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 and 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, we demonstrated that neonatal intravenous injection of a gamma 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 6 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. We 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. This grant is designed to test several viral vectors to transfer the normal gene to dogs that have a naturally occurring genetic disease, mucopolysaccharidosis VII. The dogs and children with this and similar lysosomal storage diseases have abnormal corneas, heart valves, skeleton, and brain and the approaches we are testing are to determine a long-term safe and effective therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK054481-17
Application #
8242708
Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Mckeon, Catherine T
Project Start
1994-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2014-03-31
Support Year
17
Fiscal Year
2012
Total Cost
$466,606
Indirect Cost
$152,147
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Veterinary Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Hinderer, Christian; Bell, Peter; Katz, Nathan et al. (2018) Evaluation of Intrathecal Routes of Administration for Adeno-Associated Viral Vectors in Large Animals. Hum Gene Ther 29:15-24
Gurda, Brittney L; De Guilhem De Lataillade, Adrien; Bell, Peter et al. (2016) Evaluation of AAV-mediated Gene Therapy for Central Nervous System Disease in Canine Mucopolysaccharidosis VII. Mol Ther 24:206-216
Peck, Sun H; Casal, Margret L; Malhotra, Neil R et al. (2016) Pathogenesis and treatment of spine disease in the mucopolysaccharidoses. Mol Genet Metab 118:232-43
Simonaro, Calogera M; Tomatsu, Shunji; Sikora, Tracy et al. (2016) Pentosan Polysulfate: Oral Versus Subcutaneous Injection in Mucopolysaccharidosis Type I Dogs. PLoS One 11:e0153136
Flanagan-Steet, Heather; Aarnio, Megan; Kwan, Brian et al. (2016) Cathepsin-Mediated Alterations in TGFß-Related Signaling Underlie Disrupted Cartilage and Bone Maturation Associated With Impaired Lysosomal Targeting. J Bone Miner Res 31:535-48
Hinderer, Christian; Bell, Peter; Louboutin, Jean-Pierre et al. (2016) Neonatal tolerance induction enables accurate evaluation of gene therapy for MPS I in a canine model. Mol Genet Metab 119:124-30
Peck, Sun H; O'Donnell, Philip J M; Kang, Jennifer L et al. (2015) Delayed hypertrophic differentiation of epiphyseal chondrocytes contributes to failed secondary ossification in mucopolysaccharidosis VII dogs. Mol Genet Metab 116:195-203
Bradbury, Allison M; Gurda, Brittney L; Casal, Margret L et al. (2015) A review of gene therapy in canine and feline models of lysosomal storage disorders. Hum Gene Ther Clin Dev 26:27-37
Xing, Elizabeth M; Wu, Susan; Ponder, Katherine P (2015) The effect of Tlr4 and/or C3 deficiency and of neonatal gene therapy on skeletal disease in mucopolysaccharidosis VII mice. Mol Genet Metab 114:209-16
Swain, G P; Prociuk, M; Bagel, J H et al. (2014) Adeno-associated virus serotypes 9 and rh10 mediate strong neuronal transduction of the dog brain. Gene Ther 21:28-36

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