Friday, August 15, 2025
Study of human cells and mice may have implications for other lysosomal storage disorders
Scientists at the National Institutes of Health (NIH) successfully reduced the severity of late-onset Tay-Sachs (LOTS) disease in human cell cultures and a mouse model by 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. Similar disorders for which this breakthrough has implications include GM1 gangliosidosis, Sandhoff disease, Niemann-Pick disease, Krabbe disease and Gaucher disease.
LOTS is a genetic disorder caused by a mutation in the HEXA gene that causes a deficiency of an enzyme that is critical to breaking down a fatty substance in the brain, known as GM2 ganglioside. The buildup of this fatty substance 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.
“With LOTS, a slight correction will go a long way. This editing may only need to increase enzyme activity by about 10% to keep symptoms from getting worse, and improve their quality of life,” said paper author Dr. Richard Proia of NIH’s National Institute of Diabetes and Digestive and Kidney Diseases. “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.”
Scientists believe that this level of pre-clinical work has laid the foundation on which to build toward testing in human participants. Researchers estimate that LOTS affects about 500 people worldwide, and they currently have about 25 participants in an ongoing study at the NIH Clinical Center in Bethesda, Maryland. The human cells used in this study were donated by one of the participants who is unique because they have two copies of the mutated gene.
“I’ve never met a study participant who was so eager and enthusiastic to be part of the scientific process,” said study author Dr. Cynthia Tifft of NIH’s National Human Genome Research Institute. “It’s inspiring to work with someone who stays positive and engaged while this disorder robs them of control over their body. I’m motivated everyday knowing that the work we’re doing matters.”
While the current breakthrough is not a cure or viable treatment yet, researchers believe they are on the path to a potential treatment. Future studies will investigate the best ways to deliver the genetic edit to the central nervous system and brain. Many other gene-editing studies have used a method known as an adeno-associated virus (AAV) to deliver DNA edits to targeted cells. An AAV is a non-enveloped virus that can be engineered as a delivery vehicle but faces issues in many adults who may already have developed antibodies against some of the common virus particles used for the delivery mechanism. Another hurdle is engineering a delivery method that can cross the blood-brain barrier, an area where AAV vectors may need improvement.
Researchers have specifically 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. People with LOTS have about a 4-6% beta-hexosaminidase A enzyme activity level, while infants have no activity in the enzyme, thus making the buildup of damaging GM2 ganglioside more rapid. Children diagnosed with the juvenile form of the disease often die in their teens.
Mutations in the HEXA gene that cause Tay-Sachs disease are known to be 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.
The NIDDK, part of the NIH, conducts and supports basic and clinical research and research training on some of the most common, severe, and disabling conditions affecting Americans. The Institute’s research interests include diabetes and other endocrine and metabolic diseases; digestive diseases, nutrition, and obesity; and kidney, urologic, and hematologic diseases. For more information, visit https://www.niddk.nih.gov/.
About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
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Reference
Allende, M et al. “CNS-targeted base editing of the major late-onset Tay-Sachs mutation alleviates disease in mice.” The Journal of Clinical Investigation. J Clin Invest. https://doi.org/10.1172/JCI183434.