Staci Kallish, DO and NTSAD Board Vice President wrote the following lay summary of an article published and shared online. Select PDF to read online article.
• A study recently published demonstrates the development of the fist human model of Sandhoff disease (SD).
• This work was completed by a number of scientists well-known to NTSAD, including Cynthia Tifft, MD, PhD, Richard Proia, PhD, and Miguel Sena-Esteves, PhD and their colleagues and was published March 1st in the Journal of Lipid Research.
• This study used fibroblasts (skin cells) from an infant with SD to create iPS cells (induced pleuripotent stem cells; cells which can them be transformed into other cell types).
• The researchers also used gene-editing technology called CRISPR/Cas9 to correct one of the Sandhoff mutations in some of these cells to create healthy cells.
• They then induced both groups of cells into groups of brain cells called organoids. This allowed them to study early brain development in the SD model compared to an unaffected model.
• As they expected, the researchers saw early ganglioside storage in the cells in the SD organoids, but not in the healthy control organoids. However, they were surprised that they saw cells overgrowing rather than degenerating. The SD organoids became larger than the controls, mimicking the enlarged brain size seen in patients with SD. They also saw changes in expression of other genes in the SD organoids, in genes which control cell maturation, which suggests that having a gangliosiosis may affect brain development in other ways in addition to the build up of storage material.
• Finally, the researchers used gene therapy (similar to the SD gene therapy being studied in SD animal models) to treat the organoids. They saw improvements in SD organoid size and reductions in ganglioside storage after gene therapy treatment. This demonstrates that organoids can be useful models of disease for the study of potential therapies. This also serves as a "proof of principle", the first evidence that gene therapy can correct abnormalities seen in SD in human cells.