STRUCTURE-FUNCTION RELATIONSHIPS OF LYSOSOMAL ENZYMES

神经节苷脂降解的遗传损伤导致一组

Genetic impairment of ganglioside degradation results in a group of diseases known as the sphingolipidoses. These are very serious disorders that generally cause mental retardation and severely shorten life span. We have been developing mouse models for these disorders through gene disruption in embryonic stem cells. Thus far we have modeled the three types of the GM2 gangliosidoses (Tay-Sachs disease, Sandhoff disease and the GM2 Activator Deficiency) through conventional gene disruption techniques. We are currently developing models of the three clinical types of Gaucher disease using a novel method to insert human disease mutations into embryonic stem cells. The models are being used to identify therapeutic procedures that may be effective in the treatment of these diseases. Currently we are focusing on two approaches, bone marrow transplantation (BMT) and the use of ganglioside synthesis inhibitors. Syngeneic BMT in the Sandhoff disease model has been found to be effective in elongating the life span of the animals (from 4.5 months to 7-8 months) and improving neurologic function. The basis for the therapeutic effect is under investigation. Oral treatment using the ganglioside synthesis inhibitor N-butyldeoxynojirimycin (NB-DNJ) has been found to substantially reduce the level of ganglioside accumulation in the brains of Tay-Sachs disease mice. We are currently testing the efficacy of NB-DNJ in the more severely affected Sandhoff disease model.