New gene, new strides in gangliosidosis

Imagine a new factory built to produce snacks. Several machines work together to transform potatoes into chips — from washing, slicing and salting the potatoes to cooking and packaging them. A conveyor belt takes the prepared chips to be packaged and sent to warehouses. But the conveyor belt machinery is faulty from the very beginning, so when the factory begins production, chips are prepared but nothing is packaged or sent out. All the chips pile up in one place. Over time, these piles of chips interfere with the machinery, causing the whole factory to shut down.

Something similar happens in the brain of Jojo, a little girl born with the neurodegenerative disorder GM1 gangliosidosis. Lipids accumulate in her brain cells because the machinery that breaks down those lipids is faulty.

GM1 gangliosidosis is caused by mutations in the GLB1 gene that codes for an enzyme called lysosomal β-galactosidase. This enzyme breaks down a lipid called GM1 ganglioside. The deficiency of this enzyme causes GM1 ganglioside to accumulate, which results in severe symptoms, including delayed growth and development, enlarged liver and spleen, poor muscle tone, skeletal abnormalities and impaired vision.

When Jojo first arrived at the National Institutes of Health in 2016 at the age of 7, she was able to walk, talk and write. Within three years, she needed help standing, walking, speaking and doing almost every activity. In 2019, 10-year-old Jojo became the first person to receive an experimental gene therapy treatment for GM1 gangliosidosis.

In 2023, Laura Allende and her colleagues at the NIH were working on a disorder similar to GM1 gangliosidosis: Tay-Sachs disease. Tay-Sachs is caused by a mutation in the HEXA gene, which codes for an enzyme responsible for degrading GM2 ganglioside. When Allende genetically altered mice to mirror the mutation in humans, she found that the mice had less severe symptoms than humans. This led her team to think an alternative gene was creating a bypass pathway to break down the accumulated lipids in the mice, leading to a less severe form of the disease.

Ernesto Del Aguila III/National Human Genome Research Institute

Jojo, the first recipient of a new GM1 gangliosidosis gene therapy treatment, and Cynthia Tifft, an author on the JLR study, celebrate with a tea party.

The researchers postulated that an alternative gene, sialidase NEU3, was helping to degrade the lipids. So, even when the HEXA gene malfunctioned, the bypass pathway created by NEU3 caused the mice to have less severe Tay-Sachs.

Allende and her team then hypothesized that NEU3 can also mitigate symptoms in GM1 gangliosidosis. In a recent article published at the Journal of Lipid Research, they confirmed that NEU3 provided an alternate route for GM1 ganglioside degradation, leading to a less severe form of the GM1 gangliosidosis.

To do this, the researchers genetically altered one group of mice to lack mutations of the GLB1 gene and a second group to lack both GLB1 and NEU3 genes. They compared the symptoms of both groups and compared their GM1 lipid levels. The mice with NEU3 had less severe symptoms while those lacking both genes showed symptoms similar to those in human patients.

So, why can’t humans, who also have the NEU3 gene, use the bypass pathway to degrade the lipids?

“We tested human cells for the NEU3 gene and its associated enzyme activity,” Allende said. “We found that the gene is not so active in humans, due to having a different genetic sequence than the one found in mice.”

But Allende thinks this discovery can still help people with the disease.

“Knowing about NEU3 will help open up new potential therapeutics for GM1 gangliosidosis in humans,” she said. “Our next step will be to observe how NEU3 operates. If we can turn on this alternative pathway in humans or make the NEU3 enzyme more active towards lipid degradation, then we can help alleviate the symptoms and progression of this disease in patients.”

GM1 gangliosidosis affects infants and can progress quickly, sometimes resulting in death during childhood; the earlier the disease is diagnosed the greater the chances are for a longer and better life.