Fibroblast screening for chaperone therapy in β-galactosidosis

We performed screening of β-galactosidase-deficient fibroblasts for possible chemical chaperone therapy using N-octyl-4-epi-β-valienamine (NOEV) in patients with GM1-gangliosidosis and Morquio B disease (β-galactosidosis). Fibroblasts were cultured with NOEV for 4 days and β-galactosidase activity was measured. Mutation analysis was performed simultaneously. Two separate criteria were set for evaluation of the chaperone effect: a relative increase of enzyme activity (more than 3-fold), and an increase up to more than 10% normal enzyme activity. Among the 50 fibroblast strains tested, more than 3-fold increase was achieved in 17 cell strains (34%), and more than 10% normal activity in 10 (20%). Both criteria were satisfied in 6 (12%), and either of them in 21 (42%). Juvenile GM1-gangliosidosis was most responsive, and then infantile GM1-gangliosidosis. This enhancement was mutation-specific. We estimate that the NOEV chaperone therapy will be effective in 20–40% of the patients, mainly in juvenile and infantile GM1-gangliosidosis patients. A molecular design may produce mutation-specific chaperone compounds for the other disease phenotypes. This cellular screening will be useful for identification of human patients with β-galactosidase deficiency for chaperone therapy to be started in the near future.