A flock of genetically modified sheep has been used by scientists to identify a promising treatment for a deadly inherited brain disease that afflicts young children. The researchers, based in the UK and US, say their work could lead to the development of drugs to relieve childhood Batten disease.
In the UK, Batten disease affects between 100 and 150 children and young adults and is inherited from two asymptomatic parents each carrying a rare recessive genetic mutation.
Children who carry two copies of this defective gene begin to suffer from vision loss, cognitive impairment and mobility problems. Convulsions and premature death ensue. “The effect on families is devastating,” said Professor Jonathan Cooper of Washington University School of Medicine in St Louis, one of the project leaders.
The researchers first started experiments, together with colleagues at Collaborations Pharmaceuticals, which showed that mice with a form of Batten disease, known as CLN1 disease, could be treated with a missing enzyme .
“It was encouraging, but we needed to test the treatment in larger brains with a structure more like a child’s,” said another project leader, Professor Tom Wishart, from the Roslin Institute in the United States. ‘University of Edinburgh, where cloning techniques were used to create Dolly the Sheep. in 1996. “You can’t directly extrapolate from mouse experiments to humans. Having a larger intermediate model is important.
Project scientists used the Crispr-Cas9 gene-editing technique to create a version of the faulty gene responsible for CLN1 in sheep. “The sheep ovaries were taken from the slaughterhouses, the eggs were taken and fertilized. Crispr reagents were added to make the required changes in CLN1 and the eggs were then implanted into surrogate sheep. The scientists were able to create a small flock of sheep, each engineered to carry a single functional copy of the CLN1 gene.
“They are asymptomatic carriers, like parents of children with Batten disease,” Wishart added. “From these, we could then breed sheep that have two defective copies. They develop a disease like these children and have become the subjects of our therapeutic trials.
Children succumb to this version of Batten disease because they lack an enzyme made by healthy CLN1 genes. Without it, the performance of their body’s lysosomes, which recycle waste that accumulates in cells, is impaired. This process is impeded in Batten disease.
Research in mice found that injecting the missing enzyme into the brain produced noticeable improvements. But jumping straight to human trials was neither practical nor safe, the group said.
“You can miss two crucial issues,” Cooper added. “How to get the drug to the right place in a bigger brain and how to increase the dosage.”
The answers were provided by experiments on half a dozen sheep from Roslin’s flock with two faulty CLN1 genes. These showed many hallmarks of the disease that affects humans. By calculating an appropriate dose and the route to deliver it to the brains of sheep, improvements in their disease could be observed by the team, whose research is published by the Journal of Clinical Investigation.
The results are promising, say the scientists, but they point out that it will take several more years of research to optimize the treatment.
“We have gained enormous knowledge that will one day help in the development of therapies for children,” Wishart said. His point was supported by Cooper. “We still have a long way to go, but we have taken a very important step.”