Abstract
Top of pageAbstract Mucopolysaccharidosis IIIB (Sanfilippo syndrome type B) is a lysosomal storage disorder resulting from mutations in NAGLU, the gene encoding the enzyme alpha-N-acetylglucosaminidase that is required for the lysosomal degradation of heparan sulfate. The disease is characterized by profound mental retardation and eventual neurodegeneration, accompanied by relatively mild somatic manifestations. There is no available therapy. We have used a mouse knockout model of the disease to test gene therapy by genetically modified bone marrow. Bone marrow from Naglu −/− male mice was transduced with human NAGLU cDNA in an MND-MFG vector, and transplanted into 6–8 week-old lethally irradiated female −/− mice. Sham-treated mice received bone marrow transduced with eGFP cDNA in an MND vector. Analysis of alpha-N-acetylglucosaminidase in serum and white cells at 3 and 6 months after transplantation showed wide variability of expression, ranging from marginal to almost 30 times wild type. Biochemical studies showed that a fraction of normal alpha-N-acetylglucosaminidase activity (as little as provided by transplantation of unmodified +/+ bone marrow) could normalize biochemical defects (glycosaminoglycan storage and beta-hexosaminidase elevation) in liver and spleen. By contrast, only the highest level of activity had any effect on kidney and brain. Morphologic studies by light and electron microscopy showed a decreased number of vacuolated neurons and microglia in several areas of the brain, and an increased number of normal-appearing cells. Quantitation of the change in a section of the cortex is presented in the Table. Immunohistochemistry showed a marked reduction in staining for Lamp1 (a marker of storage in microglia) and for subunit c of ATP synthase (a marker of neuronal pathology). These results show that genetically modified cells of hematopoietic origin can reduce the pathologic manifestations in the brain of the mouse model of mucopolysaccharidosis IIIB.
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