HomeHealthGene-edited sheep offer hope for treatment of deadly childhood disease

Gene-edited sheep offer hope for treatment of deadly childhood disease

Scientists have used a flock of genetically engineered sheep to find a promising treatment for a deadly hereditary brain disease that affects young children. The researchers, based in the UK and US, say their work could lead to the development of drugs to alleviate infantile Batten disease.

In the UK, Batten’s disease affects between 100 and 150 children and young adults and is inherited from two asymptomatic parents, each carrying a rare recessive gene mutation.

Children who carry two copies of this defective gene begin to suffer from vision loss, impaired cognition and mobility problems. Seizures and early death follow. “The effect on families is devastating,” said Professor Jonathan Cooper of Washington University School of Medicine in St. Louis, one of the project’s leaders.

Researchers first began experiments, in collaboration with colleagues at Collaborations Pharmaceuticals, that showed that mice affected by a form of Batten’s disease known as CLN1 disease could be treated with a missing enzyme.

“That 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, of Edinburgh University’s Roslin Institute, where cloning techniques were used to create Dolly. to make the Sheep. in 1996. “You can’t extrapolate directly from mouse experiments to humans. Having an intermediate size larger model is important.”

The project scientists used the Crispr-Cas9 gene editing technique to create a version of the defective gene responsible for CLN1 in sheep. “Sheep ovaries were collected in slaughterhouses, eggs were removed and fertilized. Crispr reagents were added to make the required changes in CLN1, and the eggs were then implanted in surrogate sheep.” The scientists were able to create a small flock of sheep, each designed to carry a single functional copy of the CLN1 gene.

“These are asymptomatic carriers, like the parents of children with Batten disease,” Wishart added. “From this we could then breed sheep that have two defective ones. These continue to develop a disease like those children, and became the subject of our therapy trials.”

Children succumb to this version of Batten’s disease because they lack an enzyme made by healthy CLN1 genes. Without it, the performance of their body’s lysosomes, which recycle waste material that accumulates in cells, is compromised. In Batten’s disease, this process is impeded.

The study in mice showed that injecting the missing enzyme into the brain produced noticeable improvements. But jumping straight to trials on humans wasn’t practical or safe, the group reasoned.

“You can miss two crucial issues,” Cooper added. “How to deliver the drug to the right place in a larger brain and how to scale up the dosage.”

The answers were given by experiments on half a dozen sheep bred from the Roslin herd with two defective CLN1 genes. These showed many features of the disease that affects humans. By calculating an appropriate dose and route to deliver it to sheep’s brains, improvements in their disease could be observed by the team, whose study is published in the Journal of Clinical Investigation.

The results are promising, the scientists say, but they emphasize that several more years of research will be needed to optimize the treatment.

“We have gained tremendous insights that will one day aid 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.”

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