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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS022376-18
Application #
6539632
Study Section
Medical Biochemistry Study Section (MEDB)
Program Officer
Tagle, Danilo A
Project Start
1985-07-01
Project End
2005-05-31
Budget Start
2002-06-01
Budget End
2003-05-31
Support Year
18
Fiscal Year
2002
Total Cost
$343,219
Indirect Cost
Name
University of California Los Angeles
Department
Biochemistry
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Ryazantsev, Sergey; Yu, Wei-Hong; Zhao, Hui-Zhi et al. (2007) Lysosomal accumulation of SCMAS (subunit c of mitochondrial ATP synthase) in neurons of the mouse model of mucopolysaccharidosis III B. Mol Genet Metab 90:393-401
Jordan, Maria C; Zheng, Yi; Ryazantsev, Sergey et al. (2005) Cardiac manifestations in the mouse model of mucopolysaccharidosis I. Mol Genet Metab 86:233-43
Zheng, Yi; Ryazantsev, Sergey; Ohmi, Kazuhiro et al. (2004) Retrovirally transduced bone marrow has a therapeutic effect on brain in the mouse model of mucopolysaccharidosis IIIB. Mol Genet Metab 82:286-95
Ohmi, Kazuhiro; Greenberg, David S; Rajavel, Kavitha S et al. (2003) Activated microglia in cortex of mouse models of mucopolysaccharidoses I and IIIB. Proc Natl Acad Sci U S A 100:1902-7
Li, Hong Hua; Zhao, Hui-Zhi; Neufeld, Elizabeth F et al. (2002) Attenuated plasticity in neurons and astrocytes in the mouse model of Sanfilippo syndrome type B. J Neurosci Res 69:30-8
Rajavel, K S; Neufeld, E F (2001) Nonsense-mediated decay of human HEXA mRNA. Mol Cell Biol 21:5512-9
Yu, W H; Zhao, K W; Ryazantsev, S et al. (2000) Short-term enzyme replacement in the murine model of Sanfilippo syndrome type B. Mol Genet Metab 71:573-80
Zhao, K W; Neufeld, E F (2000) Purification and characterization of recombinant human alpha-N-acetylglucosaminidase secreted by Chinese hamster ovary cells. Protein Expr Purif 19:202-11
Li, H H; Yu, W H; Rozengurt, N et al. (1999) Mouse model of Sanfilippo syndrome type B produced by targeted disruption of the gene encoding alpha-N-acetylglucosaminidase. Proc Natl Acad Sci U S A 96:14505-10
Schmidtchen, A; Greenberg, D; Zhao, H G et al. (1998) NAGLU mutations underlying Sanfilippo syndrome type B. Am J Hum Genet 62:64-9

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