703 Preclinical evidence for nitric oxide-releasing SB414 in a psoriasis animal model

Abstract

Psoriasis is an immune-mediated inflammatory skin disease attributed to dysregulated interactions between keratinocytes and immune cells. IL-1β is a cytokine responsible for enhancing the infiltration of activated immune cells, triggering the release of additional pro-inflammatory cytokines, and is also a key signal responsible for the maturation of naïve T cells into Th17 cells. In several inflammatory skin disorders the aberrant activation of this helper T-cell subset results in the production and release of IL-17, which binds to its cognate receptor and prompts inflammasome activation and initiates a positive inflammatory feedback loop. Nitric oxide has the potential to disrupt IL-17 propagation locally in the skin via its ability to disrupt the assembly of the NLRP3 inflammasome. Topical application of imiquimod (IMQ) produces a cutaneous inflammatory phenotype on the back of Balb/c mice that is utilized as a model of psoriasis. In this study, IMQ was applied daily to the backs of mice. The mice were then treated with SB414, a topical nitric oxide-releasing cream, BID for 10 days. Compared to untreated controls, 6% SB414, demonstrated a statistically significant reduction in the psoriasis back pathology starting at day 3 and was maintained until the end of the experiment showing a 31%, 40%, and 28% decrease in composite psoriasis score, erythema and plaque score, respectively. In this model, pro-inflammatory cytokines associated with the IL-23/IL-17 axis are significantly upregulated (Day 4) in ear tissue after IMQ application. Compared to untreated controls, 6% SB414 treatment reduced tissue levels of pro-inflammatory cytokines: IL-1β, IL-6, IL-22, IL-17A, IL-17F and IL-33 by 84%, 55%, 64%, 87%, 71% and 71%, respectively. These data support the potential for a nitric-oxide releasing topical treatment to reduce the pro-inflammatory cytokines associated with perturbation of the IL-23/IL-17 axis and result in decreased psoriasis pathology.