Rare kidney diseases impact markedly on the life expectancy and quality of life of affected individuals. The current diagnostic and therapeutic management of rare kidney diseases is highly unsatisfactory. We are typically unable to explain the genetic or molecular abnormality underlying the disease phenotype, to predict the individual risk and rate of disease progression, or to quantitate the risk of relatives to develop the same disorder. Even in patients with known genetic causes, individual risk prediction is limited by considerable phenotypic variability. Molecular disease and progression risk markers are lacking. Effective therapies are largely unavailable; the lack of suitable disease models is a major barrier to progress in therapeutic development.
Diseases of the kidney are well suited to high-throughput research approaches due to the opportunity to examine molecular events in the end organ that is manifesting the disease: kidney biopsy, a standard diagnostic procedure, provides a unique opportunity to study intrarenal biological processes ex vivo using transcriptomic, proteomic and morphological approaches. Urine is a readily available non-invasive bioresource to study molecular readouts directly derived from the organ of interest, the kidney. Amniotic fluid, the fetal urine, allows prenatal epigenetic, proteomic and metabolomic profiling in the context of renal maldevelopment. Recent technological progress in exosome isolation from urine and amniotic fluid even has created the opportunity to study non-invasively cellular biomaterials originating from the diseased tissues.
EURenOmics has prioritized five disease groups based on their urgent need and significant potential for diagnostic and therapeutic progress: Steroid-resistant nephrotic syndrome, membranous nephropathy, tubulopathies, complement disorders and malformations of the kidney and urinary tract. The consortium has access to a unique assembly of large existing patient cohorts and biorepositories, encompassing more than 15,000 patients with >10,000 DNA, >3,000 serum, 2,000 urine, 500 amniotic fluid and 3,000 kidney biopsy specimens. Some 30 academic and industry partners have joined EURenOmics to apply a wide range of high-throughput technologies, innovative systems biology approaches and a plethora of in vitro, ex vivo and in vivo models to study disease mechanisms and explore novel therapeutic approaches.
Initial research efforts focus on methodological standardization, involving procedures for acquisition and processing of biospecimens but also the construction of an integrated phenome database for uniform clinical phenotyping. The next objective is to search for new genes causing, modifying or predisposing to individual disease phenotypes. Screening strategies encompass next-generation sequencing of known genes, regulatory regions, exomes and whole genomes, application of cutting-edge bioinformatic tools for data mining, filtering and gene network analysis, and extensive genotype-phenotype analyses utilizing standardized phenotypic information. Novel epitopes/antigens and antibodies are searched systematically in those disorders in which an auto-immune pathology is suspected. The protein products of the newly identified gene variants, as well as the mechanisms of auto-antibody formation, are functionally characterized by an array of in vitro, ex vivo and in vivo technologies. Multi-level -omics profiling (mRNA, miRNA, peptidome/proteome, metabolome) in body fluids and renal tissues is performed to identify unique molecular disease signatures (deep phenotyping), develop a prognostically indicative new ontology of rare kidney diseases, discover molecular markers and pathways associated with disease activity and progression, and develop diagnostic tools and biomarkers. Finally, in vitro and in vivo models will be developed that allow high-throughput screening of compound libraries for novel therapeutic agents reversing or attenuating disease phenotypes.
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