Treatment of skeletal and non-skeletal alterations of Mucopolysaccharidosis type IVA by AAV-mediated gene therapy

Joan Bertolin, Víctor Sánchez, Albert Ribera, Maria Luisa Jaén, Miquel Garcia, Anna Pujol, Xavier Sánchez, Sergio Muñoz, Sara Marcó, Jennifer Pérez, Gemma Elias, Xavier León, Carles Roca, Veronica Jimenez, Pedro Otaegui, Francisca Mulero, Marc Navarro, Jesús Ruberte, Fatima Bosch

Research output: Contribution to journalArticleResearchpeer-review

8 Citations (Scopus)


Mucopolysaccharidosis 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.

Original languageEnglish
Article number5343
Number of pages14
JournalNature communications
Issue number1
Publication statusPublished - 9 Sept 2021


  • Animals
  • Cartilage, Articular/metabolism
  • Chondroitinsulfatases/deficiency
  • Dependovirus/genetics
  • Disease Models, Animal
  • Gene Expression Regulation, Enzymologic
  • Genetic Therapy/methods
  • Genetic Vectors/genetics
  • Humans
  • Male
  • Microscopy, Electron, Transmission
  • Mucopolysaccharidosis IV/enzymology
  • Musculoskeletal System/metabolism
  • Rats, Sprague-Dawley
  • Reverse Transcriptase Polymerase Chain Reaction
  • Treatment Outcome


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