LAURÉAT 2019
Dr Guy LENAERS
Le Docteur Guy Lenaers est Directeur de MitoLab (unité mixte CNRS et INSERM) et Directeur du Pôle de Recherche et d’Enseignement en Médecine Mitochondriale (PREMMI), en relation avec le CHU et l’Université d’Angers. L'objectif principal est de lutter contre la cécité génétique de l'enfant, d’identifier l’origine génétique des NOH chez des patients âgés de moins de 12 ans dans la perspective d’améliorer le conseil génétique et de définir des voies thérapeutiques permettant de ralentir l’évolution de la perte de vision chez ces enfants.
THÈME DE RECHERCHE :
« Metabolic analysis of RTN4IP1 alleles responsible for Optic Neuropathies and Mitochondrial Encephalopathies »
SUBVENTION JED : 15.000 €
OBJECTIF DU PROJET :
Inherited Optic Neuropathies (ION) and Mitochondrial Encephalopathies (MiEnc) may share a common genetic origin, with gene mutations affecting differently the protein function. This is the case for RTN4IP1, for which we have identified the first recessive mutations responsible for a gradient of clinical phenotypes ranging from isolated ION to very severe MiEnc (MIM 616732). In all cases, an alteration of the mitochondrial function is the culprit mechanism, as RTN4IP1 encodes a matricial protein possibly involved in the respiratory complex I assembly. Nevertheless, the differential consequences of RTN4IP1mutations on the mitochondrial physiology and cellular metabolism remain poorly described.
Our proposal consists in gaining deep comparative insights in the pathophysiology of IONs and MiEnc related to RTN4IP1 mutations, using a panel of technologies to describe mitochondrial physiology and metabolomics signature. Together, these recent and powerful technologies, inspiring the concept of precision medicine dedicated to rare diseases, allow characterizing the disease pathophysiology and the opening of new routes for therapies.
To reach these goals, using the CRISPR-Cas9 technology, we will create neuronal cell lines deleted for RTN4IP1, in which we will then express constitutively pathogenic RTN4IP1 alleles responsible for ION and MiEnc. From each cell line, we will analyze the extensive mitochondrial physiology and perform non- target metabolomics. Statistical analyses will benefit from our solid expertise in univariate/multivariate, parametric/non-parametric and supervised/non-supervised data analysis methods, applied to large sets of data. Comparative interpretation of the data should point on mechanisms and metabolites characterizing the status of the two diseases (IONs vs MiEnc) and the mitochondrial functions of RTN4IP1, and provide routes and criteria to evaluate therapeutic pathways to reduce the severity of the symptoms associated to these pathologies.