The GATA-3 approach TREATMENT OF TYPE 2
Type 2 inflammatory diseasesMost significant cause of death in the world
GATA-3ideal target for the treatment of type 2 inflammatory diseases
GATA-3 is responsible for the production of key inflammatory cytokines IL-4, IL-5, IL-9 and IL-13 by overactive immune cells, in particular Th2-lymphocytes and innate lymphoid cells 2 (ILC2).
Downregulating GATA-3 leads to a reduced expression of these cytokines and thereby normalization of the dysregulated type 2 immunity (immunomodulation). Broadly antagonizing several inflammatory processes and mediators at the same time is making GATA-3 an ideal target for the therapy of type 2 inflammatory diseases.
sterna biologicals is the only company that has successfully made GATA-3 druggable and clinically demonstrated that GATA-3 downregulation could provide for a truly novel, first-in-class, broad-spectrum, non-steroidal, anti-inflammatory therapy.
Traditionally, type 2 inflammation was considered an over-active response of the adaptive immune system, characterized by Th2 cells, IgE production and an activation of eosinophils and mast cells. Typical mediators of such responses include key inflammatory cytokines IL-4, IL-5, IL-9 and IL-13.
However, it is increasingly accepted that type 2 inflammation is initiated and maintained by the adaptive as well as the innate immune system with epithelial cells and innate lymphoid cells 2 (ILC2) both playing an important role.
All of these cellular players have one feature in common: they demonstrate expression and up-regulation of GATA-binding factor 3 (GATA-3), a so-called master transcription factor. Master transcription factors are key molecules in the regulation of intracellular signaling processes and responsible for an integrated cellular response to multiple signals. They exert their activity by binding to promoter sites of genes, thereby enabling their transcription.
GATA-3 is responsible for the production of IL-4, IL-5, IL-9 and IL-13 by overactive immune cells, in particular Th2-lymphocytes and ILC2. This makes GATA-3 the ideal therapeutic target for type 2 inflammatory diseases as reducing GATA-3 leads to the down regulation of several key inflammatory cytokines and pathways (broad spectrum approach) and thereby the normalization of the dysregulated type 2 immunity. This ultimately provides the desired anti-inflammatory therapeutic effect.
sterna’s hgd40Using DNAzymes to make GATA-3 druggable
When it comes to making GATA-3 druggable, small molecules and monoclonal antibodies come with incapacitating limitations. While the direct modulation of the function of transcription factors by small molecules is still widely regarded as ‘impossible’ [Hagenbuchner & Ausserlechner, Biochem Pharmacol. 2016], monoclonal antibodies cannot directly reach GATA-3 due to its intracellular location in the cytosol and nucleus.
sterna’s proprietary active pharmaceutical ingredient hgd40 is a special type of catalytic antisense oligonucleotide – a DNAzyme.
The highly attractive characteristics of hgd40 are:
- unmodified (natural) 34mer deoxynucleotide, stabilized by inverted thymidine at 3' end
- cellular uptake without delivery system
- specifically cleaves GATA-3 mRNA of humans and tox species
- excellent safety profile; no immune system activation (e.g. via TLR-9)
- fully automated solid phase manufacturing; well established, proven and robust chemical process technology; linear scalability into commercial scale
Applying the results of a decade of research and development of DNAzymes in the field of immunology, sterna biologicals has successfully advanced two lead programs for the treatment of asthma and ulcerative colitis into phase 2 clinical development. Both programs leverage sterna’s proprietary active pharmaceutical ingredient hgd40 which offers fundamental advantages over established as well as newer forms of therapy. Therewith, sterna biologicals seeks to provide a novel therapeutic option to patients suffering from chronic type 2 inflammatory diseases.
Additionally, sterna biologicals has established further technical and medical validation through hgd40-based programs in COPD and atopic dermatitis.
Further literatureRead more about the scientifically validated GATA-3 approach
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.