The ganglioside storage diseases are a group of incurable neurodegenerative diseases that involve the storage of either gangliosides GM1 or GM2 in lysosomes of the CNS and visceral tissues. GM1 gangliosidosis arises from a genetic deficiency of the enzyme that breaks down ganglioside GM1 within lysosomes. Sandhoff disease (SD) arises from a genetic deficiency in the enzyme that breaks down ganglioside GM2. Both GM1 gangliosidosis and SD lead to progressive neurodegeneration and brain dysfunction. There are currently no effective therapies for either of these ganglioside storage diseases.

Substrate reduction therapy (SRT) is an experimental strategy that aims to decrease the rate of GSL biosynthesis in order to counterbalance the impaired rate of break down. The idea here is that if we can manage ganglioside accumulation, we might prevent or delay disease progression. The imino sugar N-butyldeoxygalactonojirimycin (NB-DGJ) is a competitive inhibitor of the key enzyme catalyzes the first step in GSL biosynthesis and is used for SRT.

We recently obtained proof of concept for early intervention SRT in mouse models of GM1 and Sandhoff's disease. We found that NB-DGJ significantly reduced total brain and GM1 and GM2 ganglioside content when administered from p-2 to p-5 in control and storage disease mutants. These neonatal ages in mice are comparable to pre-natal ages in humans as they precede the period of active brain myelinogenesis and cerebellar development. Our most recent findings also show that NB-DGJ significantly reduces ganglioside accumulation in these mutants when given from p-9 to p-15, i.e., during critical periods of myelinogenesis and cerebellar development. As observed in the mouse embryos, NB-DGJ treatment reduces brain ganglioside content in the neonatal mice without producing any adverse effects on brain growth or development. Also, no observable adverse effects of the treatment are seen on body growth or behavior. In other words, NB-DGJ is remarkably effective in targeting ganglioside accumulation in either normal or mutant mice without adverse consequences. These observations may have direct translational benefit to the clinic for the treatment of neonatal ganglioside storage disease.