Beta-galactosidase deficiency: an approach to chaperone therapy.

Abstract

We propose a new molecular therapeutic approach to lysosomal diseases with severe neurological manifestations. Some low-molecular-weight compounds, acting as competitive inhibitors of a lysosomal enzyme in vitro, were found to stabilize and restore catalytic activities of the enzyme molecule as a molecular chaperone. We started this trial first in Fabry disease (generalized vasculopathy) using galactose and 1-deoxygalactonojirimycin, and then in beta-galactosidase deficiency disorders (beta-galactosidosis) with generalized neurosomatic and/or systemic skeletal manifestations (GM(1)-gangliosidosis and Morquio B disease), using a newly developed chemical compound N-octyl-4-epi-beta-valienamine (NOEV). Administration of this chaperone compound resulted in elevation of intracellular enzyme activity in cultured fibroblasts from patients and genetically engineered model mice. In addition, substrate storage was improved after NOEV had been transported into the brain tissue via the blood-brain barrier. We hope this new approach (chemical chaperone therapy) will be useful for certain patients with beta-galactosidosis and potentially other lysosomal storage diseases with central nervous system involvement.

• Authors: Yoshiyuki Suzuki
• Journal: Journal of inherited metabolic disease (J Inherit Metab Dis) 2006 Apr-Jun Vol. 29 Issue 2-3 Pg. 471-6 ISSN: 1573-2665 [Electronic] United States
• PMID: 16763919 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Hexosamines
• Molecular Chaperones
• N-octyl-beta-valienamine
• G(M1) Ganglioside
• GLB1 protein, human
• beta-Galactosidase

Topics

• Animals
• Cells, Cultured
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Enzyme Induction (drug effects)
• Enzyme Inhibitors (pharmacology, therapeutic use)
• Fibroblasts (drug effects, metabolism)
• G(M1) Ganglioside (metabolism)
• Gangliosidosis, GM1 (drug therapy, metabolism)
• Hexosamines (pharmacology, therapeutic use)
• Humans
• Mice
• Mice, Transgenic
• Molecular Chaperones (metabolism)
• Mutation
• beta-Galactosidase (biosynthesis, deficiency, genetics)