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dc.contributor.authorColella, Pasqualina
dc.contributor.authorSellier, Pauline
dc.contributor.authorGomez, Manuel J 
dc.contributor.authorBiferi, Maria G
dc.contributor.authorTanniou, Guillaume
dc.contributor.authorGuerchet, Nicolas
dc.contributor.authorCohen-Tannoudji, Mathilde
dc.contributor.authorMoya-Nilges, Maryse
dc.contributor.authorvan Wittenberghe, Laetitia
dc.contributor.authorDaniele, Natalie
dc.contributor.authorGjata, Bernard
dc.contributor.authorKrijnse-Locker, Jacomina
dc.contributor.authorCollaud, Fanny
dc.contributor.authorSimon-Sola, Marcelo
dc.contributor.authorCharles, Severine
dc.contributor.authorCagin, Umut
dc.contributor.authorMingozzi, Federico
dc.identifier.citationEBioMedicine. 2020; 61:103052es_ES
dc.description.abstractPompe 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.es_ES
dc.description.sponsorshipThis 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.es_ES
dc.publisherElsevier es_ES
dc.titleGene therapy with secreted acid alpha-glucosidase rescues Pompe disease in a novel mouse model with early-onset spinal cord and respiratory defects.es_ES
dc.typejournal articlees_ES
dc.rights.licenseAttribution-NonCommercial-NoDerivatives 4.0 Internacional*
dc.contributor.funderFrench Muscular Dystrophy Association 
dc.contributor.funderUnión Europea 
dc.contributor.funderEuropean Research Council 
dc.repisalud.orgCNICCNIC::Unidades técnicas::Bioinformáticaes_ES
dc.rights.accessRightsopen accesses_ES

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Attribution-NonCommercial-NoDerivatives 4.0 Internacional
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