Forsøksdyr: The role of AXL signalling targeted therapy for treatment of kidney fibrosis

Godkjenningsdato 10.10.2018

Godkjenningsperiode 15.10.2018-14.10.2022

Updated summary: Kidney fibrosis is the pathohistological correlate of chronic kidney disease (CKD), which is common, often unavoidable, irreversible and can eventually lead to end-stage renal disease. Effective therapy for kidney fibrosis is still lacking although it is a common consequence in patients suffering from disorders such as diabetes and/or hypertension. Recently the receptor tyrosine kinase AXL has been shown to play an important role in development of fibrotic diseases of the kidney, liver and lung. Several published papers are supporting the role of AXL in development of fibrosis and targeting the AXL signalling pathway show efficient pre-clinical prevention of inflammation and fibrosis development. Furthermore, it has also been shown that Axl inhibition can reduce hypertension and renal dysfunction.
Recently, a role of sAXL as a predictive biomarker for response to AXL directed therapy has emerged. Understanding the turnover of sAXL in the body is warranted before it can be used as a biomarker in clinical trials.

BerGenBio is developing both small molecule inhibitors and antibodies that target AXL and key AXL signalling pathways. The aim of this project is to explore the effect of AXL signalling inhibitors alone and in combination with standard therapeutic agents being used in the clinic against kidney fibrosis.

We hypothesise that treatment with AXL or AXL signalling inhibitors can prevent and/or reverse the development of kidney fibrosis. This project will help to elucidate further the impact of AXL signalling in inflammation and development of kidney fibrosis and investigate the potential anti-AXL therapy for treatment of this disease.

We hereby apply for the use of a total number of 630 mice in this project over the course of 4 years.
Replacement, Reduction and Refinement
-Tissues from the Norwegian Kidney biopsy registry as well as tissue from historic animal experiments have revealed a higher expression levels of AXL and AXL regulated markers in the diseased cohort.
-Previously performed in vivo studies with the AXL targeting agents and multiple ongoing clinical trials in cancer involving bemcentinib have shown effective AXL inhibition. An extensive amount of in vitro and in vivo studies have been performed to establish the rational for targeting AXL in fibrotic diseases. Also the dose range and well tolerability/low toxicity of the AXL inhibitors to be investigated in this project has been thoroughly established.
- Kidney fibrosis is a disease that develops as a consequence of multiple systemic diseases such as hypertension and diabetes. It is not possible to generate a kidney fibrosis model in vitro as several compartments of the kidney are affected and the disease interacts with the systemic impact of e.g. hypertension. Therefore, cell culture studies cannot replace the complexity of a mouse model in response to drug treatment.
- A maximum number of animals per experimental group will be limited to 10. Several experimental groups will be included in one experiment to minimize the number of control animals to be used. Personnel performing these experiments are experienced with the proposed models.