Scientists Lay Foundation for Gene-Editing Therapy for Late-Onset Tay-Sachs

NIH scientists successfully reduced the severity of late-onset Tay-Sachs (LOTS) disease in human cell cultures and a mouse model using a novel gene-editing treatment. LOTS is a rare form of Tay-Sachs disease, with signs and symptoms such as muscle weakness, loss of coordination, muscle spasms and sometimes loss of mental function beginning in late childhood to adulthood.

LOTS is a genetic disorder caused by a mutation in the HEXA gene that causes a deficiency of an enzyme critical to breaking down a fatty substance in the brain, known as GM2 ganglioside. GM2 buildup damages nerve cells in the brain and spinal cord. The amount of enzyme still being produced by the body affects the severity of the disease and the age of onset. By deploying the correction to the HEXA gene, scientists were able to increase the activity of the enzyme, known as beta-hexosaminidase A, delay symptom onset and significantly extend lifespan in the mouse model.

Scientists believe this work has laid the foundation for building testing in human participants. LOTS affects about 500 people worldwide. The human cells used in this study were donated by a study participant who is unique because they have two copies of the mutated gene.

While the current breakthrough is not a cure or viable treatment yet, researchers believe they are on the right path. Future studies will investigate the best ways to deliver the genetic edit to the central nervous system and brain.

Researchers have targeted LOTS for this research because other forms of Tay-Sachs disease occur more suddenly. The infantile form of the disorder is usually diagnosed within the first 3-6 months of life and is fatal by 4-5 years of age. Children diagnosed with the juvenile form of the disease often die in their teens.

Mutations in the HEXA gene that cause Tay-Sachs are found more often in certain populations—including Eastern and Central European Jewish communities (Ashkenazi Jews), certain French-Canadian communities in Quebec, the Cajun community of Louisiana and the Old Order Amish community in Pennsylvania.

In the United States, pregnant women and their partners are often given a blood test to identify carriers of the HEXA gene change that causes Tay-Sachs disease.