TY - JOUR
T1 - Treatment of skeletal and non-skeletal alterations of Mucopolysaccharidosis type IVA by AAV-mediated gene therapy
AU - Bertolin, Joan
AU - Sánchez, Víctor
AU - Ribera, Albert
AU - Jaén, Maria Luisa
AU - Garcia, Miquel
AU - Pujol, Anna
AU - Sánchez, Xavier
AU - Muñoz, Sergio
AU - Marcó, Sara
AU - Pérez, Jennifer
AU - Elias, Gemma
AU - León, Xavier
AU - Roca, Carles
AU - Jimenez, Veronica
AU - Otaegui, Pedro
AU - Mulero, Francisca
AU - Navarro, Marc
AU - Ruberte, Jesús
AU - Bosch, Fatima
N1 - © 2021. The Author(s).
PY - 2021/9/9
Y1 - 2021/9/9
N2 - 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.
AB - 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.
KW - Animals
KW - Cartilage, Articular/metabolism
KW - Chondroitinsulfatases/deficiency
KW - Dependovirus/genetics
KW - Disease Models, Animal
KW - Gene Expression Regulation, Enzymologic
KW - Genetic Therapy/methods
KW - Genetic Vectors/genetics
KW - Humans
KW - Male
KW - Microscopy, Electron, Transmission
KW - Mucopolysaccharidosis IV/enzymology
KW - Musculoskeletal System/metabolism
KW - Rats, Sprague-Dawley
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - Treatment Outcome
U2 - 10.1038/s41467-021-25697-y
DO - 10.1038/s41467-021-25697-y
M3 - Article
C2 - 34504088
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 5343
ER -