A synthetic chaperone corrects the trafficking defect and disease phenotype in a protein misfolding disorder.

Mutations in proteins that induce misfolding and proteasomal degradation are common causes of inherited diseases. Fabry disease is a lysosomal storage disorder caused by a deficiency of alpha-galactosidase A activity in lysosomes resulting in an accumulation of glycosphingolipid globotriosylceramide (Gb3). Some classical Fabry hemizygotes and all cardiac variants have residual alpha-galactosidase A activity, but the mutant enzymes are unstable. Such mutant enzymes appear to be misfolded, recognized by the ER protein quality control, and degraded before sorting into lysosomes. Hence, correction of the trafficking defect of mutant but catalytically active enzyme into lysosomes would be beneficial for treatment of the disease. Here we show that a nontoxic competitive inhibitor (1-deoxygalactonojirimycin) of alpha-galactosidase A functions as a chemical chaperone by releasing ER-retained mutant enzyme from BiP. The treatment with subinhibitory doses resulted in efficient, long-term lysosomal trafficking of the ER-retained mutant alpha-galactosidase A. Successful clearance of lysosomal Gb3 storage and a near-normal lysosomal phenotype was achieved in human Fabry fibroblasts harboring different types of mutations. Small molecule chemical chaperones will be therapeutically useful for various lysosomal storage disorders as well as for other genetic metabolic disorders caused by mutant but nonetheless catalytically active enzymes.