest for IBD, clinical development of AMPK agonists has been limited by severe adverse effects associated with systemic administration including metabolic complications (i.e. lactic acidosis) and cardiac hypertrophy. Thus, approaches like the one we propose that can target AMPK agonists specifically to intestinal APCs are vital to safely activating the AMPK pathway that’s dampened in IBD and restoring tolerance. Our preliminary data identify the AMPK agonist PF-739 as having tolerogenic activity, marked by a dampening of pro-inflammatory IL-12p70 production coupled with a significant increase in anti-inflammatory IL-10 secretion in LPS stimulated dendritic cells (DCs), features that promote Treg induction. We hypothesize that targeting AMPK-activating compounds to APCs will decrease intestinal inflammation during experimental colitis and human IBD without the metabolic and cardiac risks historically associated with untargeted AMPK agonists. Accordingly, we will prepare and characterize enteric-coated nanoparticles of PF-739 (QR401) that can be used for the proposed in vivo studies. Successful completion of this project will establish proof-of-concept for a first-in-class APC-targeted immunotherapy for IBD. A future Phase II STTR proposal would continue development in IND-enabling studies. Qrono is committed to developing oral tolerogenic therapies for IBD, and these data will help us raise private investment necessary for future clinical trials.