Chemical chaperone therapy for GM1-gangliosidosis

We have proposed a chemical chaperone therapy for lysosomal diseases, based on a paradoxical phenomenon that an exogenous competitive inhibitor of low molecular weight stabilizes the target mutant molecule and restores its catalytic activity as a molecular chaperone intracellularly. After Fabry disease experiments, we investigated a new synthetic chaperone compound N-octyl-4-epi-β-valienamine (NOEV) in a G_M1-gangliosidosis model mice. Orally administered NOEV entered the brain through the blood-brain barrier, enhanced β-galactosidase activity, reduced the substrate storage, and clinically improved neurological deterioration. We hope that chemical chaperone therapy will prove useful for some patients with G_M1-gangliosidosis and potentially other lysosomal storage diseases with central nervous system involvement. Received 10 October 2007; received after revision 31 October 2007; accepted 6 November 2007