Therapeutic effects on atopic dermatitis by anti-RelA short interfering RNA combined with functional peptides Tat and AT1002.

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.

• Authors: Tamae Uchida, Takanori Kanazawa, Misako Kawai, Yuuki Takashima, Hiroaki Okada
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 338 Issue 2 Pg. 443-50 (Aug 2011) ISSN: 1521-0103 [Electronic] United States
• PMID: 21531792 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• AT1002
• Gene Products, tat
• Oligopeptides
• RNA, Small Interfering
• Rela protein, mouse
• Transcription Factor RelA

Topics

• Animals
• Cells, Cultured
• Dermatitis, Atopic (drug therapy, genetics, pathology)
• Drug Delivery Systems (methods)
• Drug Therapy, Combination
• Female
• Gene Products, tat (administration & dosage, genetics)
• Gene Silencing (physiology)
• Male
• Mice
• Mice, Inbred ICR
• Oligopeptides (administration & dosage, genetics)
• RNA, Small Interfering (administration & dosage, antagonists & inhibitors, genetics)
• Skin Absorption (genetics)
• Transcription Factor RelA (administration & dosage, genetics)