Sandhoff disease, one of the
GM2 gangliosidoses, is a lysosomal storage disorder characterized by the absence of β-
hexosaminidase A and B activity and the concomitant lysosomal accumulation of its substrate,
GM2 ganglioside. It features catastrophic neurodegeneration and death in early childhood. How the lysosomal accumulation of
ganglioside might affect the early development of the nervous system is not understood. Recently, cerebral organoids derived from induced pluripotent stem (iPS) cells have illuminated early developmental events altered by disease processes. To develop an early neurodevelopmental model of
Sandhoff disease, we first generated iPS cells from the fibroblasts of an
infantile Sandhoff disease patient, then corrected one of the mutant HEXB alleles in those iPS cells using CRISPR/Cas9 genome-editing technology, thereby creating isogenic controls. Next, we used the parental
Sandhoff disease iPS cells and isogenic HEXB-corrected iPS cell clones to generate cerebral organoids that modeled the first trimester of neurodevelopment. The
Sandhoff disease organoids, but not the HEXB-corrected organoids, accumulated
GM2 ganglioside and exhibited increased size and cellular proliferation compared with the HEXB-corrected organoids. Whole-transcriptome analysis demonstrated that development was impaired in the
Sandhoff disease organoids, suggesting that alterations in neuronal differentiation may occur during early development in the
GM2 gangliosidoses.