Abstract
Enzyme replacement therapy and substrate reduction therapy have proved useful in reversing many pathological consequences of many nonneural lysosomal storage diseases but have not yet reversed pathology or influenced disease outcome in Krabbe's disease (KD). This Review discusses the relative merits of stem cell therapy, molecular chaperone therapy, gene therapy, substrate reduction therapy, enzyme replacement therapy, and combination therapy. Given the limitations of these approaches, this Review introduces the idea of using tiny, 6-nm, intensely fluorescent quantum dots (QDs) to deliver a cell-penetrating peptide and 6 histidine residue-tagged β-D-galactocerebrosidase across the blood-brain barrier. We can therefore follow the fate of injected material and ensure that all targets are reached and that accumulated material is degraded. Uptake of lysosomal hydrolases is a complex process, and the cell-penetrating peptide JB577 is uniquely able to promote endosomal egress of the QD cargo. This Review further shows that uptake may depend on the charge of the coating of the QD, specifically, that negative charge directs the cargo to neurons. Because KD involves primarily glia, specifically oligodendroglia, we experiment with many coatings and discover a coating (polyethylene glycol 600 amino) that has a positive charge and targets oligodendrocytes. A similar effect is achieved by treating with chondroitinase ABC to degrade the extracellular matrix, indicating that enzyme replacement has several hurdles to overcome before it can become a routine CNS therapy. © 2016 Wiley Periodicals, Inc.