Project Summary/Abstract Approximately 500,000 people in the U.S. suffer from cutaneous lupus lesions (CLE), with a significant impact on quality of life.4 Yet, there is no cure, the treatment options are limited, and no new drug has been FDA- approved for over 50 years.84 As such, CLE represents a high unmet need for directed therapeutics. Skin lesions are caused by a complex autoimmune response dependent on genetic and environmental factors.80 These lesions have common histological features such as interface dermatitis with interferon-regulated chemokines expression.19 Anandamide (AEA) is a primary endocannabinoid involved in (i) modulation of the innate and the adaptive immune system, (ii) processing of sensory input such as pruritus and pain, and (iii) maintenance of skin barrier integrity.152,153 AEA’s primary pathway for decreasing inflammation is through binding to CB2 receptors, which are predominantly expressed by macrophages and lymphocytes in peripheral organs with immune function, including the skin.164 Preliminary data (i) demonstrate upregulation of CB2 receptors in lesional human CLE tissue and (ii) show that AEA-treated peripheral blood mononuclear cells from CLE patients produce lower levels of cytokines. Given all this, AEA is a promising drug candidate for treatment of CLE. AEA faces a variety of delivery challenges, however, including instability, limited penetration into the stratum corneum, and rapid metabolism by fatty acid amide hydrolase (FAAH).134-135 To overcome these challenges, AEA was loaded into a novel topical silica- derived particle delivery system that has been demonstrated to enhance bioavailability of several other APIs. The resulting formulation (AEA-ZP) was shown to (i) enhance penetration of AEA into the stratum corneum, (ii) provide extended release of AEA in the skin, and (iii) significantly reduce the size and severity of lupus lesions in two murine lupus studies as compared to controls, including unencapsulated AEA. During this Phase I proposal, the AEA-ZP prototype will be evaluated for efficacy in vivo in a new mouse model, and preliminary toxicity data will be obtained. In vitro mechanism-of-action studies will be conducted using blood and lesional tissue from human CLE patients; such data is expected to inform clinical development decisions relating to target patient populations in which specific biomarker profiles might indicate patients that are more likely to respond to treatment with AEA-ZP. In parallel, higher loaded AEA-ZP prototypes will be developed in preparation for dose-ranging safety and efficacy studies to follow, and accelerated stability testing performed.