PROJECT SUMMARY Atopic dermatitis/AD (or ‘atopic eczema’) is a complex, chronic, inflammatory skin disease that affects upwards of 35 million Americans. AD is characterized by a disruption of epidermal-barrier function, inflamed dry and thick skin, severe pruritus and significant impact on patients’ quality of life. Current standard of care involves topical emollients, avoidance of trigger factors and anti-inflammatory strategies including the use of corticosteroids, antihistamines, or broad and recently also specific immunommodulators, such as dupilumab. While broad immunosuppressive therapies can help partly manage the disease, chronic usage results in undesirable side- effects and drug tolerance, resulting in lowered patient compliance and inefficacy. Furthermore, dupilumab is ineffective in a significant portion of patients, suggesting the heterogeneity of AD and need for individualized treatment based on patient profiling. There is a pressing need for the clinical development of targeted immunomodulatory therapeutics, without immunosuppressive side effects, designed to take into account patient profiling and to safely and selectively target pathogenic mediators of AD. HSP90 has been recently classified as an ‘alarmin’ and has key roles in mediating the interplay between the innate and the adaptive immune system as well as known roles in the JAK/STAT and MAP kinase pathway and IL-4, IL-13, and IL-17 signaling. These pathways have key roles in AD-related immune dysregulation. Regranion has recently acquired a potent novel small molecule HSP90 inhibitor (RGRN-305, previously Debio0932) with a good safety profile and attractive pharmacological properties that shows alleviation of psoriatic symptoms, reduced epidermal thickness, and dramatic reduction in levels of TNFα and IL-17, pro-inflammatory cytokines in clinically relevant animal models of psoriasis. These studies laid the foundation for ongoing clinical evaluation in the treatment of moderate-to- severe psoriasis (ClinicalTrials.gov Identifier: NCT03675542) and set a precedence for investigation of HSP90 as a therapeutic target in AD. The focus of this proposal is to accomplish key milestones that will transition this technology for commercialization as a safe and efficacious oral AD therapeutic that targets the upstream proteomic mediators of the disease. The study aims involve i.) rigorous evaluation of the efficacy and mechanism of action of oral RGRN-305 in multiple clinically relevant AD models that incorporate a comparative efficacy study versus corticosteroid treatment, and ii.) characterization of the gene and protein expressions of HSP90 pathway- related markers in normal, nonlesional and AD lesional human skin samples from moderate-to-severe AD patients. A role for HSP90 in the pathogenesis and persistence of AD has not been elucidated. Given that the etiology of AD is multifaceted, characterizing the expression profile of epidermal HSP90 pathway and related cytokines and chemoki...