Delivery of lysosomal enzymes for therapeutic use: glucocerebrosidase as an example

Enzyme therapies for lysosomal storage diseases have developed over the past decade into the standard-of-care for affected patients. Such therapy for Gaucher disease has been the prototype, using natural source or recombinant forms of human acid beta-glucosidase (GCase). In Gaucher disease, macrophages are the repository for the pathological lipid and the target for delivery of GCase. The macrophage mannose receptor provides a Trojan horse for intracellular delivery of intravenously administered GCase (man-GCase) with mannosyl-terminated oligosaccharide chains. Passage through several hostile compartments (e.g., plasma) leads to inefficient delivery of man-GCase to macrophage lysosomes. However, regular infusions of man-GCase re-establishes health in affected patients. Similar results are being obtained in several other lysosomal storage diseases. Evolving gene and chaperone approaches provide alternative treatment strategies.