Evaluation of N-nonyl-deoxygalactonojirimycin as a pharmacological chaperone for human GM1 gangliosidosis leads to identification of a feline model suitable for testing enzyme enhancement therapy

• Published in: Molecular genetics and metabolism Vol. 107; no. 1-2; pp. 203 - 212
• Main Authors: Rigat, Brigitte A., Tropak, Michael B., Buttner, Justin, Crushell, Ellen, Benedict, Daphne, Callahan, John W., Martin, Douglas R., Mahuran, Don J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-09-2012
• Subjects: 1-Deoxynojirimycin - administration & dosage; 1-Deoxynojirimycin - analogs & derivatives; 1-Deoxynojirimycin - pharmacology; Animals; beta-Galactosidase - antagonists & inhibitors; beta-Galactosidase - chemistry; beta-Galactosidase - metabolism; Cats; Cell Line, Tumor; Disease Models, Animal; Endoplasmic reticulum quality control; Enzyme Replacement Therapy; Fibroblasts - drug effects; Fibroblasts - metabolism; Gangliosidosis, GM1 - drug therapy; Gangliosidosis, GM1 - genetics; Gangliosidosis, GM1 - metabolism; Hot Temperature; Humans; Hydrogen-Ion Concentration; Indexing in process; Large animal model; Lysosomal storage disease; Morquio disease type B; Mutant Proteins - antagonists & inhibitors; Mutant Proteins - chemistry; Mutant Proteins - metabolism; Mutation; Protein Denaturation - drug effects; Small molecule therapy; Treatment Outcome; β-D-galactosidase; Morquio disease type B; Endoplasmic reticulum quality control; Large animal model; Small molecule therapy; Lysosomal storage disease; β-D-galactosidase
• ISSN: 1096-7192; 1096-7206
• DOI: 10.1016/j.ymgme.2012.06.007

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.
► We identify NN-DGJ as a pharmacological chaperone for human GM1 gangliosidosis. ► NN-DGJ enhances residual activity in cells with 3 out of 7 missense mutations tested. ► NN-DGJ acts as a pharmacological chaperone in cells from a feline model of GM1. ► This GM1 feline model is the first suitable for testing chaperone therapy in vivo.