UMMS Affiliation

Department of Neurology; Horae Gene Therapy Center

Publication Date


Document Type



Cell Biology | Cells | Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Developmental Biology | Genetic Phenomena | Lipids | Nervous System Diseases | Neuroscience and Neurobiology | Nutritional and Metabolic Diseases


Sandhoff disease, one of the GM2 gangliosidoses, is a lysosomal storage disorder characterized by the absence of beta-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.


Clustered Regularly Interspaced Short Palindromic Repeats/Cas9, GM2 gangliosidosis, Tay-Sachs disease, brain development, brain lipids, gangliosides, patient-derived induced pluripotent stem cells, sphingolipids, storage diseases

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Open Access Author’s Choice—Final version free via Creative Commons CC-BY license.

DOI of Published Version



J Lipid Res. 2018 Mar;59(3):550-563. doi: 10.1194/jlr.M081323. Epub 2018 Jan 22. Link to article on publisher's site

Journal/Book/Conference Title

Journal of lipid research

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PubMed ID


Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.