Off-label use of FDA-approved 4-phenylbutyric acid yields positive results in treating rare genetic disorders like Sandhoff and Tay-Sachs.
In a pioneering study, researchers at McMaster University have discovered a possible treatment for Sandhoff and Tay-Sachs diseases—two rare and typically fatal lysosomal storage disorders that lead to the gradual destruction of nerve cells in the brain and spinal cord (1✔ ✔Trusted Source
4-Phenylbutyric acid mitigates ER stress-induced neurodegeneration in the spinal cords of a GM2 gangliosidosis mouse model
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After years of studying the diseases’ underlying mechanisms, the research team has pinpointed an FDA-approved drug that could greatly enhance the quality of life for patients and their families affected by these conditions.
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The Struggles of Patients with Sandhoff and Tay-Sachs Diseases
“Sandhoff and Tay-Sachs are devastating diseases,” says Suleiman Igdoura, a professor of biology and pathology who has been researching these conditions for years. “They’re marked by progressive loss of motor functions – from sitting, standing, and swallowing to even breathing – as neurons in the nervous system die. Watching someone go through this is heartbreaking.”
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Early Symptoms and Potential for Later Onset
Tay-Sachs disease, the more common of the two disorders, typically manifests within the first year of life, progressing quickly and often proving fatal within a few years. In rare cases, symptoms of Tay-Sachs and Sandhoff disease appear later in childhood or even in early adulthood, progressing more slowly and offering a longer—but still profoundly challenging—life course.
“Patients often require intensive hospital care as symptoms worsen, and our current treatment options are severely limited,” explains Igdoura. “But now, there’s hope.”
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Spinal Cord as the Starting Point for Disease Progression
By studying late-onset cases, Igdoura and his team uncovered that these diseases begin in the spinal cord, where chronic stress on a cellular component called the endoplasmic reticulum triggers programmed cell death. Observing the decline in spinal cord neurons in late-onset patients provided crucial insights into how the disease progresses throughout the body.
FDA-Approved 4-PBA as a Potential Treatment
This breakthrough led to the identification of a potential therapeutic compound: 4-phenylbutyric acid (4-PBA), an FDA-approved drug initially developed for another condition. Testing in a mouse model of the disease showed that 4-PBA significantly improved motor function, extended lifespan, and increased the number of healthy motor neurons.
The team’s findings were recently published in the journal Human Molecular Genetics.
A Ray of Hope for Families Affected by Tay-Sachs and Sandhoff
As one of the few labs in the world studying Sandhoff and Tay-Sachs, Igdoura and his team are optimistic that this discovery could be transformative.
“We receive heartbreaking stories from families around the world affected by these diseases,” says Igdoura. “Offering an FDA-approved drug for off-label use could provide hope and improve both life expectancy and quality of life for these patients.”
Further research is underway to identify the optimal human dosage of 4-PBA.
Research Findings Extend to Alzheimer’s and ALS
The insights gained from studying Sandhoff and Tay-Sachs may also have broader implications, potentially informing research into other neurodegenerative diseases such as Alzheimer’s and ALS.
“There may be lessons here that apply to a range of neurodegenerative conditions,” Igdoura says.
Reference:
- 4-Phenylbutyric acid mitigates ER stress-induced neurodegeneration in the spinal cords of a GM2 gangliosidosis mouse model – (https://academic.oup.com/hmg/advance-article/doi/10.1093/hmg/ddae153/7889395)
Source-Eurekalert
