The Journal of Allergy and Clinical Immunology
Volume 121, Issue 4 , Pages 910-916.e5, April 2008

Effective prevention and therapy of experimental allergic asthma using a GATA-3–specific DNAzyme

  • Serdar Sel, MD

      Affiliations

    • Department of Clinical Chemistry and Molecular Diagnostics, Medical Faculty, Philipps University of Marburg, Marburg, Germany
    • These authors contributed equally to this work.
    • ,
  • Michael Wegmann, PhD

      Affiliations

    • Department of Clinical Chemistry and Molecular Diagnostics, Medical Faculty, Philipps University of Marburg, Marburg, Germany
    • Sterna Biologicals GmbH and Co KG, Marburg, Germany
    • These authors contributed equally to this work.
    • ,
  • Tanja Dicke, MSc

      Affiliations

    • Department of Clinical Chemistry and Molecular Diagnostics, Medical Faculty, Philipps University of Marburg, Marburg, Germany
    • Sterna Biologicals GmbH and Co KG, Marburg, Germany
    • These authors contributed equally to this work.
    • ,
  • Sarper Sel, MD

      Affiliations

    • Department of Clinical Chemistry and Molecular Diagnostics, Medical Faculty, Philipps University of Marburg, Marburg, Germany
    • ,
  • Wolfgang Henke, PhD

      Affiliations

    • Molecular Biological Research Laboratory, Department of Otorhinolaryngology, Charité Berlin, Berlin, Germany
    • ,
  • Ali Ö. Yildirim, PhD

      Affiliations

    • Clinical Research Group, Clinic of Internal Medicine (Respiratory Medicine), University Hospital Giessen and Marburg GmbH, Marburg, Germany
    • ,
  • Harald Renz, MD

      Affiliations

    • Department of Clinical Chemistry and Molecular Diagnostics, Medical Faculty, Philipps University of Marburg, Marburg, Germany
    • Sterna Biologicals GmbH and Co KG, Marburg, Germany
    • Corresponding Author InformationReprint requests: Harald Renz, MD, Department of Clinical Chemistry and Molecular Diagnostics, Universitätsklinikum Giessen und Marburg GmbH, Baldingerstr, 35033 Marburg, Germany.
    • ,
  • Holger Garn, PhD

      Affiliations

    • Department of Clinical Chemistry and Molecular Diagnostics, Medical Faculty, Philipps University of Marburg, Marburg, Germany
    • Sterna Biologicals GmbH and Co KG, Marburg, Germany

Received 21 June 2007; received in revised form 20 December 2007; accepted 24 December 2007. published online 06 March 2008.

Background

Allergic bronchial asthma is a chronic inflammatory disease of the airways. The transcription factor GATA-3 was shown to play an important role in TH2 cell activation, but also in the regulation of other cell types involved in bronchial asthma including mast cells, eosinophils, and epithelial cells. DNAzymes represent a new class of antisense molecules that combines the specificity of DNA base pairing with an inherent RNA-cleaving enzymatic activity.

Objective

To develop a GATA-3 mRNA-specific DNAzyme and analyze its allergy-preventing activity in murine models of experimental allergic asthma.

Methods

The most active DNAzyme (termed gd21) was selected by in vitro cleavage assays. Allergic airway inflammation was assessed by inflammatory cell and cytokine analysis within bronchoalveolar lavage. Lung histology, including goblet cell hyperplasia and lung function, was analyzed using head-out body-plethysmography.

Results

Intranasal administration of gd21 prevented airway inflammation and mucus production and inhibited development of airway hyperresponsiveness to methacholine in models of acute allergic airway inflammation. Similar effects were also detected in a model of chronic experimental asthma. Interestingly, gd21 was at least as effective as other antisense molecules, and off-target effects were not detected. Further experiments indicated that pulmonary surfactant may facilitate the cellular uptake of gd21 by acting as an endogenous transfectant.

Conclusion

These results indicate that topical application of the GATA-3–specific DNAzyme is a promising novel approach for the treatment of allergic bronchial asthma.

Key words: Allergic asthma, GATA-3, DNAzymes, TH2 cells, antisense DNA, small interference RNA

Abbreviations used: AHR, Airway hyperresponsiveness, asDNA, Antisense DNA, BAL, Bronchoalveolar lavage, BDNF, Brain-derived neurotrophic factor, FACS, Fluorescence-activated cell sorting, HE, Hematoxylin and eosin, MCh, β-Methacholine, MCP, Macrophage chemoattractant peptide, NGF, Nerve growth factor, PAS, Periodic acid-Schiff, siRNA, Small interference RNA, TLR, Toll-like receptor

 

 Supported by Deutsche Forschungsgemeinschaft Sonderforschungsbereich/Transregio 22 and Sterna Biologicals GmbH and Co KG.

 Disclosure of potential conflict of interest: M. Wegmann, H. Renz, and H. Garn are cofounders of Sterna Biologicals. The rest of the authors have declared that they have no conflict of interest.

PII: S0091-6749(08)00003-1

doi:10.1016/j.jaci.2007.12.1175

The Journal of Allergy and Clinical Immunology
Volume 121, Issue 4 , Pages 910-916.e5, April 2008

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