The GATA-3 approach TREATMENT OF CHRONIC
INFLAMMATORY DISEASES

GATA-3 is a key master transcription factor in chronic inflammation. GATA-3 downregulation could provide a novel, first-in-class anti-inflammatory treatment approach.
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Chronic inflammatory diseasesMost significant cause of death in the world

Chronic inflammatory diseases are the most significant cause of death in the world with the World Health Organization (WHO) ranking chronic inflammatory diseases as the greatest threat to human health [Chronic Inflammation, StatPearls, NCBI Bookshelf, Jan. 2020]. Despite the widespread use of corticosteroids and the availability of biologicals, there remains a significant unmet medical need for novel anti-inflammatory drugs in the treatment of chronic inflammatory diseases. Current therapies often fail to provide adequate long-term disease control or are associated with substantial side effects, underscoring the importance of developing more targeted and safer therapeutic options.

GATA-3PROMISING TARGET FOR THE TREATMENT OF CHRONIC INFLAMMATORY DISEASES

The master transcription factor GATA-3 plays a central role in chronic inflammatory diseases by inducing pro-inflammatory Th2/ILC2 cytokines (IL-4, IL-5, IL-9, IL-13) and promoting the differentiation of effector cells. Antagonizing these mediators and processes makes GATA-3 a promising target for the therapy of chronic inflammatory diseases.

sterna biologicals is the only company that has successfully made GATA-3 druggable and clinically demonstrated that the downregulation of GATA-3 could provide for a truly novel, first-in-class, non-steroidal, anti-inflammatory therapy.

sterna’s hgd40Using DNAzyme TECHNOLOGY TO MAKE GATA-3 DRUGGABLE

Making GATA-3 druggable is challenging due to the significant limitations of both small molecules and monoclonal antibodies

In the past, addressing transcription factors was considered impossible but recent examples suggest that this perception is changing [e.g. Hagenbuchner & Ausserlechner, Biochem Pharmacol. 2016, Tao & Wu, Methods Mol Biol; Radaeva et al, Drug Discovery Today. 2021]. For example, monoclonal antibodies cannot directly reach GATA-3 due to its intracellular location in the cytosol and nucleus.

In contrast, antisense oligonucleotides offer a promising solution to the limitations faced by small molecules and antibodies. Sterna's proprietary active pharmaceutical ingredient, hgd40, is a novel catalytic antisense oligonucleotide—specifically, a DNAzyme—that targets the mRNA of GATA-3, potentially overcoming these challenges.


+Synthetic 34mer deoxy-nucleotide, stabilised by inverted thymidine at 3' end
DNAzymes (= single-stranded DNA) are catalytically active DNA molecules. Molecules belonging to the so-called 10-23 family are known to specifically bind to and cleave mRNA molecules. They consist of two binding domains flanking a central catalytic domain. The latter is composed of 15 deoxynucleotides, the sequence of which is conserved throughout all molecules within this specific DNAzyme family. In contrast, the binding domains are variable and are designed to specifically bind the mRNA of the targeted gene of interest.
+DNAzymes Step 1

Literature

Yan et al., “Therapeutic DNAzymes: From Structure Design to Clinical Applications,” Advanced Materials (2023)

Greulich et al., “A GATA3-specific DNAzyme attenuates sputum eosinophilia in eosinophilic COPD patients: A feasibility randomized clinical trial,” Respir. Res., (2018)

Garn and Renz, “GATA-3-specific DNAzyme - A novel approach for stratified asthma therapy,” Eur. J. lmmunol., (2017)

Krug et al., “Blood eosinophils predict therapeutic effects of a GATA3-specific DNAzyme in asthma patients,” J. Allergy Clin. lmmunol., (2017)

Popp et al., “Rectal Delivery of a DNAzyme That Specifically Blocks the Transcription Factor GATA3 and Reduces Colitis in Mice,” Gastroenterology, (2017)

Homburg et al. "Safety and tolerability of a novel inhaled GATA3 mRNA targeting DNAzyme in patients with TH2-driven asthma" J Allergy Clin Immunol. (2015): 797-800.

Krug et al., "Allergen-induced asthmatic responses modified by a GATA3-specific DNAzyme" New Engl J Med. (2015).

Fuhst et al., "Toxicity profile of the GATA-3-specific DNAzyme hgd40 after inhalation exposure." Pulm Pharmacol Ther (2013).

Turowksa et al., " Biodistribution of the GATA-3-specific DNAzyme hgd40 after inhalative exposure in mice, rats and dogs." Toxicol Appl Pharmacol (2013).

Dicke et al., "Absence of unspecific innate immune cell activation by GATA-3-specific DNAzymes." Nucleic Acid Ther (2012).

Schmidts et al., "Development of drug delivery systems for the dermal application of therapeutic DNAzymes." Int J Pharm (2012).

Schmidts et al., "Protective effect of drug delivery systems against the enzymatic degradation of dermally applied DNAzyme." Int J Pharm 410 (2011): 75-82.

Schmidts et al., "Development of multiple W/O/W emulsions as dermal carrier system for oligonucleotides: effect of additives on emulsion stability." Int J Pharm 398 (2010): 107-113.

Sel et al., "Effective prevention and therapy of experimental asthma using a GATA-3 specific DNAzyme." JACI 121 (2008): 910-916.