Show simple item record

dc.contributor.authorCagin, Umut
dc.contributor.authorPuzzo, Francesco
dc.contributor.authorGomez, Manuel J 
dc.contributor.authorMoya-Nilges, Maryse
dc.contributor.authorSellier, Pauline
dc.contributor.authorAbad, Catalina
dc.contributor.authorvan Wittenberghe, Laetitia
dc.contributor.authorDaniele, Nathalie
dc.contributor.authorGuerchet, Nicolas
dc.contributor.authorGjata, Bernard
dc.contributor.authorCollaud, Fanny
dc.contributor.authorCharles, Severine
dc.contributor.authorSola, Marcelo Simon
dc.contributor.authorBoyer, Olivier
dc.contributor.authorKrijnse-Locker, Jacomina
dc.contributor.authorRonzitti, Giuseppe
dc.contributor.authorColella, Pasqualina
dc.contributor.authorMingozzi, Federico
dc.identifier.citationMol Ther. 2020; 28(9):2056-2072es_ES
dc.description.abstractPompe disease is a neuromuscular disorder caused by disease-associated variants in the gene encoding for the lysosomal enzyme acid α-glucosidase (GAA), which converts lysosomal glycogen to glucose. We previously reported full rescue of Pompe disease in symptomatic 4-month-old Gaa knockout (Gaa-/-) mice by adeno-associated virus (AAV) vector-mediated liver gene transfer of an engineered secretable form of GAA (secGAA). Here, we showed that hepatic expression of secGAA rescues the phenotype of 4-month-old Gaa-/- mice at vector doses at which the native form of GAA has little to no therapeutic effect. Based on these results, we then treated severely affected 9-month-old Gaa-/- mice with an AAV vector expressing secGAA and followed the animals for 9 months thereafter. AAV-treated Gaa-/- mice showed complete reversal of the Pompe phenotype, with rescue of glycogen accumulation in most tissues, including the central nervous system, and normalization of muscle strength. Transcriptomic profiling of skeletal muscle showed rescue of most altered pathways, including those involved in mitochondrial defects, a finding supported by structural and biochemical analyses, which also showed restoration of lysosomal function. Together, these results provide insight into the reversibility of advanced Pompe disease in the Gaa-/- mouse model via liver gene transfer of secGAA.es_ES
dc.description.sponsorshipThis work was supported by Genethon, the French Muscular Dystro-phy Association (AFM), and Spark Therapeutics. It was also sup-ported by the European Union’s Research and Innovation Programunder grant agreement number 667751 (to F.M.), the EuropeanResearch Council Consolidator Grant under grant agreement number617432 (to F.M.), and Marie Skłodowska-Curie Actions-IndividualFellowship (MSCA-IF) grant agreement number 797144 (to U.C.)es_ES
dc.publisherCell Press es_ES
dc.titleRescue of Advanced Pompe Disease in Mice with Hepatic Expression of Secretable Acid α-Glucosidase.es_ES
dc.typejournal articlees_ES
dc.rights.licenseAttribution-NonCommercial-NoDerivatives 4.0 Internacional*
dc.contributor.funderGenethon (Francia) 
dc.contributor.funderFrench Muscular Dystrophy Association 
dc.contributor.funderSpark Therapeutics (Estados Unidos) 
dc.contributor.funderUnión Europea 
dc.contributor.funderEuropean Research Council 
dc.contributor.funderMinisterio de Ciencia e Innovación (España) 
dc.identifier.journalMolecular therapy : the journal of the American Society of Gene Therapyes_ES
dc.repisalud.orgCNICCNIC::Unidades técnicas::Bioinformáticaes_ES
dc.rights.accessRightsopen accesses_ES

Files in this item

Acceso Abierto
Acceso Abierto

This item appears in the following Collection(s)

Show simple item record

Attribution-NonCommercial-NoDerivatives 4.0 Internacional
This item is licensed under a: Attribution-NonCommercial-NoDerivatives 4.0 Internacional