Prevention and Treatment of Fibrosis and Chronik Injury progressionA novel therapeutic approach for prevention and treatment of chronic injury, progressive loss of functional parenchymal cells, or fibrosis of an organ, by activation of a newly identified signaling axis. ChallengeInjury in an organ triggers a complex signaling cascade that involves various cellular and molecular responses, ultimately culminating in tissue fibrosis, loss of functional parenchyma and organ failure. The progressive fibrosis and impaired regenerative capacity are unmet biomedical challenges, because once chronic lesions have manifested, no effective therapies are available. Thus for example the progression of chronic kidney disease (CKD), which affects 10% of the western civiliztion inevitevely leads to organ failure and the need of organ transplantation. Our SolutionA novel signaling axis was identified, which revealed a therapeutic target. It was found that an increase of the ARNT-homodimer level in cells, activates BMP signaling responses, which ultimately result in an anti-fibrotic and pro-regenerative response. These effects protect an organ against chronic injury, progressive loss of functional parenchymal cells or fibrosis. It was found, that ARNT dimerization leads to protection from progression of fibrosis, which may be mediatet for example by 1) inhibitors of protein phasphatase 2A (PP2A), i.e. LB-100 or vivo morpholinos, 2) inhibitors of the transcriptional repressor complex FKBP12/YY1, i.e. GPI-1046 or vivo morpholinos or 3) an Expression construct, which is capable of rising the expressing of ARNT in said organ (Figure 1)
In a mouse model a significant attenuation of fibrosis could be achieved also in the liver and the heart by treatment with GPI-1046. This proves, that a therapy based on increasing the ARNT homodimer is effective in multiple organs.
Advantages
ApplicationsOrgan protection against chronic injury through (1.) preventive preconditioning (administered before organ injury), or (2.) interventional treatment (initiated when injury had already been established). Protective effect targets parenchymal organs like kidney, heart and liver. Development StatusIn vivo proof of concept successfully achieved. Some drugs are already in clinics. Patent StatusWe filed PCT international IP rights in the name of the Georg-August-Universität Göttingen, University Medical Center, and are looking for a licensing partner, who develops and markets a product. ReferencesJ Clin Invest. 2018. doi.org/10.1172/JCI89632., Tampe et al. ContactDr. Martin Andresen |