Toward the successful delivery of lysosomal enzymes across the blood–brain barrier

Abstract

AbstractThe development of enzyme replacement therapy (ERT) has been one of the most remarkable successes of translational studies, bridging laboratory discoveries to clinical settings. Although ERT is very effective in clearing peripheral tissue storage in many lysosomal storage diseases (LSD), negotiating the blood‐brain barrier (BBB) remains a key challenge in delivering corrective lysosomal enzymes into the brain. In recent years, brain delivery of lysosomal enzymes has been vigorously pursued for treating neurodegenerative LSD. Delivery strategies include high‐dose and long‐term treatment regimens, manipulation of receptor‐mediated transport, biochemical engineering of enzymes, use of transport vectors, and enzyme administration by alternative routes. Most studies have investigated biochemical or histological improvements in central nervous system (CNS) storage after treatment. Few studies, however, have directly focused on the mechanisms of lysosomal enzyme transport across the BBB. In previous studies, we discovered that the luminally expressed mannose 6‐phosphate/insulin‐like growth factor‐II receptor is a universal transporter of lysosomal enzymes. We and others have also successfully manipulated receptor‐mediated transport by using endogenous characteristics of the BBB. Interestingly, accumulating evidence indicates that some lysosomal enzymes employ multiple mechanisms for their transport across the BBB. This review provides a detailed discussion of the kinetics of lysosomal enzyme transport across the BBB, and the manipulation of transport characteristics based on studies of the transport of β‐glucuronidase, sulfamidase, arylsulfatase A and acid α‐glucosidase. Furthermore, recent achievements in treating abnormalities in CNS storage and their contribution to developing new therapeutic approaches are also discussed.