761 Topically-delivered gene suppressing nanocontruct targets IL-17RA for psoriasis

Abstract

Activated interleukin (IL)-23/Th17 signaling is critical for psoriasis pathogenesis, and systemic IL-17 inhibitors are highly effective therapy. However, most patients have mild to moderate disease and no targeted topical therapeutic option. We developed a topically-delivered gene regulating nanoconstruct, comprised of antisense DNA or siRNA in a dense spherical configuration. These spherical nucleic acids or SNAs penetrate the skin barrier to knock down cutaneous gene targets. We generated anti-human and anti-mouse liposomal DNA SNAs targeting the IL-17A receptor (ILRA) and tested their efficacy in reducing IL17RA and improving markers of psoriasis in human 3D and imiquimod-induced mouse models of psoriasis. SNAs reduced human keratinocyte IL-17RA expression by 83% versus scrambled SNAs (p<0.001). 100nM IL17RA SNAs, applied to the surface of cytokine-generated psoriatic 3D rafts every other day from day 7 to 13, inhibited keratinocyte proliferation, reduced IL17RA mRNA (by 67%; p<0.01) and IL-17-induced genes (e.g., DEFβ4, TNF, and PI3 by 64%, 73%, and 71%, respectively; all p<0.001), and improved differentiation (e.g., increased LOR by 2.7-fold; p<0.05) compared to scrambled SNA and vehicle controls. By day 6 in the imiquimod-induced psoriasis-like mouse, topical IL17RA SNA (50μM) reduced psoriasis severity (modified PASI) by 75% (p<0.001) and epidermal thickness (histology) by 52% (p<0.001) compared to controls. IL17RA SNA decreased IL17RA, DEF4, and S100A7 mRNA by 57%, 82%, and 55%, respectively compared to the scrambled SNA control (p<0.01). These data suggest that targeted suppression of IL17RA, or both IL-17R and TNFα using a bispecific SNA, is a promising new treatment strategy for mild to moderate psoriasis.