Abstract
Lysosomal storage disorders (LSDs) are a group of about fifty life-threatening conditions caused by genetic defects affecting lysosomal components. The underscoring molecular deficiency leads to widespread cellular dysfunction through most tissues in the body, including peripheral organs and the central nervous system (CNS). Efforts during the last few decades have rendered a remarkable advance regarding our knowledge, medical awareness, and early detection of these genetic defects, as well as development of several treatment modalities. Clinical and experimental strategies encompassing enzyme replacement, gene and cell therapies, substrate reduction, and chemical chaperones are showing considerable potential in attenuating the peripheral pathology. However, a major drawback has been encountered regarding the suboptimal impact of these approaches on the CNS pathology. Particular anatomical and biochemical constraints of this tissue pose a major obstacle to the delivery of therapeutics into the CNS. Approaches to overcome these obstacles include modalities of local administration, strategies to enhance the blood-CNS permeability, intranasal delivery, use of exosomes, and those exploiting targeting of transporters and transcytosis pathways in the endothelial lining. The later two approaches are being pursued at the time by coupling therapeutic agents to affinity moieties and drug delivery systems capable of targeting these natural transport routes. This approach is particularly promising, as using paths naturally active at this interface may render safe and effective delivery of LSD therapies into the CNS.