The Sanfilippo syndrome type B is a heritable, neurodegenerative disease caused by deficiency of the lysosomal enzyme alpha-N-acetylglucosaminidase and the consequent failure to degrade heparan sulfate. Profound mental retardation and behavioral disturbances in childhood are accompanied by relatively mild somatic manifestations. We have developed a mouse model of the disease by targeted disruption of the mouse gene (Naglu) encoding alpha-N-acetylglucosaminidase, in order to gain better understanding of the pathophysiology of the disease and to develop therapy. Though clinically and behaviorally more mildly affected than their human counterparts, the mutant mice have the expected biochemical and pathological features, including heparan sulfate storage, striking vacuolation of macrophages and distinctive bodies in neurons. In addition we have found increased reactivity/proliferation of astrocytes, changes in mRNA levels of the FGF growth factor/receptor genes and immunoreactivity of subunit c of mitochondrial ATP synthase (SCMAS) in neurons.
Aim 1 is to further characterize the phenotype of the murine model of Sanfilippo B syndrome, particularly with respect to the neuronal bodies that show SCMAS reactivity, and to determine whether there is an accompanying defect of mitochondrial function.
Aim 2 is to use microarray analysis in order to identify changes in gene expression in brain. The underlying hypothesis is that failure to degrade heparan sulfate doesn't just result in space-filling storage, but has a more global effect on regulation of many genes and gene products.
Aim 3 is to explore the therapeutic effect of a) transplantation of bone marrow, b) transplantation of bone marrow genetically modified with the Naglu gene in a retroviral vector and c) administration of an alpha-N-acetylglucosaminidase fused to a protein translocation domain to allow transfer across the blood-brain barrier. A transgenic mouse will be generated for immune tolerance of therapeutic alpha-N-acetylglucosaminidase. The overall goal of these studies is to understand and prevent the brain damage that characterizes the Sanfilippo syndrome type B.
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