Research Home University of California – Los Angeles, Dr. Elizabeth Neufeld We have been actively studying the mouse model of the Sanfilippo Syndrome, type B, that we had generated by disrupting the mouse gene encodinga-N-acetylglucosaminidase. Our "NaGlu" mouse colony is thriving, and we have been able to transfer heterozygous mice to investigators in the US and abroad for starting their own colonies. All of the recipient laboratories, as well as our own, are using the mice to develop potential therapies for the Sanfilippo Syndrome. In addition, we hope that these mice will help us understand why the effect of the Sanfilippo Syndrome is so disproportionately severe in the brain. We have examined the possibility of enzyme replacement. Unfortunately, the recombinant a-N-acetylglucosaminidase produced by genetically engineered CHO cells proved not to carry the signal (mannose 6-phosphate) for targeting to lysosomes of most cells. Instead, we prepared an enzyme targeted to macrophages (a cell type found very much affected in this disease). Mutant NaGlu mice treated with this enzyme showed a very high level of enzyme uptake in liver and spleen but none in brain. We are trying to chemically modify the enzyme for broader targeting, to test whether it can reach the cells that need it most, namely the neurons in the brain. In studying the brains of NaGlu -/- mice by electron microscopy, we noted that while cells in the liver, spleen and kidney had the characteristic appearance of lysosomal storage of mucopolysaccharide, neurons looked quite different. Neurons (the brain cells responsible for learning and behavior) have inclusions that probably contain other, as yet unidentified material. Of particular interest is the finding of inclusions that react strongly with an antibody against a mitochondrial protein called SCMAS. Our results suggest that there may be some abnormality in the turnover of mitochondria (energy-generating bodies that are essential for the function of neurons). Although we don’t understand this abnormality at the present time, or how it ties in with the a-N-acetylglucosaminidase deficiency, we believe that it may be a clue to the deterioration of brain function in Sanfilippo Syndrome and to strategies for pharmacologic intervention.