Targeting the IL-17 Receptor Using Liposomal Spherical Nucleic Acids as Topical Therapy for Psoriasis

Abstract

The activation of T helper 17 signaling plays a critical role in psoriasis pathogenesis, and systemicallyadministered IL-17 inhibitors are highly effective therapy for moderate-to-severe disease. We generated topically-delivered gene-regulating nanoconstructs, comprised of spherically-arrayed antisense DNA (liposomal spherical nucleic acids [L-SNAs]), which are able to penetrate human skin to knock down cutaneous gene targets. Topically-applied L-SNAs targeting the gene encoding the mouse IL-17A receptor (Il17ra) reversed the development of psoriasis clinically, histologically, and transcriptionally in imiquimod-treated psoriasis-like mouse skin. Il17ra L-SNAs reduced the modified PASI by 74% versus controls and decreased epidermal thickness by 56%. Il17ra L-SNA reduced Il17ra protein expression by 75% and significantly decreased the mRNA expression of psoriasis markers, including Defb4, Il17c, S100a7, Pi3, Krt16, and Tnfa versus scrambled spherical nucleic acid (Scr SNA) controls. A human IL17RA L-SNA penetrates 3-dimensional cultures and normal human explants to knock down IL17RA mRNA by 63% and 66%, respectively. After topical application to psoriatic 3-dimensional rafts, anti-human IL17RA L-SNAs reduced the expression of IL17RA (by 72%) and the IL-17induced genes IL17C (by 85%), DEFB4 (by 83%), TNFA (by 77%), and PI3 (by 65%) versus scrambled L-SNA and vehicle controls (all P < 0.001). Taken together, these data suggest that targeted suppression of IL17RA is a promising new topical treatment strategy for psoriasis.

Assessment of Transdermal Delivery of Topical Compounds in Skin Scarring Using a Novel Combined Approach of Raman Spectroscopy and High-Performance Liquid Chromatography

“…There are limitations to this study: firstly, the reliance of the ability to section longitudinally through each dermal layer and accurately correlate with corresponding H&E sections in HPLC. It is also important to acknowledge that skin explants do not have the same permeability, elasticity, movement, and pharmacokinetics as intact skin, however our group have previously published work 15 (and more recently other groups) [27][28] demonstrating that it is possible to assess topical penetration on skin explants. The inability to use a true placebo compared to the treatment (since the treatment topical has no evidence to prove known actives) is another limitation, although in this case we were able to demonstrate how compounds could be identified in the absence known proven activity.…”

Gene Delivery to the Skin – How Far Have We Come?

“…This is an excellent example of how to combine different delivery approaches for effective gene therapy. Recently, Liu and coworkers [ 84 ] reported the development of an LNP-based AON formulation targeting the IL-17A receptor expression as a topical treatment for psoriasis. The topical application to a psoriasis-like mouse model and 3D skin models and normal human explants resulted in a 72%–75% reduced protein expression of the IL-17A receptor compared with the untreated control.…”

Formulation‐based approaches for dermal delivery of vaccines and therapeutic nucleic acids: Recent advances and future perspectives

“…SNAs prepared with lipid-based nanoparticles such as liposomes possess the ability to overcome the barriers to transdermal drug delivery and silence gene expression in the epidermis. Liu et al reported the use of SNAs to silence the expression of IL-17 receptor A (IL-17RA) in mice with imiquimod-induced psoriasis 151 . The authors reported a significant alleviation of the psoriatic lesions five days after treatment with of IL-17RA SNA compared to controls.…”