Investigating the efficacy of transcription factor-specific DNAzymes in animal models of inflammatory skin diseases

Inflammatory skin diseases cover a wide range of skin conditions that cause dry, itchy, scaly skin and affects millions around the world. Current therapies are mostly symptomatic and often associated with a wide range of side effects. Therefore, there is a growing need for a more specific therapy ta...

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Bibliographische Detailangaben
1. Verfasser: Ibrahim, Rouba
Beteiligte: Garn, Holger (PD Dr.) (BetreuerIn (Doktorarbeit))
Format: Dissertation
Sprache:Englisch
Veröffentlicht: Philipps-Universität Marburg 2016
Medizin
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Zusammenfassung:Inflammatory skin diseases cover a wide range of skin conditions that cause dry, itchy, scaly skin and affects millions around the world. Current therapies are mostly symptomatic and often associated with a wide range of side effects. Therefore, there is a growing need for a more specific therapy targeting key molecules in the pathogenesis of such diseases. Investigations revealed a central role for different T helper subsets in the immunopathology of these skin diseases. Atopic dermatitis (Th2), contact dermatitis (Th1) and Psoriasis (Th1, Th17), are associated with one or more of these Th-phenotypes. The differentiation and activation of T helper subtypes is regulated by different transcription factors. This study focused on two specific transcription factors GATA3 and Tbet, which regulate the differentiation and activation of Th2 and Th1, respectively. The levels of these transcription factors were found to be elevated in diseases with the respective Th phenotype, which made them interesting targets for DNAzyme-based therapy. In order to test the efficacy of such transcription factor-specific DNAzymes, two different animal models of inflammatory allergic skin diseases were established. In the first model skin injury and the hapten oxazolone were used to elicit a Th2-dominant contact hypersensitivity with features similar to those of atopic dermatitis. In the second model, Ovalbumin was used to induce a Th1-dominated inflammation in OVA-specific T cell receptor- transgenic mice after systemic sensitization with OVA/CFA. Effects of topical preventive treatment with GATA3-specific DNAzyme (hgd40) were investigated in the oxazolone model. The DNAzymes were formulated in w/o/w emulsion for protection against degradation and an enhanced skin penetration. Compared to placebo and control non-specific DNAzyme ODNg3, prophylactic treatment with hgd40 significantly reduced skin swelling. It also resulted in lower numbers of CD4+ cells infiltrating the dermis. This was associated with a downregulation of GATA3 mRNA expression in the skin early in the sensitization phase. Similar reduction in skin swelling was also observed after a semi-therapeutic treatment, in which hgd40 was first applied 24 h prior to challenge but not during sensitization. Using the OVA/CFA model, effects of the Tbet-specific DNAzyme td32 treatment were evaluated. Data indicated a significant reduction in skin swelling following prophylactic treatment with emulsions containing td32. No such effect was observed in the control DNAzyme ODNg3 or placebo groups. In addition, no influence on the progression of skin swelling in this Th1-skewed skin inflammation after treatment with hgd40 was detected, which further supports the hypothesis of specific targeting of Tbet. In summary, this study shows that treatment with DNAzymes, targeting Th1- and Th2- specific transcription factors Tbet and GATA3 improved inflammatory symptoms in vivo. These results pose the DNAzyme as promising tools for future topical treatment of inflammatory skin diseases.
Beschreibung:98 pages.
DOI:https://doi.org/10.17192/z2016.0207