The goal of this proposal is to determine the effects of enzyme replacement therapy (ERT) on the cognitive and hearing functions and on the associated pathologic alterations in mice with mucopolysaccharidosis type VII (MPS VII). We demonstrated that intravenous injections of phosphorylated beta-glucuronidase started at birth resulted in relatively high levels of enzyme in the brain. However, it has yet to be determined whether phosphorylation is absolutely required for efficient uptake into the central nervous system (CNS). ERT initiated at birth also resulted in a reduction of lysosomal storage in the ear and in neurons of the CNS which correlated with improved hearing and performance in the Morris Water Maze test, respectively. Continued ERT alone or in combination with bone marrow transplantation (BMT) resulted in long term reduction of lysosomal storage in neurons. We hypothesize that: 1) phosphorylation of beta- glucuronidase is required for efficient uptake in the brain and 2) ERT alone or in combination with BMT will result in long-term improvements in cognitive and hearing functions. We have four specific aims: 1) We will determine the pharmacokinetics and the effect of histopathology of non-phosphorylated beta-glucuronidase in the MPS VIII mouse. 2) We will determine the functional consequences of enzyme replacement with non-phosphorylated beta-glucuronidase initiated at birth on behavior and hearing and hearing at six weeks of age. 3) We will determine how long the improvements in behavior and hearing can be maintained by continued treatment with enzyme alone or in combination with BMT. 4) We will determine the effects of continued enzyme replacement or enzyme replacement followed by BMT on the progressive neuronal loss in the CNS and on the histopathology of the ear. Severe CNS abnormalities are common to many lysosomal storage disease. Since these features are difficult to treat, evidence of functional CNS improvement from ERT would have important implications.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD035671-03
Application #
6182599
Study Section
Medical Biochemistry Study Section (MEDB)
Program Officer
Oster-Granite, Mary Lou
Project Start
1998-05-01
Project End
2001-04-30
Budget Start
2000-05-01
Budget End
2001-04-30
Support Year
3
Fiscal Year
2000
Total Cost
$207,425
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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