Por favor, use este identificador para citar o enlazar este Item:http://hdl.handle.net/20.500.12105/13728
Título
Treatment of skeletal and non-skeletal alterations of Mucopolysaccharidosis type IVA by AAV-mediated gene therapy.
Autor(es)
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 | Navarro, Marc | Ruberte, Jesús | Bosch, Fatima | Mulero, Francisca CNIO
Fecha de publicación
2021-09-09
Cita
Nat Commun. 2021;12(1):5343.
Idioma
Inglés
Tipo de documento
journal article
Resumen
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.
Palabras clave
ENZYME-REPLACEMENT THERAPY | MOUSE MODEL | N-ACETYLGALACTOSAMINE-6-SULFATE SULFATASE | ELOSULFASE ALPHA | KERATAN SULFATE | DRUG DELIVERY | MURINE MODEL | MPS IVA | MORQUIO | LIVER
MESH
Disease Models, Animal | Animals | Cartilage, Articular | Chondroitinsulfatases | Dependovirus | Gene Expression Regulation, Enzymologic | Genetic Therapy | Genetic Vectors | Humans | Male | Microscopy, Electron, Transmission | Mucopolysaccharidosis IV | Musculoskeletal System | Rats, Sprague-Dawley | Reverse Transcriptase Polymerase Chain Reaction | Treatment Outcome
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