Gene-Therapy on Foetuses to Treat Fatal Neurodegenerative Disease

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Prenatal gene therapy has been used to prevent acute neuronopathic Gaucher’s disease. The disease is caused by mutations that disrupt the GBA gene and the enzyme in which it encodes. The disruptions lead to a build-up of fatty molecules in brain cells and other parts of the body, which in turn contributes to organ dysfunction. As a result, children suffering from this disease rarely live past the age of 2.

The study, published in Nature Medicine, used mouse models, supplying normal copies of GBA gene to developing foetuses using a virus in an attempt to minimise the irreversible brain damage that arises due to the fatty build-up.

Some forms of Gaucher’s disease can be treated by supplying normal copies of the GBA enzyme to break down lipids, but the enzyme is unable to cross from the blood into the brain. However, the disease is so devastating that colleagues were sceptical about his team’s ability to treat it, says Waddington. “People told me, ‘You’re not going to touch this.’”

The viral delivery of the GBA gene copy had a impressive level of success in mice. The mice models carrying GBA mutations normally live for only 15 days after birth; treated mice, however, survived for at least 18 weeks and were able to move about normally.

Simon Waddington, lead author of the latest study, says he used to meet with shocked stares when he talked about treating foetuses with gene therapy. “It had gotten to the point where I’d given up on telling people that foetal gene therapy is a good idea,” says Waddington, who studies gene therapy at University College London. “And now, not infrequently, people turn to me and say, ‘You know what would be a good idea? Foetal gene therapy.’”

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Not only have attitudes changed, the work has been praised by peers in the industry. The work is impressive, says Tippi MacKenzie, a fetal-medicine specialist at the University of California, San Francisco. MacKenzie has been conducting a clinical trial of prenatal stem-cell transplants. “Fetal gene therapy or enzyme-replacement therapy may be the next frontier,” she says. “It is wonderful to see this kind of rigorous research, to take us one step further.”

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The early action taken with foetal gene therapy has some huge benefits:

  • Minimising the damage caused by genetic disease, some of which cause irreversible symptoms before birth
  • The blood-brain barrier isn’t yet fully formed meaning that administration is much easier
  • As the foetal immune system is still developing, newly expressed proteins are less likely to be recognised as foreign and rejected from the body.

However, like with all therapeutic approaches, there are some potential risks that mustn’t be ignored.

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With prenatal gene therapy must think not only about the foetus, but also about the mother, who will inevitably receive a dose of treatment as well, says Jerry Chan, an obstetrician and gynaecologist at Duke–NUS Medical School in Singapore.

Clinicians must also be absolutely certain that the mutation they’ve found will cause disease, notes Waddington. This may mean combining genetic tests with other tests performed in utero to confirm the disorder. “We’re now at the point where it’s possible to diagnose these diseases,” he says. “It’s making people think: maybe we should be doing this.”

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