ScholarlyCommons

Title

Therapeutic Neonatal Hepatic Gene Therapy in Mucopolysaccharidosis VII Dogs

Author(s)

Katherine Parker Ponder
John R. Melniczek
Lingfei Xu
Margaret A. Weil
Thomas M. O'Malley
Patricia A. O'Donnell
Van W. Knox
Gustavo D. Aguirre
Hamutal Mazrier
N Matthew Ellinwood
Margaret M. Sleeper, University of PennsylvaniaFollow
Albert M. Maguire
Susan W. Volk, University of PennsylvaniaFollow
Robert L. Mango
Jean Zweigle, University of PennsylvaniaFollow
John H. WolfeFollow
Mark E. Haskins, University of PennsylvaniaFollow

Document Type

Journal Article

Date of this Version

10-1-2002

Publication Source

Proceedings of the National Academy of Sciences

Volume

99

Issue

20

Start Page

13102

Last Page

13107

DOI

10.1073/pnas.192353499

Abstract

Dogs with mucopolysaccharidosis VII (MPS VII) were injected intravenously at 2–3 days of age with a retroviral vector (RV) expressing canine β-glucuronidase (cGUSB). Five animals received RV alone, and two dogs received hepatocyte growth factor (HGF) before RV in an attempt to increase transduction efficiency. Transduced hepatocytes expanded clonally during normal liver growth and secreted enzyme with mannose 6-phosphate. Serum GUSB activity was stable for up to 14 months at normal levels for the RV-treated dogs, and for 17 months at 67-fold normal for the HGF/RV-treated dog. GUSB activity in other organs was 1.5–60% of normal at 6 months for two RV-treated dogs, which was likely because of uptake of enzyme from blood by the mannose 6-phosphate receptor. The body weights of untreated MPS VII dogs are 50% of normal at 6 months. MPS VII dogs cannot walk or stand after 6 months, and progressively develop eye and heart disease. RV- and HGF/RV-treated MPS VII dogs achieved 87% and 84% of normal body weight, respectively. Treated animals could run at all times of evaluation for 6–17 months because of improvements in bone and joint abnormalities, and had little or no corneal clouding and no mitral valve thickening. Despite higher GUSB expression, the clinical improvements in the HGF/RV-treated dog were similar to those in the RV-treated animals. This is the first successful application of gene therapy in preventing the clinical manifestations of a lysosomal storage disease in a large animal.

Comments

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Recommended Citation

Parker Ponder, K., Melniczek, J. R., Xu, L., Weil, M. A., O'Malley, T. M., O'Donnell, P. A., Knox, V. W., Aguirre, G. D., Mazrier, H., Ellinwood, N. M., Sleeper, M. M., Maguire, A. M., Volk, S. W., Mango, R. L., Zweigle, J., Wolfe, J. H., & Haskins, M. E. (2002). Therapeutic Neonatal Hepatic Gene Therapy in Mucopolysaccharidosis VII Dogs. Proceedings of the National Academy of Sciences, 99 (20), 13102-13107. http://dx.doi.org/10.1073/pnas.192353499