The effect of neonatal gene therapy on skeletal manifestations in mucopolysaccharidosis VII dogs after a decade

• Published in: Molecular genetics and metabolism 2013-06, Vol.109 (2), p.183-193
• Main Authors: Xing, Elizabeth M., Knox, Van W., O'Donnell, Patricia A., Sikura, Tracey, Liu, Yuli, Wu, Susan, Casal, Margret L., Haskins, Mark E., Ponder, Katherine P.
• Format: Article
• Language: English
• Subjects: Acetabulum; Animals; Animals, Newborn; Dog; Dogs; Dysostosis multiplex; Female; Femur Head - pathology; Gene therapy; Genetic Therapy; Glucuronidase - genetics; Glucuronidase - metabolism; Hindlimb - pathology; Joint Capsule - blood supply; Joint Capsule - enzymology; Joints - pathology; Male; Mucopolysaccharidosis; Mucopolysaccharidosis VII - diagnostic imaging; Mucopolysaccharidosis VII - pathology; Mucopolysaccharidosis VII - therapy; Radiography; Retroviral vector; Treatment Outcome; β-Glucuronidase
• ISSN: 1096-7192; 1096-7206
• DOI: 10.1016/j.ymgme.2013.03.013

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 6months and were dead by 2years. 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 11years of age compared with untreated MPS VII dogs at 2years 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. •The effect of neonatal gene therapy at 6 to 11years after birth is evaluated.•Mobility was maintained in treated dogs.•Many but not all radiographic and histochemical parameters were improved.•These results should predict the effect of enzyme replacement therapy if started at birth.