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Treatment of Skeletal and Non-Skeletal Alterations of Mucopolysaccharidosis Type IVA by AAV-Mediated Gene Therapy

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source: Nature communications

year: 2021

authors: Bertolin J,Sánchez V,Ribera A,Jaén ML,Garcia M,Pujol A,Sánchez X,Muñoz S,Marcó S,Pérez J,Elias G,León X,Roca C,Jimenez V,Otaegui P,Mulero F,Navarro M,Ruberte J,Bosch F


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.

organization: Center of Animal Biotechnology and Gene Therapy, Bellaterra, Spain.

DOI: 10.1038/s41467-021-25697-y

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