University of Hertfordshire

RNA Aptamer Delivery through Intact Human Skin

Research output: Contribution to journalArticle

Documents

  • Jon D Lenn
  • Jessica Neil
  • Christine Donahue
  • Kellie Demock
  • Caitlin Vestal Tibbetts
  • Javier Cote-Sierra
  • Susan H Smith
  • David Rubenstein
  • Jean-Philippe Therrien
  • P Shannon Pendergrast
  • Jason Killough
  • Marc B Brown
  • Adrian C Williams
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Original languageEnglish
Pages (from-to)282-290
Number of pages9
JournalJournal of Investigative Dermatology
Volume138
Issue2
Early online date20 Sep 2017
DOIs
Publication statusPublished - 1 Feb 2018

Abstract

It is generally recognized that only relatively small molecular weight (typically < ∼ 500 Da) drugs can effectively permeate through intact stratum corneum. Here, we challenge this orthodoxy using a 62-nucleotide (molecular weight = 20,395 Da) RNA-based aptamer, highly specific to the human IL-23 cytokine, with picomolar activity. Results demonstrate penetration of the aptamer into freshly excised human skin using two different fluorescent labels. A dual hybridization assay quantified aptamer from the epidermis and dermis, giving levels far exceeding the cellular half maximal inhibitory concentration values (>100,000-fold), and aptamer integrity was confirmed using an oligonucleotide precipitation assay. A T helper 17 response was stimulated in freshly excised human skin resulting in significantly upregulated IL-17f, and IL-22; topical application of the IL-23 aptamer decreased both IL-17f and IL-22 by approximately 45% but did not result in significant changes to IL-23 mRNA levels, confirming that the aptamer did not globally suppress mRNA levels. This study demonstrates that very-large-molecular-weight RNA aptamers can permeate across the intact human skin barrier to therapeutically relevant levels into both the epidermis and dermis and that the skin-penetrating aptamer retains its biologically active conformational structure capable of binding to endogenous IL-23.

Notes

This document is the Accepted Manuscript of the following article: Jon D. Lenn, et al, ‘RNA Aptamer Delivery through Intact Human Skin’, Journal of Investigative Dermatology, Vol. 138 (2): 282-290, February 2018. Under embargo until 20 September 2018. The final, published version is available online at DOI: https://doi.org/10.1016/j.jid.2017.07.851.

ID: 13308774