Servicio de Información Comunitario sobre Investigación y Desarrollo - CORDIS


OSAI Informe resumido

Project ID: 322947
Financiado con arreglo a: FP7-IDEAS-ERC
País: France

Mid-Term Report Summary - OSAI (Membranous nephropathy : a model for solving organ-specific auto-immunity (OSAI))

Membranous nephropathy (MN) is a rare disease that affects the kidney glomerulus and is responsible for massive urinary loss of proteins and renal failure in 30% of patients. It results in the formation of immune deposits on the outer aspect of the glomerular basement membrane and formation of the membrane attack complex of complement (MAC) which is the major effector of proteinuria. Since the recent identification of podocyte target antigens, it is considered a model of organ-specific auto-immune disease. Our objectives are to get further insight into the genetic and immunologic mechanisms of the disease and to propose new treatments by using innovative and cutting-edge technological approaches.
By using random peptide libraries, we have identified immunodominant conformational epitopes on neutral endopeptidase (NEP) responsible for neonatal allo-immune disease, which opens the way to specific immunoadsorption in the mothers and to identification of additional epitopes on PLA2R antigen associated with adult MN. We have contributed to the description of a new family of allo-immune MN caused by enzyme replacement therapy (aryl sulfatase) which could be resumed after tolerance induction.
We have embarked on a genetic program aimed to identify triggering factors and genetic variants. By sequencing the HLA-D locus, we have identified risk and protective allelotypes and are currently investigating the critical amino acid residues in the groove of the HLA class II molecule which facilitate the binding of PLA2R derived peptides. This approach combined to a holistic analysis of the circulating HLA class II peptidome (collaboration with Dario Neri and Tim Fugmann involving soon an ERC postdoc, Zürich) will hopefully provide new insights into triggering factors and molecular mimicry.
We have shown that anti-NEP IgG1 antibodies can serve as effectors by blocking enzymatic activity in addition to activating complement, and that activation of the mannose binding lectin pathway is not mandatory for the development of full-blown MN. Because MAC is a major mediator of proteinuria, one of our major goals is to contribute to the design new inhibitors of the C3 and C5 convertases by covalent docking and of the MAC assembly (collaboration with Bogdan Iorga involving an ERC postdoc, Paris). This program is run in parallel with Jean-Christophe Cintrat at the Saclay high-throughput screening platform where one of our engineers will be screening the Prestwick library, the protein-protein interaction inhibition (2P2I) chemical library as well as the compounds tested in silico by Bogdan Iorga.
In order to increase the availability of drugs at the podocyte where injury occurs and to reduce risks of severe adverse events by systemic administration, we have established collaboration with Clément Sanchez group at the Collège de France for the use of a new generation nanovectors (quantum rattles) which can be loaded with anti-complement or cytoprotective compounds.
During the first half of the ERC contract, we have set up the tools and collaborations which hopefully will provide breakthroughs in pathophysiology and treatment of MN, and much beyond of organ-specific auto-immune disorders. In parallel, we have been proactive in knowledge and technology transfer by using the PLA2R assays in retrospective studies and controlled trials of patients with MN treated with rituximab, which contributed to establish the high prognostic value of PLA2R as a biomarker. We also applied our genetics knowledge and technology to the study of steroid sensitive nephrotic syndrome, a disease with some intriguing commonalities with MN, which led to identification of a haploblock at 6p21, containing HLA-DR genes as well as the HLA-DQA1 and -DQB1 genes, significantly associated with the disease.

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