Gene therapy in mouse fetuses treats deadly disease

The method could minimize damage from disease if a condition is diagnosed in utero.

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Gene therapy administered in the womb could be used to treat a deadly genetic disease, a study in fetal mice suggests.

The results could add to the increasingly popular notion of prenatal gene therapy as a way to minimize the damage wrought by some genetic diseases.

The US Food and Drug Administration approved the first gene therapy for adults and children last year, and more treatments are crowding pharmaceutical pipelines around the world.

Simon Waddington, lead author of the latest study, says he used to meet with shocked stares when he talked about treating fetuses with gene therapy. “It had gotten to the point where I’d given up on telling people that fetal 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? Fetal gene therapy.’”

The mouse study, published on 16 July in Nature Medicine1, uses prenatal gene therapy to tackle a condition — acute neuronopathic Gaucher's disease — caused by mutations in a gene called GBA. These mutations disrupt the breakdown of a particular fatty molecule, or lipid. As a result, the lipid accumulates in brain cells and other parts of the body, contributing to organ dysfunction .

The study looks at whether the disease can be treated by using a virus to supply normal copies of GBA to a developing fetus. That could minimize the irreparable brain damage that arises as the lipid accumulates.

Some forms of Gaucher's disease can be treated by supplying normal copies of the GBA enzyme to break down lipids, but that enzyme cannot cross from the blood into the brain. Children with acute neuronopathic Gaucher's disease rarely live past two years. 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.’”

Difficult crossing

One hurdle was simply getting the virus to carry the healthy gene into the brain. Viruses used in previous tests had to be injected directly into the brain, and then they diffused only a short distance from the injection site. But in 2009, researchers showed2,3 that a particular virus, simply injected into the blood, could reach the central nervous system. From there, it dispersed throughout the brain.

Waddington began working with mice, loading up his virus with a normal copy of GBA, and looking for ways to express it specifically in the central nervous system. His team tested its virus in fetal mice carrying GBA mutations that cause symptoms similar to neuronopathic Gaucher's disease. Such mice normally live for only 15 days after birth; treated mice, however, survived for at least 18 weeks and were able to move about normally.

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.”

Early action

Treating fetuses has several potential advantages. Chief among them is the potential to minimize the damage caused by a genetic disease. Some diseases — such as neuronopathic Gaucher's disease and spinal muscular atrophy — can cause irreversible symptoms before birth.

It is also easier to administer some therapies to the brain in a developing fetus than in an adult or child, because the blood–brain barrier — a membrane that prevents some molecules from crossing into the brain from the blood — has not yet fully formed. “Even one day after birth, it’s harder to get into the brain,” says Jerry Chan, an obstetrician and gynaecologist at Duke–NUS Medical School in Singapore.

And the fetal immune system is also still developing, making it less likely to recognize the newly expressed protein as foreign. Adult immune systems sometimes generate antibodies against the new protein, which could prevent it from carrying out its function.

Chan and others have previously tested fetal gene therapy to treat haemophilia in mice and macaques, and Chan expects that there will be interest in doing so for several metabolic diseases similar to Gaucher's.

But there are risks. Researchers developing a prenatal gene therapy must think not only about the fetus, but also about the mother, who will inevitably receive a dose of treatment as well, says Chan.

And clinicians have to 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.”

Nature 559, 313-314 (2018)

doi: 10.1038/d41586-018-05726-5


  1. 1.

    Massaro, G. et al. Nature Med. (2018).

  2. 2.

    Foust, K. D. et al. Nature Biotechnol. 27, 59-65 (2009).

  3. 3.

    Duque, S. et al. Mol. Ther. 17, 1187-1196 (2009).

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