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- Title
Treatment of skeletal and non-skeletal alterations of Mucopolysaccharidosis type IVA by AAV-mediated gene therapy.
- Authors
Bertolin, Joan; Sánchez, Víctor; Ribera, Albert; Jaén, Maria Luisa; Garcia, Miquel; Pujol, Anna; Sánchez, Xavier; Muñoz, Sergio; Marcó, Sara; Pérez, Jennifer; Elias, Gemma; León, Xavier; Roca, Carles; Jimenez, Veronica; Otaegui, Pedro; Mulero, Francisca; Navarro, Marc; Ruberte, Jesús; Bosch, Fatima
- 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. Mucopolysaccharidosis type IVA (MPSIVA) is a lysosomal storage disorder causing severe skeletal and non-skeletal alterations in patients. Here, the authors generate a MPSIVA rat model that mimics the disabling human pathology and develop an AAV9-Galns gene therapy to treat the disease.
- Subjects
GENE therapy; ENZYME replacement therapy; DYSPLASIA; MUCOPOLYSACCHARIDOSIS; ANIMAL disease models; SKELETAL abnormalities
- Publication
Nature Communications, 2021, Vol 12, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-021-25697-y