A BIOCHEMICAL AND IMMUNOCYTOCHEMICAL STUDY ON THE TARGETING OF ALGLUCERASE IN MURINE LIVER

A current hypothesis is that functional glucocerebrosidase needs to be delivered to the lysosomes of tissue macrophages to guarantee success ful enzyme therapy for Gaucher's disease. In this study, biochemical a nd immunohistochemical techniques were applied to identify in mice the localization of intravenously administered alglucerase (human modifie d placental glucocerebrosidase). Only in liver and spleen was a signif icant increase of glucocerebrosidase activity observed, with a maximum level at 15 minutes after enzyme infusion. The uptake of enzyme by li ver was sufficiently high to allow more detailed studies on the (sub)c ellular distribution of human alglucerase. The enzyme in liver is loca lized both in the endosomal-lysosomal system of the Kupffer cells and the endothelial cells lining the lumen of the sinusoids. Uptake by bot h of these types of cell is prevented by mannan. The results suggest t hat the cellular mechanisms responsible for improvement of Gaucher pat ients receiving alglucerase treatment is probably more complicated tha n previously recognized.