Résumé :
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Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant inherited, slow progressing, late onset degenerative muscle disorder, characterized by progressive eyelid drooping (ptosis) and difficulties with swallowing (dysphagia). The pharyngeal and cricopharyngeal muscles (CPM) are among the specific targets in OPMD. The genetic mutation is an abnormal expansion of a (GCG)n repeat in the coding region of the poly(A) binding protein nuclear 1 (PABPN1) gene, leading to an expanded polyalanine tract at the N-terminal of the protein. PABPN1 is a ubiquitously expressed polyadenylation factor, implicated in the maturation of mRNA. The main pathological hallmark of the disease is intranuclear aggregates of mutated PABPN1. In OPMD, although the cause of the disease and the consequences on affected muscles are known, the physiopathological mechanisms leading from the mutation to the alteration of the myogenic program remain to be determined. We have demonstrated that cell cultures isolated from non-affected muscles have a normal proliferation and differentiation phenotype, whereas cultures isolated from affected muscles have a reduced myogenicity and proliferative capacity as compared to control cells. Since OPMD is selectively expressed in defined group of small muscles and satellite cells can be isolated and amplified from non-affected muscles, a pilot phase I-II study of cell therapy has being conducted for the first time in OPMD patients, consisting of the grafting of autologous non affected myoblasts into the pharyngeal muscle during a myotomy. 12 patients have been treated, a very good tolerance has been observed and the functional evaluation of these patients is on-going.In the frame of the clinical trial, we have obtained muscle biopsies from OPMD patients obtained during the grafting procedure. From these biopsies, we have isolated and immortalized muscle progenitors cells to provide us with valid in vitro models both to study the physiopathology of OPMD and to evaluate therapeutic strategy. To analyze the physiopathological mechanisms triggered by the OPMD mutation, we are comparing in parallel myoblasts from affected and non-affected muscles of the same OPMD patients as well as with cultures from age matched controls, using cellular and molecular approaches. These studies should help us to better understand the pathological processes involved in this disease, to determine why it is restricted to certain muscles, and to distinguish the mechanisms which are common to normal muscle ageing from those specific of this disease.
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