Source: The Guardian

Scientists have created a flock of sheep that carry the gene for a lethal inherited brain disorder in humans. The condition, Batten disease, usually starts in childhood and is invariably fatal, often within a few years of diagnosis.

The project, which is designed to test treatments for the disease, is based at Edinburgh University’s Roslin Institute, where cloning techniques were used to create Dolly the sheep in 1996. The scientists acknowledge that the approach could be controversial as it involves creating animals programmed to die, but stress that their aim is to alleviate human suffering.

“We have deliberately re-created the condition in a large mammal because sheep have a brain of a similar size and complexity to that of a child,” said Tom Wishart, project leader. “That means treatments we test on them are much more likely to be relevant to humans than those tested only on cell cultures or mice and rats.”

In the UK, Batten disease affects between 100 and 150 children and young adults. It is inherited from two symptomless parents who each carry a rare recessive gene mutation. That mutation interferes with the operation of lysosomes, which act as the waste disposal systems for cells. Children who carry two copies of the faulty gene begin to suffer loss of vision, impaired cognition and mobility problems. Seizures and early death follow. “It is devastating for families,” Wishart said.

There are several types of Batten disease, he added. “One of the more rapid types is CLN1, and that’s what we have recreated in our sheep.”

The Roslin scientists used the gene-editing technique Crispr-Cas9 to create the faulty CLN1 gene in the sheep. “We collected sheep embryos from the abattoir,” Wishart said. “Then we fertilised them and added Crispr reagents to alter their genetic structure before implanting the embryos into a surrogate sheep’s uterus.”

Three sheep were born that each possessed two copies of the CLN1 gene with the same mutation found in affected humans. They began to show many symptoms of Batten disease, including changes in behaviour and brain size. “The progress of the disease in sheep closely resembled its development in children,” said Wishart. “That was crucial for it showed we had created an accurate model of Batten disease.”

Other sheep were engineered to carry only a single copy of the gene. “These are symptomless carriers, like the parents of Batten disease children,” said Wishart. “From these we can breed sheep that have two faulty copies of the CLN1 gene. These will go on to develop a disease like those children, and will be the ones to test our therapies.”

Researchers are working on several treatments, including gene therapy in which healthy genes are delivered by viruses to replace mutated versions. Many of these techniques are being developed using cell culture and research on mice and rats.

It is a terrible necessity – to reproduce such a condition Tom Wishart

“These studies are crucial in making basic discoveries,” said Wishart. “But if we do not use these few larger animals in refining those discoveries, all that early work could be wasted.

“It is a terrible necessity – to reproduce such a condition. However, we are talking about using maybe only 10 or so animals for this research with the ultimate aim of finding treatments that could add years to the lives of young patients.

“Unlike humans, we can study sheep before their outward symptoms develop to gain new understanding of how the disease unfolds. This knowledge will be invaluable.”