Many
genetic disorders are due to
protein misfolding and excessive premature degradation in the endoplasmic reticulum (ER). When a gene mutation does not affect the functionality of the
protein, it may still promote the premature clearance of the
protein by ER-associated degradation (ERAD), resulting in a loss of function. Competitive inhibitors are often effective active-site-specific chaperones when used at sub-inhibitory concentrations. Active-site-specific chaperones assist in the folding of mutant lysosomal
enzymes in the ER, thereby promoting their escape from ERAD, enhancing trafficking to the lysosome and increasing the level of residual
enzyme activity. In
Fabry disease, degradation of various mutant forms of a-
galactosidase A (alpha-gal A) has been shown to take place in the ER as a result of
protein misfolding. One of the most potent inhibitors of alpha-gal A,
1-deoxygalactonojirimycin, has also been shown to be effective in enhancing residual alpha-gal A activity in cultured fibroblasts and lymphoblasts established from patients with
Fabry disease caused by a variety of missense mutations.
Oral administration of
1-deoxygalactonojirimycin to transgenic mice expressing a mutant form of human alpha-gal A (R301Q) yielded higher alpha-gal A activity in major tissues, compared with untreated transgenic mice.