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

Haoming Liu, Richard S. Kang, Katherine Bagnowski, Jeong Min Yu, Sara Radecki, Weston L. Daniel, Bart R. Anderson, Subbarao Nallagatla, Andrew Schook, Rishika Agarwal, David A. Giljohann, Amy S. Paller*

*Corresponding author for this work

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

The activation of T helper 17 signaling plays a critical role in psoriasis pathogenesis, and systemically-administered 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-17-induced 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.

Original languageEnglish (US)
Pages (from-to)435-444.e4
JournalJournal of Investigative Dermatology
Volume140
Issue number2
DOIs
StatePublished - Feb 2020

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

Cite this

Liu, H., Kang, R. S., Bagnowski, K., Yu, J. M., Radecki, S., Daniel, W. L., Anderson, B. R., Nallagatla, S., Schook, A., Agarwal, R., Giljohann, D. A., & Paller, A. S. (2020). Targeting the IL-17 Receptor Using Liposomal Spherical Nucleic Acids as Topical Therapy for Psoriasis. Journal of Investigative Dermatology, 140(2), 435-444.e4. https://doi.org/10.1016/j.jid.2019.06.146