Therapeutic approaches for lysosomal storage diseases

Abstract

The lysosomal storage disorders (LSDs) comprise a heterogeneous group of inborn errors of metabolism characterized by tissue substrate deposits, most often caused by a deficiency of the enzyme normally responsible for catabolism of various byproducts of cellular turnover. Individual entities are typified by involvement of multiple body organs, in a pattern reflecting the sites of substrate storage. It is increasingly recognized that one or more processes, such as aberrant inflammation, dysregulation of apoptosis and/or defects of autophagy, may mediate organ dysfunction or failure. Several therapeutic options for various LSDs have been introduced, including hematopoietic stem cell transplantation, enzyme replacement therapy and substrate reduction therapy. Additional strategies are being explored, including the use of pharmacological chaperones and gene therapy. Most LSDs include a variant characterized by primary central nervous system (CNS) involvement. At present, therapy of the CNS manifestations remains a major challenge because of the inability to deliver therapeutic agents across the intact blood-brain barrier. With improved understanding of underlying disease mechanisms, additional therapeutic options may be developed, complemented by various strategies to deliver the therapeutic agent(s) to recalcitrant sites of pathology such as brain, bones and lungs.

Keywords: enzyme replacement therapy; gene therapy; lysosomal storage disease; pharmacologic chaperone; substrate reduction therapy.