GM2 Gangliosidosis also known as Tay-Sachs disease
https://www.jci.org/articles/view/183434
GM2 Gangliosidosis also known as Tay-Sachs disease is a rare hereditary brain disorder caused by a defect in the HEXA gene, which prevents cells from breaking down a fatty substance called GM2 ganglioside. This buildup damages nerve cells and leads to progressive loss of movement and mental function. The late-onset form (LOTS) develops in young adults, and researchers are working towards new treatments. In this study, researchers tested a precise gene-editing approach known as base editing to correct the most common LOTS mutation, called HEXA c.805G>A. Using a tool called an adenine base editor (ABE), they were able to repair the mutation in patient cells, restoring about half of the normal enzyme activity needed to clear GM2 ganglioside. The team then created mice carrying the same human LOTS mutation. These mice showed the same key features of the disease, GM2 buildup, movement problems, brain inflammation, and shortened lifespan. After treating the mice with a single dose of a harmless virus carrying the ABE, the defective gene was partially corrected in the brain and spinal cord. This restored enzyme activity, reduced toxic GM2 storage, lowered brain inflammation, improved movement, and almost doubled the animals’ lifespan. These findings demonstrate that base editing can directly correct the root genetic cause of Tay-Sachs disease in the brain. While further investigation is necessary to adapt this therapy safely for humans, the results offer hope for a one-time, lasting treatment for people with late-onset Tay-Sachs and similar neurodegenerative disorders.