Short-term enzyme replacement in the murine model of Sanfilippo syndrome type B

The Sanfilippo syndrome type B (MPS III B) is an autosomal recessive diseas e caused by deficiency of alpha -N-acetylglucosaminidase (EC 3.2.1.50), one of the lysosomal enzymes required for the degradation of heparan sulfate. The disease is characterized by profound neurodegeneration but relatively m ild somatic manifestations, and is usually fatal in the second decade, A mo use model had been generated by disruption of the Naglu gene in order to fa cilitate the study of pathogenesis and the development of therapy for this currently untreatable disease. Recombinant human alpha -N-acetylglucosamini dase (rhNAGLU) was prepared from secretions of Lec1 mutant Chinese hamster ovary cells. The enzyme, which has only unphosphorylated high-mannose carbo hydrate chains, was endocytosed by mouse peritoneal macrophages via mannose receptors, with half-maximal uptake at ca, 10(-7) IM. When administered in travenously to 3 month-old mice, rhNAGLU was taken up avidly by liver and s pleen but marginally if at all by thymus, lung, kidney, heart, and brain (i n order of diminishing uptake). The half-life of the enzyme was 2.5 days in liver and spleen. Immunohistochemistry and electron microscopy showed that only macrophages were involved in enzyme uptake and correction in these tw o organs, yet the storage of glycosaminoglycan was reduced to almost normal levels. The results show that the macrophage-targeted rhNAGLU can substant ially reduce the body burden of glycosaminoglycan storage in the mouse mode l of Sanfilippo syndrome III B. (C) 2000 Academic Press.