Descrizione del progetto
Approccio genico contro la malattia renale cronica
La malattia renale cronica (MRC) è una condizione complessa ed eterogenea associata alla perdita progressiva della funzione renale e colpisce milioni di persone in tutto il mondo. Diversi studi sottolineano l’ereditarietà della MRC attraverso l’identificazione di loci genetici associati. Tuttavia, questi geni non possono spiegare tutti i casi di suscettibilità alla MRC. La missione del progetto GeneCKD, finanziato dall’UE, è identificare le basi genetiche della MRC e svelare le vie causali della malattia. L’attenzione sarà rivolta alla proteina uromodulina, specifica del rene, e alla progettazione di nuovi interventi per contrastare gli effetti tossici dell’espressione anomala di uromodulina. I risultati aiuteranno la diagnosi precoce e apriranno la strada alla terapia genica della MRC.
Obiettivo
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.
Campo scientifico
Programma(i)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Argomento(i)
Meccanismo di finanziamento
HORIZON-AG - HORIZON Action Grant Budget-BasedIstituzione ospitante
52621 Ramat Gan
Israele