Abstract
Atopic dermatitis (AD) has high morbidity and poor prognosis because safe and effective treatments are scarce. Recently, short interfering RNA (siRNA) has shown promise as an effective treatment for targeting specific aberrantly expressed genes. However, naked siRNAs are too inefficient because of various enzymatic, membrane, and cellular barriers. We previously reported that a Tat analog acting as a cell-penetrating peptide, combined with AT1002, which reversibly increases paracellular transport of molecules across the epidermal barrier in epidermis-disrupted mice and enhances the skin permeation of water-soluble siRNA. In the present study, to develop a novel treatment for AD, we determined the intradermal permeation of siRNAs and the antiallergic effects of a siRNA that silences RelA, a member of the nuclear factor-κB family, using Tat and AT1002 peptides in an AD mouse model. We first showed that the Tat analog and AT1002 delivered siRNA into the skin of ICR mice and, upon topical application to the AD-induced ears of NC/Nga mice, changed zonula occludens protein 1 expression. In addition, the silencing effects on the mRNA of RelA in JAWS II cells transfected with siRNA oligonucleotides for mouse RelA, complexed with Tat, were as effective as a commercial vector. Furthermore, the ear thickness, clinical skin severity, topical cytokine levels, and serum IgE production in AD model mice treated with anti-RelA siRNA with Tat and AT1002 were improved.
Footnotes
This work was supported in part by a Grant-in-Aid for Young Scientists (B) from the Japan Society for the Promotion of Science [Grant 22790049] and a grant for private universities provided by the Promotion and Mutual Aid Corporation for Private Schools of Japan.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.111.180042.
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ABBREVIATIONS:
- AD
- atopic dermatitis
- SC
- stratum corneum
- Zot
- zonula occuluta toxin
- TJ
- tight junction
- ZO-1
- zonula occludens protein 1
- siRNA
- short interfering RNA
- siRelA
- siRNA oligonucleotides for mouse RelA
- NF-κB
- nuclear factor-κB
- TNF-α
- tumor necrosis factor-α
- IL
- interleukin
- ELISA
- enzyme-linked immunosorbent assay
- FAM
- 5-carboxyfluorescein
- N/P
- molecular ratio of the amine groups in cationic carriers and phosphate groups in siRNA
- PCR
- polymerase chain reaction
- HE
- hematoxylin and eosin
- TB
- toluidine blue.
- Received February 9, 2011.
- Accepted April 25, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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