Bertolin, JoanSánchez, VíctorRibera, AlbertJaén, Maria LuisaGarcia, MiquelPujol, AnnaSánchez, XavierMuñoz, SergioMarcó, SaraPérez, JenniferElias, GemmaLeón, XavierRoca, CarlesJimenez, VeronicaOtaegui, PedroNavarro, MarcRuberte, JesúsBosch, FatimaMulero, Francisca2022-03-072022-03-072021-09-09Nat Commun. 2021;12(1):5343.http://hdl.handle.net/20.500.12105/13728Mucopolysaccharidosis type IVA (MPSIVA) or Morquio A disease, a lysosomal storage disorder, is caused by N-acetylgalactosamine-6-sulfate sulfatase (GALNS) deficiency, resulting in keratan sulfate (KS) and chondroitin-6-sulfate accumulation. Patients develop severe skeletal dysplasia, early cartilage deterioration and life-threatening heart and tracheal complications. There is no cure and enzyme replacement therapy cannot correct skeletal abnormalities. Here, using CRISPR/Cas9 technology, we generate the first MPSIVA rat model recapitulating all skeletal and non-skeletal alterations experienced by patients. Treatment of MPSIVA rats with adeno-associated viral vector serotype 9 encoding Galns (AAV9-Galns) results in widespread transduction of bones, cartilage and peripheral tissues. This led to long-term (1 year) increase of GALNS activity and whole-body correction of KS levels, thus preventing body size reduction and severe alterations of bones, teeth, joints, trachea and heart. This study demonstrates the potential of AAV9-Galns gene therapy to correct the disabling MPSIVA pathology, providing strong rationale for future clinical translation to MPSIVA patients.engVoRhttp://creativecommons.org/licenses/by-nc-sa/4.0/ENZYME-REPLACEMENT THERAPYMOUSE MODELN-ACETYLGALACTOSAMINE-6-SULFATE SULFATASEELOSULFASE ALPHAKERATAN SULFATEDRUG DELIVERYMURINE MODELMPS IVAMORQUIOLIVERDisease Models, AnimalAnimalsCartilage, ArticularChondroitinsulfatasesDependovirusGene Expression Regulation, EnzymologicGenetic TherapyGenetic VectorsHumansMaleMicroscopy, Electron, TransmissionMucopolysaccharidosis IVMusculoskeletal SystemRats, Sprague-DawleyReverse Transcriptase Polymerase Chain ReactionTreatment OutcomeAtribución-NoComercial-CompartirIgual 4.0 Internacional34504088121534310.1038/s41467-021-25697-y2041-1723Nature communicationsopen access