Mucopolysaccharidosis VII (MPS VII) is a rare lysosomal storage disease caused by deficient ?-glucuronidase (GUSB) activity, resulting in the accumulation of glycosaminoglycans (GAG). The severe form has bone and joint abnormalities, pulmonary and cardiac disease, visual deficiencies, mental retardation, and death before adulthood. The development of an effective and safe gene therapy for MPS VII could have a dramatic positive impact on the lives of patients as well as the families that care for them. Importantly, it can serve as a paradigm for other MPS syndromes or lysosomal storage diseases (LSDs). In the previous funding period, the investigators demonstrated that neonatal intravenous injection of a ?-retroviral vector (RV) with an intact long-terminal repeat (LTR) expressing canine GUSB resulted in efficient transduction of liver cells in both mice and dogs with MPS VII. Hepatocytes secreted mannose 6-phosphate (M6P)-modified GUSB into the blood, which diffused to other organs, was taken up via the M6P receptor on the plasma membrane of cells, and was trafficked to the lysosomes. Some blood cells were also transduced, which may have contributed to the therapeutic response. The effect was truly remarkable, with elimination or reduction of all major clinical manifestations for more than six years in dogs. Although no tumors developed in mice or dogs with this approach, the risk of insertional mutagenesis with an LTR-intact vector is a concern. An alternative approach is to perform ex vivo transduction of hematopoietic stem cells (HSC) with a lentiviral vector (LV). The laboratory of Dr. Mark Sands has demonstrated that this approach can effectively treat MPS VII mice, and has developed a LV that expresses the human GUSB cDNA. However, the long-term efficacy and safety of this approach in a large animal model has not yet been tested.
The aims of this renewal application are to: 1) reduce the risk of insertional mutagenesis by developing a self-inactivating RV with deletion of the enhancer of the LTR for neonatal intravenous therapy, and 2) evaluate ex vivo hematopoietic stem cell transduction with a self-inactivating LV. The investigators will analyze all treated MPS VII dogs long-term for the efficacy and safety of gene therapy, and maintain the MPS VII dog colony for future studies. If successful, this study should hasten the development of a simple and effective treatment for reducing or preventing the devastating clinical manifestations of MPS VII and lead the way for treating other LSDs.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Pediatrics Subcommittee (CHHD)
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Mckeon, Catherine T
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University of Pennsylvania
Schools of Veterinary Medicine
United States
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