The broad long-term goal is to evaluate experimental therapy for lysosomal storage diseases using the murine MPS VII model of beta-glucuronidase deficiency.
The specific aims determine the therapeutic efficacy of bone marrow transplantation (BMT), liver transplantation, retroviral mediated somatic gene transfer, and enzyme replacement therapies. Preliminary results suggested that early and aggressive enzyme replacement therapy is important in neonatal MPS VII mice during rapid development of the skeletal system and central nervous system. Enzyme replacement has the additional apparent advantage of having little risk compared to transplantation and gene transfer therapies. However, other facts to consider are the cost of continued administration of recombinant beta- glucuronidase over long periods of time and the possibility that antibodies to the enzyme or other unexpected side effects could develop in some patients and perhaps decrease the effectiveness of the therapy over time. Therefore, in older individuals there may be advantages to discontinuing enzyme replacement and initiating various forms of long-term transplantation or somatic gene transfer therapies. This project determines the efficacy of these two-step therapeutic approaches in MPS VII mice. All newborns in the study will be given enzyme replacement therapy starting at birth and then will be continued on weekly injections of recombinant enzyme until they are young adults. At this time, some of the mice will be placed on monthly injections of enzyme for long-term maintenance while others will be given either BMT, liver transplantation, or retroviral transduced MPS VII hematopoietic stem cells and enzyme injections discontinued. Comparison of these four therapeutic regimens throughout the normal 2 to 3 year predicted life span of treated MPS VII mice will provide important information useful in developing similar types of therapy for human lysosomal storage diseases. Animal models, such as the MPS VII mouse, are vital for the development of effective and relatively safe forms of therapy for human genetic diseases. Because of the availability of animal models, new and exciting hope has recently been given to children and families which suffer from MPS VII and many other types of inherited disease where product replacement may be of value.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK041082-10
Application #
2734075
Study Section
Medical Biochemistry Study Section (MEDB)
Program Officer
Mckeon, Catherine T
Project Start
1989-08-01
Project End
2000-06-30
Budget Start
1998-07-10
Budget End
2000-06-30
Support Year
10
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609
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Lessard, Mark D; Alley, Travis L; Proctor, Jennifer L et al. (2006) Attenuation of murine lysosomal storage disease by allogeneic neonatal bone marrow transplantation using costimulatory blockade and donor lymphocyte infusion without myeloablation. Clin Immunol 119:166-79
Soper, Brian W; Lessard, Mark D; Jude, Craig D et al. (2003) Successful allogeneic neonatal bone marrow transplantation devoid of myeloablation requires costimulatory blockade. J Immunol 171:3270-7
Vogler, C; Barker, J; Sands, M S et al. (2001) Murine mucopolysaccharidosis VIL: impact of therapies on the phenotype, clinical course, and pathology in a model of a lysosomal storage disease. Pediatr Dev Pathol 4:421-33
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Soper, B W; Lessard, M D; Vogler, C A et al. (2001) Nonablative neonatal marrow transplantation attenuates functional and physical defects of beta-glucuronidase deficiency. Blood 97:1498-504
Vogler, C; Levy, B; Galvin, N J et al. (1999) Enzyme replacement in murine mucopolysaccharidosis type VII: neuronal and glial response to beta-glucuronidase requires early initiation of enzyme replacement therapy. Pediatr Res 45:838-44
Soper, B W; Duffy, T M; Vogler, C A et al. (1999) A genetically myeloablated MPS VII model detects the expansion and curative properties of as few as 100 enriched murine stem cells. Exp Hematol 27:1691-704
Soper, B W; Pung, A W; Vogler, C A et al. (1999) Enzyme replacement therapy improves reproductive performance in mucopolysaccharidosis type VII mice but does not prevent postnatal losses. Pediatr Res 45:180-6
Gwynn, B; Lueders, K; Sands, M S et al. (1998) Intracisternal A-particle element transposition into the murine beta-glucuronidase gene correlates with loss of enzyme activity: a new model for beta-glucuronidase deficiency in the C3H mouse. Mol Cell Biol 18:6474-81

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