Suzuki Y
Nasu Institute for Development Disabilities, Clinical
Research Center, International University of Health and Welfare, Otawara, Japan
At present little
is known about the pathogenesis of tissue-specific expression of mutant genes
causing neurogenetic diseases. The use of animal models is indispensable to
clarify the missing link between molecular events and phenotypic expression. We
have generated a β-galactosidase-deficient knockout mouse for
research in pathogenesis and therapeutic trial of β-galactosidase deficiency disorders. Furthermore
various human mutant β-galactosidase genes were introduced into
knockout mice, achieving transgenic over-expression of phenotype-specific
mutations. These knockout-transgenic animals can serve as an authentic model of
each phenotypic of humanβ-galactosidase deficiency disorders. The
animals expressing wild-type human gene showed a complete correction pf the
enzyme activity. On the other hand, we have found that some low molecular
compounds that inhibit α-galactosidase can restore residual
activities of some mutant enzymes (Fan, Ishii, Asano, Suzuki: Nature Genet,
1999). We have applied this procedure to b-galactosidase deficiency disorders,
to human and mouse fibroblasts, using galactose analogs for restoration of the
enzyme activity. Among the compounds we tried, 1-deoxygalactonojirimycin,
N-(butyl)-deoxygalactonojirimycin, and a new compound GalX, inhibited at high
concentrations and restored at low concentrations the residual enzyme activity.
GalX had the most remarkable effect. We expect that these compounds with a
molecular structure similar to galactose will be used for a new molecular
therapy of brain disease in GM1-gangliosidosis with some specific gene
mutations. This new approach may be extended also to other lysosomal storage
diseases with severe brain pathology, and possibly further to neurogenetic
diseases of other types in future.