Advancements in Gene-Editing Offer Hope for Late-Onset Tay-Sachs Disease Treatment

Scientists at the National Institutes of Health (NIH) have achieved a significant breakthrough by reducing the severity of late-onset Tay-Sachs (LOTS) disease through a novel gene-editing approach in both human cell cultures and mouse models. This innovative research focuses on modifying the HEXA gene, which is responsible for producing an enzyme vital for breaking down a fatty substance called GM2 ganglioside in the brain. When this enzyme is deficient due to mutations, GM2 accumulates, damaging nerve cells and leading to symptoms characteristic of LOTS, such as muscle weakness, coordination loss, spasms, and potential cognitive decline.

Unlike the infantile form of Tay-Sachs, which manifests early and is often fatal by age 4 or 5, LOTS appears later in childhood or adulthood and is caused by partial enzyme deficiency. The research team successfully increased the activity of the enzyme beta-hexosaminidase A by correcting the HEXA gene mutation. This correction delayed symptom onset and significantly extended lifespan in the mouse model, demonstrating the potential of gene editing to modify disease progression.

The study, published in the Journal of Clinical Investigation, suggests that only a modest increase of around 10% in enzyme activity may suffice to prevent symptoms or improve quality of life in affected individuals. Dr. Richard Proia, a lead researcher, emphasized that this approach opens the door to developing effective treatments targeting enzyme levels, although further research is needed to adapt this strategy for human application.

Currently, about 500 individuals worldwide are affected by LOTS, with approximately 25 participants involved in ongoing NIH clinical studies. The research utilized cells donated by a participant with two copies of the mutated gene, highlighting the importance of patient engagement in advancing therapies. While this gene-editing method is not yet ready for clinical use, scientists are optimistic about future developments, including effective delivery techniques to the brain, such as overcoming challenges posed by the blood-brain barrier.

Gene-editing therapies have faced hurdles, notably the immune response to viral delivery vectors like adeno-associated viruses (AAV), and the need for delivery methods that can effectively target the central nervous system. Researchers are carefully considering these issues as they work towards translating preclinical success into human trials.

This research is particularly focused on LOTS because it progresses more slowly than infantile Tay-Sachs, giving researchers a longer window to intervene. Mutations in the HEXA gene are more prevalent in certain populations, such as Ashkenazi Jews, French Canadians, Cajuns, and Old Order Amish, where carrier screening is often part of genetic counseling.

In conclusion, this groundbreaking work establishes a promising foundation for gene-editing therapies aimed at late-onset Tay-Sachs. Though still in early stages, the approach offers hope for future treatments that could alleviate symptoms, improve quality of life, and potentially prevent disease progression in affected individuals.

Source: https://medicalxpress.com/news/2025-08-scientists-lay-foundation-potential-gene.html