Prevention and Treatment of Fibrosis and  Chronik Injury progression

A 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.

Challenge

Injury 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 Solution

A 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)

Figure 1: Inhibition of PP2A (degradation of ARNT),  or formation of the repressor complex FKBP12/YY1 (reduction of ARNt expression) protects against chronic kidney injury.

Experimental: Administration of LB-100, low-dose FK506 or GPI-1046 one day prior to a UUO surger.

Analysis of ARNt levels in different tissues revealed an up-regulation of ARNT not only in the kidney, but also for example in the heart, liver or lung (Figure 2). In a mouse model a significant attenuation of fibrosis could be achieved in the kidney, the liver and the heart by treatment with vivo morpholinos, LB-100, GPI-1046 or FK506. This proves, that a therapy based on increasing the ARNT homodimer is effective in multiple organs.
Figure 2: The relative increase of the Arnt mRNA-level was measured in different cell types. Application of FK506 or GPI-1046 decreased the ARNT suppressor complex FKBP12/YY1

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.

Figure 3: Administration of GPI-1046 (10 mg/kg subcutaneously per day) significantly attenuates the progression of fibrosis in the heart and the liver.

Experimental: GPI-1046 was administered one day prior to inducing cardiac fibrosis and liver failure due to administration of angiotensin II or carbon tetrachloride to mice.

Advantages
  • Modulation of the new ARNT signaling pathway is possible with multiple small molecules, a gene therapeutic approach or vivo morpholinos
  • Effective attenuation of fibrosis in multiple organs (heart, liver and kidney) have been shown in a mouse model
  • Prevention and treatment of fibrosis and organ injury is possible

Applications

Organ 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 Status

In vivo proof of concept successfully achieved. Some drugs are already in clinics.

Patent Status

We 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.

References

J Clin Invest. 2018. doi.org/10.1172/JCI89632., Tampe et al.

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