Marburg, Germany, 10 October 2016
- Paper summarizing role of GATA-3 in ulcerative colitis published in Gastroenterology
- SECURE study of SB012 in patients with moderate to severe ulcerative colitis continues to progress (NCT02129439)
sterna biologicals GmbH & Co. KG ("sterna biologicals") announced today that detailed mechanistic investigations of the role of GATA-3 in ulcerative colitis, performed primarily by Prof Markus Neurath's group in Erlangen (Germany), were published in Gastroenterlogy (Popp et al, 2016).
The paper demonstrates that in contrast to patients with Crohn's disease, patients with severe ulcerative colitis (UC) are characterized by significantly elevated levels of GATA-3 which in turn correlates with high levels of pro-inflammatory cytokines interleukin (IL)-4, IL-5, IL-6, IL-9, IL-13, and IL-17, as well as levels of TNF. In a mouse model mimicking major features of UC, treatment with a GATA-3-specific DNAzyme resulted in marked reduction of GATA-3 expression paralleled by reduction in key pro-inflammatory cytokines. The pivotal role of GATA-3 in UC was further confirmed using mice genetically deficient of GATA-3. Mini-endoscopic investigations demonstrated significant reduction in inflammation to a level comparable to treatment with anti TNF therapeutics. In addition, therapeutic efficacy was also confirmed in TNF-independent or TNF-refractory settings.
Prof Markus Neurath commented: "This very promising concept of inhibiting GATA-3 may be broadly applicable for the treatment of gastrointestinal diseases with a Th2 molecular signature, such as ulcerative colitis."
Jonas Renz, Managing Director of sterna biologicals, added: "Building on the strong data generated both pre-clinically and clinically with SB010, our inhaled first in class GATA-3 antagonist for the treatment of Th2-driven respiratory diseases (Krug et al., 2015), we are very excited that a central role of GATA-3 in ulcerative colitis is evidenced by this important publication. We look forward to the last patients enrolling in the SECURE study in the coming months."
Krug N, Hohlfeld J, Kirsten A, Kornmann O, Beeh K, Kappeler D, Korn S, Ignatenko S, Timmer W, Rogon C, Zeitvogel J, Nan Z, Bille J, Homburg U, Turowska A, Bachert C, Werfel T, Buhl R, Renz J, Garn H, Renz H. "Allergen-Induced Asthmatic Responses Modified by a GATA-3 Specific DNAzyme." New England Journal of Medicine. 2015.
Popp V, Gerlach K, Mott S, Turowska A, Garn H, Atreya R, Lehr H, Ho I, Renz H, Weigmann B, Neurath M. "Rectal Delivery of a DNAzyme That Specifically Blocks the Transcription Factor GATA3 Reduces Colitis in Mice." Gastroenterology. 2016 epub ahead of print.
sterna biologicals' drug candidate SB012 is an enema-applied DNAzyme-based GATA-3 antagonist for the treatment of ulcerative colitis. The GATA-3-specific DNAzyme is also contained in the drug candidate SB010 for the treatment of Th2-driven respiratory diseases and SB011 for the treatment of atopic dermatitis. GATA-3 is the master transcription factor in regulating inflammatory diseases associated with the Th2 pathway such as ulcerative colitis, allergies and allergic 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 and SB012 significantly reduced expression of these cytokines and were 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, in case of SB012 GATA-3 mRNA. After binding to the target, the catalytic domain then cleaves the mRNA, thereby inhibiting relevant cytokine expression.
About ulcerative colitis
Ulcerative colitis is characterised by a continuous mucosal inflammation which predominantly affects the large intestine. Clinical symptoms include persistent diarrhoea with severe faecal urgency and often incontinence, rectal bleeding, abdominal cramping, weight loss, and general malaise. It is estimated that the disease affects approximately 2 million people in the US, Europe, and Japan.