Description du projet
Approche génétique contre l’insuffisance rénale chronique
L’insuffisance rénale chronique (IRC) est une affection complexe et hétérogène associée à une perte progressive de la fonction rénale et touche des millions de personnes dans le monde. Diverses études soulignent l’héritabilité de l’insuffisance rénale chronique par l’identification de loci génétiques associés. Cependant, ces gènes ne peuvent pas expliquer tous les cas de susceptibilité à l’IRC. La mission du projet GeneCKD, financé par l’UE, est d’identifier la base génétique de l’IRC et de dévoiler les voies de causalité de la maladie. L’accent sera mis sur l’uromoduline, une protéine spécifique aux reins, et sur la conception de nouvelles interventions pour contrer les effets toxiques de l’expression aberrante de l’uromoduline. Les résultats contribueront à un diagnostic précoce et ouvriront la voie à une thérapie génique de l’IRC.
Objectif
Chronic Kidney Disease (CKD) is a public health challenge affecting millions globally. Patients have increased risks of mortality, morbidity, and progression to end-stage kidney disease (ESKD). CKD is often clinically silent, disease mechanisms are unclear and targeted therapies are unavailable. Recent studies support considerable contributions of underappreciated monogenic aetiologies in adults with CKD, suggesting that most inherited kidney diseases remain undiagnosed, untreated and poorly understood. Our overarching objective is to unravel the genetic basis of CKD towards early diagnosis and gene-based therapy. We therefore established the Israeli ESKD genetic cohort and already recruited clinical data and samples from 2,000 participants with ESKD. Our main objectives are: 1) to unravel known and novel CKD genes by interrogating high-risk groups for genetic CKD using next generation sequencing on a population level; 2) to study novel monogenic CKD disease mechanisms by using patient-derived kidney organoids and mutation-specific mouse models. Specifically, we will study a newly identified WDR19 mutation leading to many adult onset-ESKD cases in the Israeli Arab-Druze population; and 3) to develop gene-based targeted therapies for CKD. We will focus initially on monogenic CKD secondary to gain-of-toxic-function mutations in UMOD (encoding uromodulin, a kidney-specific protein). This relatively frequent adult CKD aetiology accounts for 0.5-2% of CKD cases worldwide. Altered uromodulin?s toxic effect is suitable for novel RNA-based therapies. Gene silencing of uromodulin with antisense oligonucleotides will be performed and studied, using a patient-derived in vitro model as well as a Umod mouse model. This project will improve CKD classification and clinical management, reveal disease mechanisms as well as novel treatments. In a broader perspective, this project will set the stage for future clinical trials and for other RNA-based gene-specific CKD treatments.
Champ scientifique
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Thème(s)
Régime de financement
HORIZON-AG - HORIZON Action Grant Budget-BasedInstitution d’accueil
52621 Ramat Gan
Israël