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

Descripción del proyecto

Las proteínas GLI podrían ayudar a combatir la enfermedad renal crónica

La enfermedad renal crónica avanza de forma progresiva hasta causar insuficiencia renal y afecta a más del 10 % de la población mundial. Aunque ha habido avances recientes en los tratamientos, la mayoría de los pacientes aún desarrolla insuficiencia renal en fase terminal. Estos tratamientos implican diálisis o trasplantes, que suponen una carga pesada para los sistemas sanitarios. La fibrosis, que conduce a la formación de tejido cicatricial y deteriora la función del órgano, es un objetivo terapéutico clave para mejorar el pronóstico de la enfermedad renal crónica. El proyecto DISRUPT-KF, financiado por el Consejo Europeo de Investigación, investiga el papel de los miofibroblastos, principales responsables de la fibrosis. Se tratará de validar nuevos inhibidores de GLI, dirigidos a las proteínas GLI1/2 implicadas en la fibrosis, pero inactivas en adultos sanos. Los resultados del proyecto podrían mostrar un gran potencial en organoides renales humanos y en modelos murinos.

Objetivo

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.