Therapy for fatal childhood brain disease shows promise in genome-edited sheep

Regular enzyme infusions could prove to be an effective treatment for a rare and fatal childhood brain disease.

Infantile Batten disease (also called CLN1 disease) is caused by mutations in a gene that encodes an enzyme called PPT1. It is part of a group of recessive genetic disorders, collectively referred to as Batten Disease - all of which are caused by mutations that give rise to defective lysosomes, meaning the cell's waste disposal and recycling system is impaired.

Jonathan Cooper, professor of paediatrics at the Hope Centre for Neurological Disorders at Washington University in St Louis, who co-led the research, explained, 'Children with this disease lack one very important enzyme that normally helps break down material inside cells so that it can be recycled. When the enzyme is missing, this causes progressive brain degeneration that leads to death.'

While affected children initially appear well, symptoms usually become apparent by two years of age and include blindness, progressive loss of motor functions, seizures, and premature death usually by age nine to 12.

No treatments for CLN1 disease have been developed yet, largely because the disease progresses quickly and the blood-brain barrier presents a challenge for targeting affected brain cells.

However, using mice models of CLN1 disease, recent work shows that monthly injections of the PPT1 enzyme directly into the brain can improve motor function, reduce signs of disease in brain cells, and reduce loss of brain matter over six months of treatment.

Co-lead, Professor Tom Wishart of the Roslin Institute at Edinburgh University, told the Guardian, 'that was encouraging but we needed to test the treatment in larger brains with a structure more like those of a child. You cannot extrapolate straight from mouse experiments to humans. Having an intermediate larger model is important.'

Therefore, the researchers used CRISPR genome editing to create sheep that carried one copy of the faulty CLN1 gene. Breeding these sheep allowed the researchers to create a flock of six sheep who inherited two copies, just as affected children do. Importantly, these sheep also showed disease symptoms similar to affected children.

Having used the mice models to find an appropriate dose of enzyme and to determine the best route for delivery, researchers were then able to extrapolate their findings to the newly developed sheep model. As with the mice, they were able to show that PPT1 infusions led to an improvement in disease symptoms, as demonstrated by MRI scans showing brain size.

'Our work has shown the potential for a new therapy to treat this devastating fatal disease,' said Professor Cooper. 'Not only did we improve the disease in mice, but we were successful in scaling 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 disease, and this is an important step forward.'

The work was published in the Journal of Clinical Investigation.