Emerging strategies for the treatment of hereditary metabolic storage disorders.

Metabolic storage disorders are caused by mutations in genes that result in insufficient activity of enzymes required for the catabolism of substances that arise from the turnover of senescent cells in the body. Among the most prevalent of these conditions are Gaucher disease and Fabry disease, which are caused by reduced activity of the housekeeping enzymes glucocerebrosidase and alpha-galactosidase A, respectively. Enzyme replacement therapy is extraordinarily effective for patients with Gaucher disease. It is under examination in patients with Fabry disease, and improvement of various clinical aspects in these patients has been documented. The blood-brain barrier prevents systemically administered enzymes from reaching the central nervous system. This limitation is a major impediment for the treatment of patients with enzyme deficiency disorders in whom the brain is involved. Alternatives to enzyme replacement therapy that have been initiated to treat systemic manifestations and brain involvement in patients with metabolic disorders include substrate reduction therapy, active site-specific chaperone therapy, and gene therapy. The present status and anticipated advances in the application of these therapeutic approaches are examined here.