Approximately 500, 000 people in the U.S. suffer from cutaneous lupus lesions (CLE), with a significant impacton 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.80These lesions have common histological features such as interface dermatitis with interferon-regulatedchemokines expression.19 Anandamide (AEA) is a primary endocannabinoid involved in (i) modulation of theinnate 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 bindingto CB2 receptors, which are predominantly expressed by macrophages and lymphocytes in peripheral organswith immune function, including the skin.164 Preliminary data (i) demonstrate upregulation of CB2 receptors inlesional human CLE tissue and (ii) show that AEA-treated peripheral blood mononuclear cells from CLE patientsproduce 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 acidamide 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 lesionsin 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 bloodand lesional tissue from human CLE patients; such data is expected to inform clinical development decisionsrelating to target patient populations in which specific biomarker profiles might indicate patients that are morelikely to respond to treatment with AEA-ZP. In parallel, higher loaded AEA-ZP prototypes will be developed inpreparation for dose-ranging safety and efficacy studies to follow, and accelerated stability testing performed.
Public Health Relevance Statement: Narrative 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 There is compelling preliminary data to support anandamide (AEA) as a promising drug candidate for CLE including in vitro work using tissue from human CLE patients and two in vivo murine studies demonstrating that AEA loaded into a novel topical silica-derived particle delivery system (AEA-ZP) significantly reduces the size and severity of lupus lesions as compared to controls, including unencapsulated AEA. The goal of this Phase I proposal is: (1) confirm efficacy of AEA-ZP in a newly developed murine model of lupus and assess preliminary toxicity; (2) identify biomarker profiles that may predict response to treatment with AEA-ZP; and (3) produce AEA-ZP prototypes with higher load factors and conduct stability testing.
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