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-beta-valienamine (NOEV) in a GM1-gangliosidosis model mice. Orally administered NOEV entered the brain through the blood-brain barrier, enhanced beta-galactosidase activity, reduced the substrate storage, and clinically improved neurological deterioration. We hope that chemical chaperone therapy will prove useful for some patients with GM1-gangliosidosis and potentially other lysosomal storage diseases with central nervous system involvement.
Suzuki
Y
Y
International University of Health and Welfare Graduate School, 2600-1 Kita-Kanemaru, Otawara 324-8501, Japan. SuzukiY@iuhw.ac.jp
D000818:Animals; D005347:Fibroblasts / Q000201:enzymology; D016537:Gangliosidosis, GM1 / Q000188:drug therapy*; D005962:Glucosylceramidase / Q000037:antagonists & inhibitors / Q000235:genetics; D006595:Hexosamines / Q000737:chemistry / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D018832:Molecular Chaperones / Q000737:chemistry / Q000627:therapeutic use*
D006595:Hexosamines; D018832:Molecular Chaperones; C116532:N-octyl-beta-valienamine; D005962:Glucosylceramidase