Chaperone therapy for neuronopathic lysosomal diseases: competitive inhibitors as chemical chaperones for enhancement of mutant enzyme activities.

[gm1 gangliosidosis]

Chaperone therapy is a newly developed molecular approach to lysosomal diseases , a group of human genetic diseases causing severe brain damage . We found two valienamine derivatives , N-octyl-4 -epi-beta -valienamine (NOEV ) and N-octyl-beta -valienamine (NOV ), as promising therapeutic agents for human beta -galactosidase deficiency disorders (mainly G (M 1 )-gangliosidosis ) and beta -glucosidase deficiency disorders (Gaucher disease ), respectively . We briefly reviewed the historical background of research in carbasugar glycosidase inhibitors . Originally NOEV and NOV had been discovered as competitive inhibitors , and then their paradoxical bioactivities as chaperones were confirmed in cultured fibroblasts from patients with these disorders . Subsequently G (M 1 )-gangliosidosis model mice were developed and useful for experimental studies . Orally administered NOEV entered the brain through the blood -brain barrier , enhanced beta -galactosidase activity , reduced substrate storage , and improved neurological deterioration clinically . Furthermore , we executed computational analysis for prediction of molecular interactions between beta -galactosidase and NOEV . Some preliminary results of computational analysis of molecular interaction mechanism are presented in this article . NOV also showed the chaperone effect toward several beta -glucosidase gene mutations in Gaucher disease . We hope chaperone therapy will become available for some patients with G (M 1 )-gangliosidosis , Gaucher disease , and potentially other lysosomal storage diseases with central nervous system involvement .

Diseases
Validation

Diseases presenting "several beta-glucosidase gene mutations" symptom

gm1 gangliosidosis

You can validate or delete this automatically detected symptom