Descripción del proyecto
Un enfoque basado en la genética contra la insuficiencia renal crónica
La insuficiencia renal crónica (IRC o CKD, por sus siglas en inglés) es una afección compleja y heterogénea asociada a la pérdida progresiva de la función renal y que afecta a millones de personas en todo el mundo. En varios estudios se subraya la heredabilidad de la IRC mediante la identificación de los locus genéticos asociados. Sin embargo, estos genes no pueden explicar todos los casos de susceptibilidad a la IRC. La misión del proyecto GeneCKD, financiado con fondos europeos, es identificar la base genética de la IRC y desvelar las vías causales de la enfermedad. Se hará hincapié en la proteína específica del riñón, la uromodulina, y en el diseño de nuevas intervenciones para contrarrestar los efectos tóxicos de la expresión aberrante de la uromodulina. Los resultados ayudarán a emitir un diagnóstico precoz y allanarán el camino hacia una terapia de la IRC basada en la genética.
Objetivo
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.
Ámbito científico
Not validated
Not validated
Programa(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Régimen de financiación
HORIZON-AG - HORIZON Action Grant Budget-BasedInstitución de acogida
52621 Ramat Gan
Israel