The mucopolysaccharidoses (MPS), a major class of lysosomal storage diseases, are a promising target for somatic cell gene therapy. That normal enzyme is synthesized and exported by normal cells and can be taken up by, and can correct, the metabolic defect in affected cells (defined as cross-correction) has been demonstrated in cocultures of affected and normal cells, as well as by bone marrow transplantation in a limited number of human and animal patients. These studies indicate that if a sufficient number of cells producing normal enzyme can be introduced into the patient, significant improvement can be expected. The number of cells need not be large. If the transplanted cells engraft and continue to multiply in sufficient numbers, improvement should be long-term. However, problems associated with histocompatibility limit heterologous transplantation as an approach to therapy. Somatic cell gene therapy is potentially a way of circumventing the problems associated with the immune response, as well as providing a more adequate source of normal enzyme for diverse tissues. In gene therapy studies of a number of different cultured cell types from human and canine patients with MPS VII, we have previously shown that the metabolic defect, including storage of glycosaminoglycans (GAG), is corrected by retroviral transfer of the normal gene for beta- glucuronidase (GUSB). In this proposal, we extend those in vitro studies to therapeutic strategies conducted in vivo in the mouse and canine homologues of MPS VII. These studies will serve as models for correction of MPS diseases by somatic cell gene therapy, and more generally, for the large class of lysosomal storage diseases. The following approaches will be tested: 1) An organoid system using autologous vector-corrected fibroblasts first in MPS VII mice and then dogs to choose long-term, high expression candidate vectors; 2) Autologous bone marrow transplantation in canine MPS VII using vector-mediated transfer to hematopoietic cells; and 3) Gene transfer to hepatocytes in vivo. The effects of the therapeutic strategies will be determined by experiments utilizing littermate controls and will include extensive clinical evaluations, comprehensive light and electron microscopic studies of tissues, enzyme assays, and quantitation of stored substrate in various tissues.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK054481-08
Application #
6381243
Study Section
Special Emphasis Panel (ZRG3-BIO (01))
Program Officer
Mckeon, Catherine T
Project Start
1994-04-01
Project End
2003-03-31
Budget Start
2001-04-01
Budget End
2003-03-31
Support Year
8
Fiscal Year
2001
Total Cost
$313,152
Indirect Cost
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
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
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
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

Showing the most recent 10 out of 56 publications