TY - JOUR
T1 - The effect of neonatal gene therapy on skeletal manifestations in mucopolysaccharidosis VII dogs after a decade
AU - Xing, Elizabeth M.
AU - Knox, Van W.
AU - O'Donnell, Patricia A.
AU - Sikura, Tracey
AU - Liu, Yuli
AU - Wu, Susan
AU - Casal, Margret L.
AU - Haskins, Mark E.
AU - Ponder, Katherine P.
N1 - Funding Information:
This study was funded by grants from the NIH ( DK054481 , HD061879 , R;R02512 , P30 DK52574 ) and the National MPS Society.
PY - 2013/6
Y1 - 2013/6
N2 - Mucopolysaccharidosis (MPS) VII is a lysosomal storage disease due to deficient activity of β-glucuronidase (GUSB), and results in glycosaminoglycan accumulation. Skeletal manifestations include bone dysplasia, degenerative joint disease, and growth retardation. One gene therapy approach for MPS VII involves neonatal intravenous injection of a gamma retroviral vector expressing GUSB, which results in stable expression in liver and secretion of enzyme into blood at levels predicted to be similar or higher to enzyme replacement therapy. The goal of this study was to evaluate the long-term effect of neonatal gene therapy on skeletal manifestations in MPS VII dogs. Treated MPS VII dogs could walk throughout their lives, while untreated MPS VII dogs could not stand beyond 6. months and were dead by 2. years. Luxation of the coxofemoral joint and the patella, dysplasia of the acetabulum and supracondylar ridge, deep erosions of the distal femur, and synovial hyperplasia were reduced, and the quality of articular bone was improved in treated dogs at 6 to 11. years of age compared with untreated MPS VII dogs at 2. years or less. However, treated dogs continued to have osteophyte formation, cartilage abnormalities, and an abnormal gait. Enzyme activity was found near synovial blood vessels, and there was 2% as much GUSB activity in synovial fluid as in serum. We conclude that neonatal gene therapy reduces skeletal abnormalities in MPS VII dogs, but clinically-relevant abnormalities remain. Enzyme replacement therapy will probably have similar limitations long-term.
AB - Mucopolysaccharidosis (MPS) VII is a lysosomal storage disease due to deficient activity of β-glucuronidase (GUSB), and results in glycosaminoglycan accumulation. Skeletal manifestations include bone dysplasia, degenerative joint disease, and growth retardation. One gene therapy approach for MPS VII involves neonatal intravenous injection of a gamma retroviral vector expressing GUSB, which results in stable expression in liver and secretion of enzyme into blood at levels predicted to be similar or higher to enzyme replacement therapy. The goal of this study was to evaluate the long-term effect of neonatal gene therapy on skeletal manifestations in MPS VII dogs. Treated MPS VII dogs could walk throughout their lives, while untreated MPS VII dogs could not stand beyond 6. months and were dead by 2. years. Luxation of the coxofemoral joint and the patella, dysplasia of the acetabulum and supracondylar ridge, deep erosions of the distal femur, and synovial hyperplasia were reduced, and the quality of articular bone was improved in treated dogs at 6 to 11. years of age compared with untreated MPS VII dogs at 2. years or less. However, treated dogs continued to have osteophyte formation, cartilage abnormalities, and an abnormal gait. Enzyme activity was found near synovial blood vessels, and there was 2% as much GUSB activity in synovial fluid as in serum. We conclude that neonatal gene therapy reduces skeletal abnormalities in MPS VII dogs, but clinically-relevant abnormalities remain. Enzyme replacement therapy will probably have similar limitations long-term.
KW - Dog
KW - Dysostosis multiplex
KW - Gene therapy
KW - Mucopolysaccharidosis
KW - Retroviral vector
KW - β-Glucuronidase
UR - http://www.scopus.com/inward/record.url?scp=84878515331&partnerID=8YFLogxK
U2 - 10.1016/j.ymgme.2013.03.013
DO - 10.1016/j.ymgme.2013.03.013
M3 - Article
C2 - 23628461
AN - SCOPUS:84878515331
SN - 1096-7192
VL - 109
SP - 183
EP - 193
JO - Molecular genetics and metabolism
JF - Molecular genetics and metabolism
IS - 2
ER -