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At birth, children appear healthy. But within a few years, toddlers and young children with childhood Batten disease, a rare but deadly brain disorder, succumb to blindness, seizures, dementia and become unable to walk. No cure exists and most die in infancy.

But new animal research from scientists at Washington University School of Medicine in St. Louis and the Roslin Institute at the University of Edinburgh in Scotland suggests that enzyme replacement therapy may slow brain degeneration. The University of Washington researchers evaluated the therapy in mice, and Scottish researchers evaluated the treatment in a sheep model of the disease. The findings point to potential treatments for the genetic condition, also known as CLN1 disease.

The study was recently published in the Journal of Clinical Investigation.

“Our work has shown the potential for a new therapy to treat this devastating, deadly disease,” said study co-lead author Jonathan D. Cooper, a professor of pediatrics, genetics and neurology at the University. from Washington. “Not only did we improve the disease in mice, but we were able to scale it up to have similar partial efficacy in the much larger brain of a sheep model of the same disease. Our goal is to be able to treat children with Batten’s disease, and this is an important step forward.

Batten disease refers to a group of inherited disorders of the nervous system that involve a cell’s inability to eliminate and recycle cellular waste. The condition, also known as neuronal ceroid lipofuscinoses, gets its name from the waste products that build up inside cells. This disease often begins in childhood and is classified according to the culprit gene and the age of onset of symptoms, which varies according to the mutated gene.

The number of people with Batten disease remains unknown; however, some researchers have estimated that it affects two to four in every 100,000 children in the United States

“Children with this condition lack a very important enzyme that normally helps break down material inside cells so it can be recycled,” Cooper said. “When the enzyme is missing, it causes progressive brain degeneration that leads to death.”

Using genetically modified mice and sheep, scientists found that supplying the animals’ brains and spinal cords with monthly doses of the deficient enzyme, known as PPT1, reduced disease severity. Specifically, the infusions improved motor function, decreased signs of disease in the brain and, over a six-month period, decreased loss of brain material.

“Using mice, we were able to administer an appropriate dose of the enzyme and determine the best route of administration,” Cooper explained. “We were then able to extrapolate this method and extend it to have similar benefits in much larger sheep brains. This is a crucial step in knowing if we could finally do the same for affected children.

Scientists from the Roslin Institute, famous for cloning the sheep Dolly in 1996 developed a sheep model for childhood Batten disease using CRISPR/Cas9 genome editing technology. “Mice have relatively simple brains, but because sheep brains are closer in size and complexity to human children, they are ideal for finding out if we can process a much larger brain as well,” Cooper said. “Sheep with the missing enzyme show similar symptoms to children with the disease, including changes in brain size. Our colleagues in Scotland measured them with MRI imaging much like you would in children, and we showed corresponding improvements in brain pathology.

Tom Wishart, Professor of Molecular Anatomy and Deputy Director of the Roslin Institute, added: “This study could only be performed by a collaborative research team. Such work is a key step towards everyone’s ultimate goal of safely conducting clinical trials of potential treatments in children affected by this devastating disease. Through studies in sheep, we gain invaluable insight into the progression of this disease, which can guide our work towards developing an effective therapy for affected children.

Nelvagal HR, Eaton SL, Wang SH, Eultgen EM, Takahashi K, Le SQ, Nesbitt R, Dearborn JT, Siano N, Puhl AC, Dickson PI, Thompson G, Murdoch F, Brennan PM, Gray M, Greenhalgh SN, Tennant P , Gregson R, Clutton E, Nixon J, Proudfoot C, Guido S. Lillico SG, Whitelaw BA, Lu J, Hofmann SL, Ekins S, Sands MS, Wishart TM, Cooper JD. Cross-species efficacy of enzyme replacement therapy for CLN1 disease in mice and sheep. The Journal of Clinical Investigation. Published online August 30, 2022. DOI:

This research was supported by the National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health (NIH) grants R43 NS107079, R43NS107079-01S1, 3R43NS107079-01S2, R56 NS117635, R01 NS124655, and R01 NS100779; Haley’s Hero Foundation; the UK Biotechnology and Biological Sciences Research Council awards research and innovation grants J004316/1 and P013732/1; the RS Macdonald Charitable Trust, the University of Washington Department of Pediatrics; and the McDonnell International Scholars Academy.

About Washington University School of Medicine

WashU Medicine is a world leader in academic medicine, including biomedical research, patient care, and educational programs with 2,700 faculty. Its National Institutes of Health (NIH) research funding portfolio is the fourth largest among U.S. medical schools, has grown 54% over the past five years, and with institutional investment, WashU Medicine is spending more a billion dollars a year for basic and clinical research. innovation and training. Its faculty practice is consistently ranked among the top five in the nation, with more than 1,790 faculty physicians practicing at more than 60 sites who also serve on the medical staff of BJC HealthCare’s Barnes-Jewish and St. Louis Children’s Hospitals. WashU Medicine has a rich history of MD/PhD training, recently dedicated $100 million in scholarships and curriculum renewal for its medical students, and is home to top-notch training programs in every medical subspecialty as well as physiotherapy, occupational therapy, and audiology and communication sciences.

Originally published by School of Medicine