Chaperone
therapy is a newly developed molecular therapeutic approach to lysosomal diseases, a group of human
genetic diseases causing severe brain damage. Based on early molecular studies during the last decade of the 20th century and early years of the 21st century, mainly on
Fabry disease and GM1-gangliosidosis, we found some mutant
enzyme proteins were unstable in the cell, and unable to express catalytic activities. Subsequently
galactose and other active-site binding substrate analogs were found stabilized and enhance the mutant
enzyme activity in culture cells. We concluded that the mutant misfolding
enzyme protein and substrate analog competitive inhibitor (chemical chaperone) form a stable complex to be transported to the lysosome, to restore the catalytic activity of mutant
enzyme after spontaneous dissociation under the acidic condition. This gene mutation-specific molecular interaction is a paradoxical phenomenon that an
enzyme inhibitor in vitro serves as an
enzyme stabilizer in situ. First we developed a commercially available compound
1-deoxygalactonojirimycin (DGJ) for
Fabry disease, and confirmed the above molecular phenomenon. Currently DGJ has become a new candidate of
oral medicine for
Fabry disease, generalized vasculopathy involving the kidneys, heart and central nervous system in the middle age. This
drug development has reached the phase 3 of human clinical study. Then we found two
valienamine derivatives, N-octyl-4-epi-β-valienamine (NOEV) and N-octyl-β-
valienamine (NOV), as promising therapeutic agents for human β-
galactosidase deficiency disorders (
GM1-gangliosidosis and
Morquio B disease) and β-
glucosidase deficiency disorders (phenotypic variations of
Gaucher disease), respectively. 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 GM1-gangliosidosis model mice have been used for confirmation of clinical effectiveness, adverse effects and pharmacokinetic studies. Orally administered NOEV entered the brain through the blood-brain barrier, enhanced β-
galactosidase activity, reduced substrate storage, and improved neurological deterioration clinically. Computational analysis revealed pH-dependent
enzyme-chaperone interactions. Our recent study indicated chaperone activity of a new DGJ derivative, MTD118, for β-
galactosidase complementary to NOEV. NOV also showed the chaperone effect toward several β-
glucosidase gene mutants in
Gaucher disease. Furthermore a commercial
expectorant drug ambroxol was found to be a chaperone for β-
glucosidase. A few Gaucher patients responded to this
drug with remarkable improvement of oculomotor dysfunction and
myoclonus. We hope chaperone
therapy will become available for some patients with
Fabry disease, GM1-gangliosidosis,
Gaucher disease, and other
lysosomal storage diseases particularly with central nervous system involvement.