Therapeutic effects of nano-encapsulated anandamide on skin inflammation in a novel PD-1H knock-out lupus mouse model

Summary: Cutaneous lupus erythematosus (CLE) is an autoimmune skin disease involving immune cell accumulation, cytokines, immune complexes, and complement in skin lesions. The endocannabinoid system, including Anandamide (AEA), a key endocannabinoid, has demonstrated therapeutic potential in modulating immune responses and maintaining skin barrier function. Our pilot study explored the therapeutic effects of AEA on spontaneous lupus skin lesions in a newly developed lupus mouse model with programmed death-1 homolog (PD-1H) knockout (KO) mice in a BALB/c background. Fourteen mice, matched for skin plaque scores, were divided into two groups and treated topically with either 4% AEA-ZP (AEA encapsulated in a novel silica-based particle delivery system, treatment) or 0% AEA-ZP (control) on skin lesions twice weekly for 8 weeks. Our preliminary data, analyzed by repeated measures two-way ANOVA, showed significant time x treatment interaction (p<0.001), indicating the effect of time on lesional scores depended on the treatment group. Post-hoc analysis showed that 4% AEA-ZP treatment progressively reduced lesional scores compared to baseline, with significant improvement from week 5 onward until the end of treatment period (1.47±0.39 at week 8 <i>vs</i> 3.50±0.42 baseline, P<0.01). In contrast, the control group (0% AEA-ZP) showed only minimal and insignificant reduction in skin scores over the same period of time. H&E stained lesion skin showed reduced epidermal skin thickness and attenuated inflammatory cell infiltration in the dermis in 4% AEA-ZP treated compared to control mice. The observed clinical and immune-modulating effects of AEA suggest it may be a viable efficacious new treatment for CLE. Encapsulation of AEA appears to enhance skin penetration and efficacy. Further studies with IMC analysis will help to elucidate the mechanism for the therapeutic potential of AEA-ZP in a novel lupus model. Minghui Yi¹, Ming-Lin Liu¹, Meena Sharma¹, Andrew Draganski², Leigh Hsu³, Dario Paggiarino³, Rui Feng¹, Victoria Werth¹ 1. University of Pennsylvania, Philadelphia, PA, United States. 2. Zylo Therapeutics Inc, Greenville, SC, United States. 3. Atticus Pharma, Greenville, SC, United States. Translational Studies: Preclinical