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 and Fatima Bosch ()
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Joan Bertolin: Center of Animal Biotechnology and Gene Therapy
Víctor Sánchez: Center of Animal Biotechnology and Gene Therapy
Albert Ribera: Center of Animal Biotechnology and Gene Therapy
Maria Luisa Jaén: Center of Animal Biotechnology and Gene Therapy
Miquel Garcia: Center of Animal Biotechnology and Gene Therapy
Anna Pujol: Center of Animal Biotechnology and Gene Therapy
Xavier Sánchez: Center of Animal Biotechnology and Gene Therapy
Sergio Muñoz: Center of Animal Biotechnology and Gene Therapy
Sara Marcó: Center of Animal Biotechnology and Gene Therapy
Jennifer Pérez: Center of Animal Biotechnology and Gene Therapy
Gemma Elias: Center of Animal Biotechnology and Gene Therapy
Xavier León: Center of Animal Biotechnology and Gene Therapy
Carles Roca: Center of Animal Biotechnology and Gene Therapy
Veronica Jimenez: Center of Animal Biotechnology and Gene Therapy
Pedro Otaegui: Center of Animal Biotechnology and Gene Therapy
Francisca Mulero: Molecular Imaging Unit, Spanish National Cancer Research Center (CNIO)
Marc Navarro: Center of Animal Biotechnology and Gene Therapy
Jesús Ruberte: Center of Animal Biotechnology and Gene Therapy
Fatima Bosch: Center of Animal Biotechnology and Gene Therapy

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-25697-y

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