Deficiencies of lysosomal β-D-
galactosidase can result in
GM1 gangliosidosis, a severe
neurodegenerative disease characterized by massive neuronal storage of
GM1 ganglioside in the brain. Currently there are no available
therapies that can even slow the progression of this disease.
Enzyme enhancement
therapy utilizes small molecules that can often cross the blood brain barrier, but are also often competitive inhibitors of their target
enzyme. It is a promising new approach for treating diseases, often caused by missense mutations, associated with dramatically reduced levels of functionally folded
enzyme. Despite a number of positive reports based on assays performed with patient cells, skepticism persists that an inhibitor-based treatment can increase mutant
enzyme activity in vivo. To date no appropriate animal model, i.e., one that recapitulates a responsive human genotype and clinical phenotype, has been reported that could be used to validate
enzyme enhancement
therapy. In this report, we identify a novel
enzyme enhancement-agent, N-nonyl-deoxygalactonojirimycin, that enhances the mutant β-
galactosidase activity in the lysosomes of a number of patient cell lines containing a variety of missense mutations. We then demonstrate that treatment of cells from a previously described, naturally occurring feline model (that biochemically, clinically and molecularly closely mimics
GM1 gangliosidosis in humans) with this molecule, results in a robust enhancement of their mutant lysosomal β-
galactosidase activity. These data indicate that the feline model could be used to validate this therapeutic approach and determine the relationship between the disease stage at which this
therapy is initiated and the maximum clinical benefits obtainable.