Antisense Technologies – An Emerging Field for the Development of New Therapeutic
Molecules: Anti-GATA3 DNAzyme as a Prototypic Example

Harald Renz, MD Institute of Laboratory Medicine Philipps University Marburg, Germany Phone +49 6421 586 6235 Email [email protected]

Transcription factors play a central role in the regulation of cellular function and activities. In
this context GATA3 has been recognized as the master-transcription factor in the regulation
of Th2 development and Th2 functions. GATA3 is expressed not only in CD4-Th2 cells, but
also in ILC2 cells, eosinophils mast cells, and basophils, among others. We have developed
an antisense molecule belonging to the DNAzyme family which specifically and selectively
targets GATA3 mRNA. DNAzymes are characterized by target-specific binding domains and
an intrinsic catalytic nucleic acid sequence. Following extensive preclinical analysis,
toxicology studies and three clinical safety studies in healthy and asthmatic individuals, a
phase IIa proof-of-concept clinical trial was performed in mild asthmatic patients. Treatment
was carried out for 28 days by daily inhalation of a single dose of 10 mg SB010. Allergen
provocations were performed before and after the treatment cause. The primary endpoint of
this study, significant reduction of the late phase asthmatic response, was reached, and
highly surprisingly, also significant effects on the early phase allergic response was
measured. The degree of improvement could be furthermore related to the level of blood
eosinophils before treatment. Based on these encouraging results, SB010 treatment has
been recently clinically tested in patients with atopic dermatitis (NCT02079688), eosinophilic
COPD (DRKS00006087), and ulcerative colitis (NCT02129439), all of these conditions with
predominant type 2 inflammation. Topical administration of SB010 on lesional skin for 14
days significantly improved skin barrier function. 28 days of inhalation of SB010 in eCOPD
patients significantly reduced sputum eosinophils and shifted systemic IL-5 and IFN-γ
production; following encouraging results in animal models we have recently completed a
clinical trial in UC patients with highly significant effects on the total Mayo score as the
primary endpoint. In addition, target regulation was observed in local tissues.These data
indicate for the first time that the transcription factor GATA3 represents potential targets for
topical pharmatherapy in asthma, eosinophilic COPD, atopic dermatitis, and ulcerative colitis.
However, additional clinical trials are warranted to firmly establish this new treatment
modality.