Gene therapy with secreted acid alpha-glucosidase rescues Pompe disease in a novel mouse model with early-onset spinal cord and respiratory defects.

Pompe disease (PD) is a neuromuscular disorder caused by deficiency of acidalpha-glucosidase (GAA), leading to motor and respiratory dysfunctions. Available Gaa knock-out (KO) mouse models do not accurately mimic PD, particularly its highly impaired respiratory phenotype. Here we developed a new mouse model of PD crossing Gaa KOB6;129 with DBA2/J mice. We subsequently treated Gaa KODBA2/J mice with adeno-associated virus (AAV) vectors expressing a secretable form of GAA (secGAA). Male Gaa KODBA2/J mice present most of the key features of the human disease, including early lethality, severe respiratory impairment, cardiac hypertrophy and muscle weakness. Transcriptome analyses of Gaa KODBA2/J, compared to the parental Gaa KOB6;129 mice, revealed a profoundly impaired gene signature in the spinal cord and a similarly deregulated gene expression in skeletal muscle. Muscle and spinal cord transcriptome changes, biochemical defects, respiratory and muscle function in the Gaa KODBA2/J model were significantly improved upon gene therapy with AAV vectors expressing secGAA. These data show that the genetic background impacts on the severity of respiratory function and neuroglial spinal cord defects in the Gaa KO mouse model of PD. Our findings have implications for PD prognosis and treatment, show novel molecular pathophysiology mechanisms of the disease and provide a unique model to study PD respiratory defects, which majorly affect patients. This work was supported by Genethon, the French Muscular Dystrophy Association (AFM), the European Commission (grant nos. 667751, 617432, and 797144), and Spark Therapeutics.This work was supported by Genethon and the French Muscular Dystrophy Association (AFM, to F.M.). It was also supported by the European Union’s research and innovation program under grant agreement no. 667751 (to F.M.), the European Research Council Consolidator Grant under grant agreement no. 617432 (to F.M.), Marie Skodowska-Curie Actions Individual Fellowship (MSCA-IF) grant agreement no. 797144 (to U.C.), and by Spark Therapeutics under a sponsored research agreement.S

Co-Administration of Simvastatin Does Not Potentiate the Benefit of Gene Therapy in the mdx Mouse Model for Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is the most common and cureless muscle pediatric genetic disease, which is caused by the lack or the drastically reduced expression of dystrophin. Experimental therapeutic approaches for DMD have been mainly focused in recent years on attempts to restore the expression of dystrophin. While significant progress was achieved, the therapeutic benefit of treated patients is still unsatisfactory. Efficiency in gene therapy for DMD is hampered not only by incompletely resolved technical issues, but likely also due to the progressive nature of DMD. It is indeed suspected that some of the secondary pathologies, which are evolving over time in DMD patients, are not fully corrected by the restoration of dystrophin expression. We recently identified perturbations of the mevalonate pathway and of cholesterol metabolism in DMD patients. Taking advantage of the mdx model for DMD, we then demonstrated that some of these perturbations are improved by treatment with the cholesterol-lowering drug, simvastatin. In the present investigation, we tested whether the combination of the restoration of dystrophin expression with simvastatin treatment could have an additive beneficial effect in the mdx model. We confirmed the positive effects of microdystrophin, and of simvastatin, when administrated separately, but detected no additive effect by their combination. Thus, the present study does not support an additive beneficial effect by combining dystrophin restoration with a metabolic normalization by simvastatin

Enseigner la langue et la littérature du Moyen Âge en France aujourd'hui

Alors que de très nombreuses productions écrites, visuelles, audio-visuelles contemporaines empruntent au Moyen Âge thèmes, objets, figures, moyennant une connaissance des medievalia très variable et une conscience épistémologique tantôt très affirmée, tantôt très floue, voire inexistante, la question de l’éducation de la jeunesse des collèges et lycées au Moyen Âge, à sa langue, à sa littérature et à sa culture en général met face à un défi dont il faut préciser l’urgence et la nécessité. De fait, la connaissance du Moyen Âge ne relève pas d’une problématique « simplement » historique ou scolaire. Elle a également pour enjeu la façon dont notre société se représente elle-même, continument et massivement, dans ses productions écrites, visuelles ou audio-visuelles, au moyen d’emprunts à une matière médiévale largement réélaborée. Plus que toute autre période de l’Histoire européenne, le Moyen Âge et sa culture apparaissent sans ambiguïté comme une matrice propre à mettre en fiction et en scène le contemporain et notre modernité, nos problématiques socio-politiques, économiques, culturelles les plus brûlantes. L’analyse et la compréhension des enjeux de cet investissement sociétal du médiéval par le contemporain nécessite des connaissances a minima que l’école se doit de fournir à ses élèves. Cantonner le Moyen Âge à l’ancien et à l’inessentiel au profit la seule et néanmoins indispensable éducation aux médias, à l’image et au web, c’est prendre le risque d’éduquer à un medium sans donner les outils permettant d’en comprendre le contenu informationnel, son traitement et leur signification profonde. Certes, au-delà du Moyen Âge, c’est toute notre culture commune qui doit être visée. Mais en livrant des pistes de réflexion sur l’enseignement du fait littéraire et linguistique médiéval dans les classes du Secondaire, ce numéro de Perspective Médiévales répond au souci de la Société des Langues et Littératures Médiévales d’Oc et d’Oïl de mieux articuler recherche universitaire et enseignement au collège et au lycée. Sébastien Douche