Disrupting the myofibroblast cell cycle to treat Kidney Fibrosis with a novel small molecule compound inhibitor (DISRUPT-KF)

Chronic kidney disease (CKD) is a progressive disease in which kidney function is gradually lost. It can develop consequent of many (kidney) diseases and it affects more than 10% of the world population. Although in recent years sodium–glucose cotransporter 2 inhibitors and novel non-steroidal mineralocorticoid antagonists are showing significant effects on CKD, the majority of patients treated still progress towards end-stage renal disease (ESRD). With dialysis or kidney transplantation as the sole treatments available in case of ESRD, the disease represents an enormous burden on healthcare costs throughout Europe. Caused by organ injury, fibrosis leads to replacement of functional tissue and organ architecture by extracellular matrix, leading to tissue scar formation and impaired function of the affected organ. This makes fibrosis a key therapeutic target to improve organ function in e.g., CKD. Myofibroblasts are the key driver cells of fibrosis across organs and research in our lab has demonstrated that targeting myofibroblasts stabilises organ function. Additionally, we have identified GLI1/2 as a myofibroblast cell-cycle progression-specific target. We found that the number of Gli proteins, transcriptional effectors of the Hedgehog signalling pathway, are significantly increased in the kidney after injury. Furthermore, GLI1/2 are ideal targets as they are not expressed during homeostasis in adults. DISRUPT-KF will validate a set of novel Gli inhibitors as disease-modifying drug candidates for CKD. Preliminary evidence shows anti-fibrotic efficacy in human 2D culture platforms and in induced pluripotent stem cell-derived kidney organoids in vitro. During DISRUPT-KF we will further verify and optimise the anti-fibrotic drug candidates in relevant in vitro (kidney fibrosis organoids) and in vivo (mice) models to validate their potential. We will also develop and execute an IP strategy and a commercial feasibility analysis to enter the anti-fibrotic CKD market.