Friday, August 15, 2025

Study of human cells and mice may have implications for other lysosomal storage disorders

Researchers 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 new 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 into 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 HEXA gene that causes a deficiency of an enzyme essential for breaking down a fat in the brain known as GM2 ganglioside. The build-up of this fat damages nerve cells in the brain and spinal cord. The amount of enzyme still produced by the body affects the severity of the disease and the age of onset. By implementing the correction to HEXA gene, the researchers were able to increase the activity of the enzyme, known as beta-hexosaminidase A, delay the onset of symptoms and significantly extend lifespan in the mouse model.

“With LOTS, a small correction will go a long way. This correction 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 the NIH’s National Institute of Diabetes and Digestive and Kidney Diseases. “We’ve found that it’s possible to open the door to increased enzyme activity, now we need to figure out how to do it in a person.”

Researchers believe this level of preclinical work has laid the foundation for building 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 are unique because they have two copies of the mutated gene.

“I have never met a study participant who was so eager and enthusiastic to be a part of the scientific process,” said study author Dr. Cynthia Tifft of the NIH’s National Human Genome Research Institute. “It is inspiring to work with someone who remains positive and committed while this disorder robs them of control over their body. I am motivated every day knowing that the work we do matters.”

Although the current breakthrough is not yet a cure or viable treatment, researchers believe they are on the way to a potential treatment. Future studies will investigate the best ways to deliver the genetic editing 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 problems in many adults who may already have developed antibodies to some of the common virus particles used for the delivery mechanism. Another hurdle is developing a delivery method that can cross the blood-brain barrier, an area where AAV vectors may need improvement.

Researchers have specifically targeted MASS 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 4-6% beta-hexosaminidase A enzyme activity level, while infants have no activity in the enzyme, which accelerates the build-up of harmful GM2 ganglioside. 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 frequently in certain populations, including Eastern and Central European Jewish communities (Ashkenazi Jews), certain French-Canadian communities in Quebec, the Cajun community in 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.

NIDDK, part of the NIH, conducts and supports basic and clinical research and research training on some of the most common, serious and debilitating conditions affecting Americans. The institute’s research interests include diabetes and other endocrine and metabolic diseases; digestive diseases, nutrition and obesity; and renal, urological and hematological 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 part of the US Department of Health and Human Services. NIH is the primary federal agency that conducts and supports basic, clinical, and translational medical research investigating the causes, treatments, and cures for both common and rare diseases. For more information about the NIH and its programs, visit www.nih.gov.

NIH…turning discovery into health^®

Reference

Allende, M et al. “CNS-targeted base editing of the large late-onset Tay-Sachs mutation ameliorates disease in mice.” Journal of Clinical Investigation. J Clin Invest. https://doi.org/10.1172/JCI183434.