Enzyme replacement therapy in mice and sheep slowed brain degeneration
Hemanth Ramesh Nervagar
The bright green staining on this slide indicates that large amounts of material accumulate within brain cells when the lysosome, the cell’s waste disposal and recycling system, is defective. This occurs in her CLN1 disease, a fatal neurological disorder that affects infants and young children because a key lysosomal enzyme is missing. Animal studies led by Washington University in St. Louis and the Rosslyn Institute in Scotland have shown that supplementing with this deficient enzyme improves the condition.
At birth, the children appear healthy. Within a few years, however, infants and young children with Batten’s disease, a rare but fatal brain disorder, develop blindness, seizures, dementia, and the inability to walk. die in infancy.
But new research in animals by scientists from the Washington University School of Medicine in St. Louis and the Rosslyn Institute at the University of Edinburgh in Scotland suggests that enzyme replacement therapy may slow brain degeneration. evaluated the treatment in mice, and Scottish researchers evaluated it in a sheep model of the disease.
This study was recently published in the Journal of Clinical Investigation.
“Our study demonstrates the potential for new therapies to treat this devastating and deadly disease,” said the study’s co-lead authors. Dr. Jonathan D. Cooper, Professor of Pediatrics, Genetics, and Neurology at the University of Washington. “Not only did we improve the disease in mice, but we successfully scaled it up to have similar partial efficacy in a much larger brain in a sheep model of the same disease. Our goal is Batten’s disease. children can be treated, which is an important step forward.”
Batten’s disease refers to a group of hereditary nervous system disorders involving the cell’s inability to remove and recycle cellular waste. Also known as neuronal ceroid lipofuscinosis, the condition is named for the waste products that build up inside cells. The disease often begins in childhood and is categorized by the causative gene and the age of onset depending on which gene is mutated.
The prevalence of Batten’s disease remains unknown. However, some researchers estimate that her 2 to 4 of her 100,000 children in the United States are affected.
“Children with this disease typically lack one very important enzyme that helps break down materials in their cells so they can be recycled.” It causes degeneration and leads to death.”
Using genetically modified mice and sheep, scientists found that monthly feedings of the animals’ brains and spinal cords with a deficient enzyme known as PPT1 reduced the severity of the disease. The injections improved motor function, reduced signs of disease in the brain, and reduced brain substance loss over six months.
“Using mice, we were able to deliver the right dose of enzyme and determine the optimal route for delivery,” Cooper explained. This is an important step in determining whether we can ultimately do the same for affected children. “
Roslyn Lab scientist — famous for cloning Dolly the sheep in 1996 — Using the genome editing technique CRISPR/Cas9, we have developed a sheep model of infantile Batten’s disease. “While mice have relatively simple brains, sheep brains are similar in size and complexity to human children, making them ideal for investigating whether much larger brains can be treated,” Cooper said. “Sheep lacking the enzyme show symptoms similar to those of disabled children, such as changes in brain size.” and showed a corresponding improvement in brain pathology.”
Dr. Tom Wishart, Professor of Molecular Anatomy and Deputy Director of the Roslin Institute, added: Work like this is an important step towards everyone’s ultimate goal of safely conducting clinical trials of potential treatments for children affected by this devastating condition. Through targeted research, we have gained invaluable insight into the progression of this condition and can guide our work to develop effective treatments for affected children. . ”
