Gene therapy of lysosomal storage disorders

Abstract

Lysosomal storage disorders (LSD) result from deficiencies in enzymes normally implicated in the catabolism of macromolecules inside the lysosome. Many of these enzymes can reach the lysosome after being secreted in the extracellular medium and recaptured by specific cell surface receptors. This has suggested a rationale for therapeutic approaches in LSD, in which the missing enzyme is provided by an external source. Current therapies based on this concept, including the administration of purified enzyme and bone marrow transplantation, have been shown to result in clinical improvements in both animal models and patients. Although considerable difficulties must be surmounted, LSD present a favourable situation for gene therapy. The gene corresponding to the affected enzyme has been identified in most diseases and cDNAs are available. Low and unregulated levels of enzyme activity should be sufficient for correction. Importantly, a variety of gene transfer strategies can be carefully evaluated in animal models.