RT Journal Article
SR Electronic
T1 Late-breaking abstract: Local and systemic distribution of the GATA-3-specific DNAzyme hgd40 after inhalative exposure
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP 4493
VO 38
IS Suppl 55
A1 Agnieszka Turowska
A1 Nadja Baumgartl
A1 Jens Kuhlmann
A1 Holger Garn
YR 2011
UL http://erj.ersjournals.com/content/38/Suppl_55/4493.abstract
AB DNAzymes represent a new class of antisense molecules that combines the specificity of DNA base pairing with an inherent RNA-cleaving enzymatic activity. We developed the DNAzyme hgd40 which was shown to effectively target the transcription factor GATA-3 that plays an important role in the regulation of Th2-mediated immune mechanisms in allergic bronchial asthma.The aim of this study was to investigate local and systemic distribution of hgd40 after local exposure in mice, rats and dogs.Using fluorescently labelled hgd40 we could demonstrate that the DNAzyme was evenly distributed in inflamed mouse lungs after single application. Moreover, hgd40 could be intracellularly detected in T cells, Goblet cells, AE type 1 cells and macrophages 2 h after i.n. application. Systemic distribution was investigated in rats and dogs in the course of toxicological studies following single and subchronic (28 d) exposure. Generally, only very low systemic hgd40 levels were detected. In rats, the highest serum concentration of hgd40 was observed 1 h post application (p.a.) and decreased over time to non-detectable levels at 24 h p.a. After 27 d of subchronic, daily inhalation, no accumulation of hgd40 occurred. The results were similar for both sexes and three different doses. Similar results were observed in dogs.Our results indicate that local hgd40 DNAzyme admimistration can target different lung cells expressing GATA-3 and thus modulate Th2-driven immune responses. Low concentration in blood and lack of accumulation after subchronic inhalative exposure indicate that GATA-3-specific DNAzyme hgd40 leads only to marginal systemic distribution.