Community Research and Development Information Service - CORDIS

FP7

EURENOMICS Report Summary

Project ID: 305608
Funded under: FP7-HEALTH
Country: Germany

Periodic Report Summary 4 - EURENOMICS (European Consortium for High-Throughput Research in Rare Kidney Diseases)

Project Context and Objectives:
Rare kidney diseases impact markedly on the life expectancy and quality of life of affected individ-uals. The current diagnostic and therapeutic management of rare kidney diseases is highly unsatis-factory. We are typically unable to explain the genetic or molecular abnormality underlying the dis-ease 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, individu-al 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 therapeutics development.
Kidney diseases are well suited to high-throughput research due to the opportunity to examine molecular events in the end organ that is manifesting the disease: kidney biopsy, a standard diag-nostic procedure, provides a unique opportunity to study intrarenal biological processes ex vivo us-ing 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 profil-ing 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 bio-materials originating from the diseased tissues.
EURenOmics has prioritized five disease groups based on their urgent need and significant po-tential for diagnostic and therapeutic progress: Steroid-resistant nephrotic syndrome (SRNS), membranous nephropathy (MN), tubulopathies, complement disorders and malformations of the kidney and urinary tract (CAKUT). The consortium has access to a unique assembly of large exist-ing 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 acquisi-tion 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 cut-ting-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 au-to-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, pepti-dome/proteome, metabolome) in body fluids and renal tissues is performed to identify unique mo-lecular disease signatures (deep phenotyping), develop a prognostically indicative new ontology of rare kidney diseases, discover molecular markers and pathways associated with disease activi-ty 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.

Project Results:
Numerous novel methodologies including groundbreaking diagnostic and disease activity assays and in vivo disease models have been established. A central ‘renal phenome’ database integrating clinical information from local and regional patient registries as well as a unique kidney-focused bioinformatic analysis pipeline including information from >70 Omics databases have been es-tablished.
Exome sequencing has been performed in 186 families (WP2: n=90, WP4: n=37, WP5: n=35, WP6: n=40). These efforts contributed to the discovery of 11 novel SRNS genes, 2 tubulopathy genes, 3 complement disease genes, 4 CAKUT genes, and 11 new genomic rearrangements in complement disorders. Moreover, causative mutations in known genes were found in 20 SRNS, 11 tubulopathy, 10 complement disease and 4 CAKUT families, adding up to a 40% diagnostic yield of exome sequencing. In addition, numerous candidate disease genes are undergoing functional char-acterization.
In parallel, targeted NG sequencing assays capturing all known genes within a disease group have been developed for glomerular (34 genes), tubular (44 genes), complement diseases (13 genes) and CAKUT (two panels, 208/388 genes). So far, panel sequencing has been applied in 1004 SRNS, 610 tubulopathy, 600 atypical hemolytic uremic syndrome (aHUS) and 657 CAKUT cases. Disease causing mutations were identified in 21% of the SRNS, 49% of the tubulopathy, 40% of the aHUS and 6% of the CAKUT patients.
The integration of patient databases and advances in gene diagnostics has allowed deep pheno-typing and genotype-phenotype association studies in the largest cohorts of genetically classi-fied patients assembled to date (e.g., WT1 and ADCK4 glomerulopathy, Schimke syndrome, Dent disease, Bartter syndrome, familial hypercalcemic hypocalciuria, renal Fanconi syndrome, AD tu-bulointerstitial kidney diseases, C3-associated aHUS).
The compilation of large biorepositories fosters unbiased searches for novel diagnostic and prognostic biomarkers. Integrative bioinformatic analysis based on tissue transcriptome infor-mation unsurfaced urinary EGF as a novel biomarker of renal failure progression in adult and pedi-atric patients with chronic kidney disease. Peptidomic, metabolomic and miRNA profiling of body fluids has yielded promising molecular signatures discriminating different forms of SRNS, comple-ment diseases and prenatal CAKUT, which are undergoing further validation.
Fundamental progress in the understanding of genetic disease penetrance was achieved. Mu-tation type dependent interallelic complementation of mutations in compound heterozygous NPHS2 nephropathy and the complementary action of a CFHR1 mutation and a common risk haplotype in the CFH gene in aHUS were identified as novel mechanisms explaining variable phenotype ex-pression in Mendelian and complex genetic disorders respectively.
Major progress was also made concerning the molecular mechanisms of auto-immune dis-ease. The B cell epitope in PLA2R, the target of autoantibodies in MN, has been identified. Aca-demic and industry partners jointly identified the HLA peptidome, paving the way for unbiased iden-tification of immune response targets in autoimmune diseases. In CFH-antibody mediated aHUS autoantibody formation was found to emerge from deficient B-cell regulation by genetic CFHR3 deficiency, demonstrating a mechanistic link between genetic disease and autoimmunity.
Regarding the search for new therapies, drug re-purposing has allowed rapid progress in sever-al areas such as rituximab for MN, eculizumab for secondary aHUS, and CoQ10 supplementation for hereditary mitochondrial podocytopathies. Promising new molecular therapies are tested exper-imentally, including monoclonal C3 and C5a antibodies for complement diseases, ET-1A receptor blockade for NPHS2 glomerulopathy, and flavaglines for TRPM6-associated hypomagnesemia. Bone marrow transplantation, applied successfully in a model of Dent disease, holds promise for certain metabolic nephropathies.

Potential Impact:
The research results expected from EURenOmics will have substantial impact on diagnostic man-agement, risk assignment and preventative and therapeutic strategies in patients with rare kidney diseases, with potential implications also for patients with common kidney and other diseases and the society at large.
Comprehensive exome sequencing of large patient cohorts is profoundly advancing the state of knowledge by unraveling the as yet unknown monogenic and complex genetic causes underly-ing the diseases of interest. The newly discovered genes are continuously included in the targeted next-generation sequencing (NGS) gene arrays developed by the partners. The advent of these NGS panels is considered a major breakthrough as it will render the current sequencing technology with its high cost and time demands obsolete and will make rapid and complete genetic diagnos-tics a routine clinical practice. For those patients in whom a genetic diagnosis cannot be estab-lished, we seek to develop disease-specific peptidomic, metabolomic and miRNA signatures and novel auto-antibody assays.
The availability of such diagnostic tests should constitute a major step towards precision medi-cine. The need for invasive kidney biopsies will be greatly reduced or eliminated. Exposure to inef-fective, potentially toxic and costly medications can be avoided and replaced by rational, risk-adapted therapies tailored to the molecular basis of mechanistically defined disease entities. The recent development of a sensitive and specific bioassay that allows to monitor therapeutic comple-ment blockade and prevent both hazardous under- and costly overtreatment with the C5 inhibitor eculizumab in complement disorders exemplifies the remarkable health and socio-economic impact of the Consortium’s activities.
In addition to the expected diagnostic progress, the anticipated identification of genetic disease causes and risk factors as well as prognostic biomarkers should greatly facilitate individual risk assignment regarding disease occurrence, progression, complications and post-transplant recur-rence compared to the currently used clinical, histopathological or imaging criteria. The efficiency of genetic counselling to families with inherited disorders will be much improved, alleviating their psychological burden and distress. Also, accurate risk assignment will form a basis for the devel-opment of early intervention and secondary prevention protocols.
Moreover, the partners are developing innovative in vitro and in vivo disease models aimed to discover novel therapeutics including alternatives to existing superexpensive drugs, and to allow a more rational, calculated use of already available agents. Our preliminary results and ongoing re-search efforts with respect to in vitro and in vivo model development, the repurposed use of ap-proved pharmaceutical agents to attenuate hereditary and immune-mediated glomerulopathies, the development of novel complement blocking monoclonal antibodies and the early work on activators of mutated magnesium channels look promising and will contribute to the IRDiRC goal of establish-ing new therapies for a significant number of rare diseases by 2020.
Finally, EURenOmics seeks to generate clinical and socioeconomic impact beyond the field of rare kidney disease. The study of the genetic abnormalities and molecular mechanisms underlying the selected disorders is hoped to produce insights into general mechanisms of kidney disease progression and even universal risk factors relevant to the general population. Our identification of a mechanism by which common genetic variation of a kidney-specific protein involved in a rare kid-ney disorder (uromodulin) predisposes to chronic kidney disease and hypertension impressively ex-emplifies the far reaching potential of rare kidney disease research.

List of Websites:
http://www.eurenomics.eu/

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Thorsten Brietz, (Financial Officer)
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Record Number: 196972 / Last updated on: 2017-04-13