A small genetic correction could be crucial to reduce the symptoms of Tay-Sachs disease: this is the hope of an American team from the National Institutes of Health (NIH) in light of their research work published in The Journal of Clinical Investigation.
Late Tay-Sachs disease (lots, for late-on-tay-sachs Disease) is a rare form of this autosomal recessive lysosomal pathology, which begins at the end of adolescence and is often diagnosed in adulthood. It manifests itself by brain ataxia, muscle weakness, peripheral neuropathy, spasms, and sometimes psychotic symptoms with mood disorders. Tay-Sachs’ disease is caused by mutations in the Hexa gene, which results in an accumulation of GM2 gangliosides in the nervous system, due to a hexosaminidase A enzyme deficit. Its severity, as well as its date of appearance depends on the quantity of hexosaminidase has produced: people with a late form have a level of enzymatic activity from around 4 to 6 %, While infants with early form have a zero level, which accelerates the accumulation of harmful GM2 gangliosides. The prevalence of Tay-Sachs disease is higher in the Jewish populations Ashkénazes and French Canadian.
The late form would concern 500 people worldwide, 25 of whom are followed at the NIH Center for Bethesda, Maryland. One of them, which has two copies of the mutated gene, has given human cells used in the study.
An increase in enzymatic activity of around 10 % would be enough to reduce symptoms
The researchers started by working on human cell cultures (fibroblasts) whose Hexa gene has changed thanks to an adenine basic publisher (ABE): this corrected the 805 g mutation> A by replacing the Guanine base in adenine. In a second step, they experienced this publisher on a Murin model, via A neurotropic virus, and observed an increase in the activity of hexosaminidase A, a reduction in the accumulation of GM2 gangliosides in the brain, a decrease in the brain expression of neuroinflammation markers, a delay in the appearance of symptoms and an extension of the life of the mouse compared to witness mice. This, with minimal “off target” effects.
In the lots, “A slight correction can do a lot. It seems that an increase of only 10 % of enzymatic activity, thanks to genetic publishing, would be enough to prevent the worsening of symptoms and would improve the quality of life ”comments Richard Proia, last author, member of the National Institute of Diabetes and Digestive and Renal Diseases of NIH. “We understood that it was possible to increase enzymatic activity, we must now succeed in doing so in a person. »»
Researchers have potential treatments online, which means finding the best way to practice genetic publishing in the central nervous system and the brain beforehand. Other close pathologies could derive benefits, such as gangliosidosis in GM1, and Sandhoff, Niemann-Pick, Krabbe, and Gaucher’s diseases.
