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.
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