Enzyme replacement and enhancement therapies: lessons from lysosomal disorders

Lysosomal storage diseases (LSDs) are caused by mutations in genes that encode lysosomal proteins, in most cases lysosomal enzymes. Most treatment strategies for LSDs are based on replacing the missing or defective lysosomal protein in the appropriate target sites of pathology. In the 1990s, several 'breakthrough' technologies led to the rapid development of enzyme replacement therapy (ERT) for LSDs. These included: the development of eukaryotic expression systems for lysosomal proteins; and the construction of new mouse models of LSDs by gene targeting. Preclinical studies in animal models have shown the efficacy of ERT for the treatment of LSDs, but have also identified its limitations, including the inability to deliver exogenous enzymes efficiently to the central nervous system (CNS). ERT became available for the first LSD — type I Gaucher disease — in 1991, and ten years of experience in more than 3,000 patients has revealed its remarkable efficacy and safety. ERT is also available for Fabry disease, and is now being evaluated in clinical trials for several other LSDs. New therapeutic strategies, including chaperone-mediated enzyme enhancement therapy (EET), are now being evaluated for LSDs. One principal advantage of EET as compared with ERT is the potential for treating diseases with CNS involvement, because low-molecularweight pharmacological chaperones are able to cross the blood–brain barrier.