The objective of the proposed research is to use feline and rat models of the human mucopolysaccharidose (MPS) to understand the pathogenesis of these disorders, and to develop and evaluate therapeutic strategies for the treatment of the respective human counterparts. This proposal is a continuation of a long-standing collaboration between investigators at the University of Pennsylvania School of Veterinary Medicine and the Mount Sinai School of Medicine. Previously our laboratories:1) established breeding colonies for the animal models (cats with MPS I & VI, and rats with MPS VI), 2) characterized the clinical course and pathophysiology of each disease, 3) developed biochemical and molecular detection assays for the lysosomal enzymes which are deficient in these diseases, cx-L-iduronidase (ID) and arylsulfatase B (ASB), 4) isolated and expressed human, feline, and rat ASB and feline ID cDNAs, 5) constructed retroviral and adeno-associated viral vectors encoding human and feline ASB and human ID, 6) evaluated bone marrow transplantation(BMT) in MPS I and VI, 7) performed enzyme replacement therapy trials in MPS I, and 8) initiated hematopoietic progenitor cell gene marking experiments in MPS VI.
The specific aims of the current proposal are to: 1) Investigate the pathogenesis of MPS I and VI: (a) continue to evaluate apoptosis and extracellular matrix synthesis involved in the pathogenesis of the skeletal lesions in MPS VI, and begin to study MPS I, (b) evaluate the relationship between improperly degraded glycosaminoglycans (GAGs) and collagen in the cornea and cultured fibroblasts of the MPS animals, (c) determine the ability of sodium magnetic resonance imaging to measure proteoglycans/GAGs in articular cartilage and the CNS for evaluating pathogenesis and therapy, and (d) investigate neuronal patho-physiology in MPS 1. 2) Collaborated in optimizing feline semen and embryo freezing techniques and the development of cloning methods for MPS I and VI cats. 3) Evaluate ganglioside reduction therapy for MPS I CNS disease, alone and in combination with other therapies. 4) Evaluate gene transfer for MPS I and VI using adeno-associated viral and lentiviral vectors, including intra-ocular, intravenous, and intra-cerebral approaches. We anticipated that these animal studies will facilitate our understanding of MPS disease pathogenesis and the development of therapy for the neuronopathic and non-neuronopathic forms.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK025759-26
Application #
6757945
Study Section
Special Emphasis Panel (ZRG1-SSS-2 (02))
Program Officer
Mckeon, Catherine T
Project Start
1979-07-01
Project End
2005-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
26
Fiscal Year
2004
Total Cost
$387,173
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; Louboutin, Jean-Pierre et al. (2015) Neonatal Systemic AAV Induces Tolerance to CNS Gene Therapy in MPS I Dogs and Nonhuman Primates. Mol Ther 23:1298-1307
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
Hinderer, Christian; Bell, Peter; Gurda, Brittney L et al. (2014) Intrathecal gene therapy corrects CNS pathology in a feline model of mucopolysaccharidosis I. Mol Ther 22:2018-27
Hinderer, Christian; Bell, Peter; Gurda, Brittney L et al. (2014) Liver-directed gene therapy corrects cardiovascular lesions in feline mucopolysaccharidosis type I. Proc Natl Acad Sci U S A 111:14894-9
Simonaro, Calogera M; Sachot, Sylvain; Ge, Yi et al. (2013) Acid ceramidase maintains the chondrogenic phenotype of expanded primary chondrocytes and improves the chondrogenic differentiation of bone marrow-derived mesenchymal stem cells. PLoS One 8:e62715
Ferla, Rita; O'Malley, Thomas; Calcedo, Roberto et al. (2013) Gene therapy for mucopolysaccharidosis type VI is effective in cats without pre-existing immunity to AAV8. Hum Gene Ther 24:163-9
Malik, Saafan Z; Lewis, Melissa; Isaacs, Alison et al. (2012) Identification of the rostral migratory stream in the canine and feline brain. PLoS One 7:e36016
Sewell, Adrian C; Haskins, Mark E; Giger, Urs (2012) Dried blood spots for the enzymatic diagnosis of lysosomal storage diseases in dogs and cats. Vet Clin Pathol 41:548-57
Ponder, Katherine P; O'Malley, Thomas M; Wang, Ping et al. (2012) Neonatal gene therapy with a gamma retroviral vector in mucopolysaccharidosis VI cats. Mol Ther 20:898-907
Cianciolo, Rachel E; Rhodes, James L; Haskins, Mark E et al. (2011) Renal failure associated with mucopolysaccharidosis type I in a cat from a MPS I research colony. Comp Med 61:441-4

Showing the most recent 10 out of 71 publications