Experimental data demonstrate that GATA-3-specific DNAzymes do not lead to unspecific immune cell activation

Marburg, Germany, 27 March 2012 

  • Results support favourable safety profile observed in toxicological studies and in recently completed first clinical trial of SB010

A paper published in Nucleic Acid Therapeutics (Dicke et al., 2012) found that the DNAzyme used in sterna biologicals’ drug candidate SB010, a novel inhaled GATA-3 antagonist for the treatment of moderate to severe Th2-driven asthma, does not lead to unspecific immune cell activation.

The researchers employed TLR-9-transfected HEK293 cells, macrophage cell lines and primary innate immune cells to establish whether the DNAzyme and especially the CpG motif of its catalytic domain leads to off-target effects. The unmethylated CpG motif is recognised by TLR-9 which can activate the innate immune system via NFκB. Furthermore, putative effects of the GATA-3-specific DNAzyme on the activation of neutrophil granulocytes and degranulation of mast cells/basophils were assessed.

No TLR-9 mediated or TLR-9 independent cell-stimulating activities of the DNAzyme were observed in any of the systems, further supporting the therapeutic potential of GATA-3- specific DNAzymes as previously reported (Sel et al., 2008).

Dicke T, Pali-Schöll I, Kaufmann A, Bauer S, Renz H, Garn H. Absence of Unspecific Innate Immune Cell Activation by GATA-3-Specific DNAzymes. Nucleic Acid Ther 2012. [Epub ahead of print]

Sel S, Wegmann M, Dicke T, Sel S, Henke W, Yildirim AO, Renz H. and Garn H. Effective Prevention and Therapy of Experimental Allergic Asthma Using a GATA-3-specific DNAzyme. J Allergy Clin Immunol 2008 (121): 910-916.

About SB010
sterna biologicals’ drug candidate SB010 is an inhaled DNAzyme-based GATA-3 antagonist. GATA-3 is the master transcription factor in regulating Th2-driven inflammatory diseases such as asthma. It is generally accepted that GATA-3 is necessary and sufficient for the production of key cytokines interleukin (IL)-4, IL- 5, and IL-13, which cause inflammation. In pre-clinical development, SB010 significantly reduced expression of these cytokines and was safe and well-tolerated in toxicological studies with negligible side-effects. DNAzymes are single-stranded DNA molecules comprising a catalytic domain flanked by two binding domains. The binding domains attach to a specific sequence of targeted mRNA (antisense), in case of SB010 GATA-3 mRNA. After binding to the target, the catalytic domain then cleaves the mRNA, thereby inhibiting relevant cytokine expression.

About asthma
Asthma is a major chronic inflammatory disease of the airways affecting an estimated 300 million people worldwide. In OECD countries, prevalence is around 10% and increasing, with greater than average prevalence amongst women, children, and the elderly.