Gene Editing Shows Promise for Treating Late-Onset Tay-Sachs

Researchers at the National Institutes of Health (NIH) have used gene editing to reduce the severity of late-onset Tay-Sachs (LOTS) disease in human cell cultures and a mouse model. The study, which focused on a mutation in the HEXA gene, demonstrated that correcting this mutation can increase the activity of a critical brain enzyme and extend lifespan in mice.

What is late-onset Tay-Sachs disease (LOTS)?

LOTS is a rare inherited condition that usually begins in late childhood or early adulthood. It is characterized by progressive neurological symptoms including muscle weakness, coordination loss and involuntary movements. Unlike the more severe infantile form of Tay-Sachs, LOTS progresses more slowly, but there are currently no approved treatments. This new approach, developed by scientists at NIH’s National Institute of Diabetes and Digestive and Kidney Diseases and National Human Genome Research Institute, offers early pre-clinical evidence of potential benefit.

Correcting HEXA gene boosts enzyme activity

The condition is caused by a mutation in the HEXA gene, which impairs production of an enzyme called beta-hexosaminidase A. This enzyme helps break down GM2 ganglioside, a fatty substance in the brain. When the enzyme is deficient, GM2 builds up, damaging nerve cells in the brain and spinal cord. People with LOTS typically have 4–6% of normal enzyme activity.

In the mouse model, correcting the HEXA mutation increased enzyme activity and delayed the onset of symptoms. The researchers estimate that even modest increases in enzyme activity, on the order of 10%, may be enough to meaningfully affect disease progression.

“We’ve figured out that opening the door to increased enzyme activity is possible, now we have to figure out how to do it in a person.”

Dr. Richard Proia.

Patient-derived cells used to evaluate gene therapy approach

Human cell cultures used in the study were derived from a participant enrolled in a LOTS study at the NIH Clinical Center in Bethesda, Maryland. The participant carries two copies of the mutated HEXA gene, providing a model system to evaluate the effects of the gene-editing intervention. NIH researchers are currently following about 25 individuals in the ongoing study, and estimate that LOTS affects about 500 people globally.

Implications for other rare lysosomal storage diseases

The findings may also be relevant to other related disorders caused by the buildup of similar substances in the brain. These include GM1 gangliosidosis, Sandhoff disease, Niemann-Pick disease, Krabbe disease and Gaucher disease.

Next steps: Improving gene delivery to the brain

While the study does not represent a treatment or cure, the authors believe it marks a significant step toward developing one. Future research will aim to identify effective delivery mechanisms for the genetic edits, particularly methods that can cross the blood-brain barrier. One strategy under consideration involves adeno-associated viruses (AAVs), which are commonly used in gene therapy to carry DNA into cells. However, AAV-based approaches must overcome challenges, including the possibility that individuals may already have antibodies against the viral vectors and the difficulty of targeting cells within the brain.

Why LOTS is ideal for gene-editing research

LOTS was chosen for this study due to its slower progression compared with other forms of Tay-Sachs disease. The infantile form is typically diagnosed in the first few months of life and is fatal by age 4 or 5 years. The juvenile form progresses more slowly but is often fatal in adolescence. Because some enzyme activity remains in people with LOTS, researchers believe this form of the disease may be more amenable to therapeutic intervention.

Genetic risk of Tay-Sachs in specific populations

Mutations in the HEXA gene occur more frequently in certain populations, including Ashkenazi Jewish, French-Canadian, Cajun and Old Order Amish communities. In the United States, carrier screening is commonly offered to pregnant individuals and their partners to identify those at risk of passing on the condition.

Reference: Allende ML, Kono M, Lee YT, et al. CNS-targeted base editing of the major late-onset Tay-Sachs mutation alleviates disease in mice. J Clin Invest. 2025. doi: 10.1172/JCI183434

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