Therapeutic strategies for the ganglioside storage diseases.

摘要

The Gangliosidoses, to include GM1 gangliosidosis and Sandhoff disease are a class of incurable lysosomal storage disorders characterized by an abnormal accumulation of gangliosides leading to progressive neurodegeneration and eventually death. GM1 gangliosidosis is caused by a genetic defect in the lysosomal-specific acid beta-galactosidase, which results in the massive accumulation of ganglioside GM1 primarily in the central nervous system (CNS). Sandhoff disease (SD) results from a defect in the beta-subunit of beta-Hexosaminidase A and leads to the accumulation of ganglioside GM2 and its asialo derivative (GA2). As there are no effective therapies for these glycosphingolipid (GSL) storage disorders, I studied substrate reduction therapy (SRT), stem cell therapy, and adeno-associated viral (AAV) gene therapy in neonatal mice as early intervention therapies and were effective in reducing CNS GSL storage. In addition, AAV gene therapy was also evaluated in the adult GM1 gangliosidosis mice. Furthermore, analysis of the brain lipids in mice, cats, and humans with Sandhoff disease revealed that the SD cat model is intermediate between the SD mouse and the SD patient with respect to GM2 and GA2 accumulation. These findings are the first to compare the different therapies and provide valuable information for the translation of mouse studies to clinical trials in patients.