Projet ANR-08-GENO-0036 – PROGERIA : Validation de modèles cellulaires et murins de Progeria et leur utilisation pré-clinique pour le développement d¿outils thérapeutiques
Programme : Du gène à la physiopathologie, des maladies rares aux maladies communes (GENOPAT) 2008
Année de financement : 2008
Coordinateur du projet : INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE - DÉLÉGATION RÉGIONALE PROVENCE ALPES CÔTE D'AZUR ET CORSE (INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE - Délégation régionale Provence Alpes Côte d'Azur et Corse)
Partenaires : Institut national de la santé et de la recherche médicale; Institut national de la santé et de la recherche médicale
Montant : 350000.0 euros
Date de début : 2009
Durée : 36 mois
Résumé : In the last 4 years, several dat on pathophysioogy of Prelamin A associated disorders have been obtained by our group and others. After these disorders have been widely explored from patient's cells and existing animals models, and even in a very promising and fast advancing context, they are only partially understood and all the therapeutic approaches developed to date are far from being imaginated as a definitive cure for Progeria. On the one hand, all of the existing mouse models having been developed and used in Progeria's studies to date, lack to perfectly reproduce either the clinical phenotype, or the cellular and pathophysiological defects; on the other hand, cells and tissues are very difficult to collect from progeria's patients, and affected pathways in these patient's cells have only been partially studied and compared to animal's cells.  Towards better understanding Progeria and related disorders, we designed and generated two specific Progeria mouse models which, in our view, should represent the only "authentic" models for Progeria. One of these models consists in a transgenic (tg) mouse over-expressing the toxic protein (Progerin) as produced in Progeria; the other model is a Knock-in model in which the most common mutation associated to Progeria, activating a cryptic splicing site in LMNA, has been introduced. Besides, we have access to biological resources from patients. 
Our present project will thus benefit of new pertinent Progeria's mouse models as well as patient's cells (lymphoblasts, fibroblasts and endothelial circulating cells) obtained during hospital visits of patients during after the clinical trial, planned over the next 3 years, has started.
This project will aim : (i) to deeply explore the pathophysiology of Progeria from the human and mouse resources; (ii) to validate these resources as being pertinent towards becoming preclinical models; and (iii) to perform, as preclinical tests both in vitro (patient's and mouse cells) and in vivo (progeria mouse models), treatments by using different existing prenylation inhibitors, alone or in combination and explore their beneficial effects at the clinical (mouse), molecular and cellular level. 
 Such explorations and subsequent results, should have a short/medium term impact on the clinical management of patients. Although we do not necessarily expect to drastically reduce the dramatic consequences associated to Progeria, we hope, more reasonably, to obtain preventive effects on bone lesions and heart failure, as well as extending the lifespan.