Inhibition of substrate synthesis as a strategy for glycolipid lysosomal storage disease therapy

The glycosphingolipid (GSL) lysosomal storage diseases are caused by mutati ons in the genes encoding the glycohydrolases that catabolize GSLs within l ysosomes. In these diseases the substrate for the defective enzyme accumula tes in the lysosome and the stored GSL leads to cellular dysfunction and di sease. The diseases frequently have a progressive neurodegenerative course. The therapeutic options for treating these diseases are relatively limited , and for the majority there are no effective therapies. The problem is fur ther compounded by difficulties in delivering therapeutic agents to the bra in. Most research effort to date has focused on strategies for augmenting e nzyme levels to compensate for the underlying defect. These include bone ma rrow transplantation (BMT), enzyme replacement and gene therapy. An alterna tive strategy that we have been exploring is substrate deprivation. This ap proach aims to balance the rate of GSL synthesis with the impaired rate of GSL breakdown. The imino sugar N-butyldeoxynojirimycin (NB-DNJ) inhibits th e first step in GSL biosynthesis and has been used to evaluate this approac h. Studies in an asymptomatic mouse model of Tay-Sachs disease have shown t hat substrate deprivation prevents GSL storage in the CNS. In a severe neur odegenerative mouse model of Sandhoff disease, substrate deprivation delaye d the onset of symptoms and disease progression and significantly increased life expectancy. Combining NB-DNJ and BMT was found to be synergistic in t he Sandhoff mouse model. A clinical trial in type I Gaucher disease has bee n undertaken and has shown beneficial effects. Efficacy was demonstrated on the basis of significant decreases in liver and spleen volumes, gradual bu t significant improvement in haematological parameters and disease activity markers, together with diminished GSL biosynthesis and storage as determin ed by independent biochemical assays. Further trials in type I Gaucher dise ase are in progress; studies are planned in patients with GSL storage in th e CNS.