Gene therapy in womb prevents a fatal neurodegenerative disease

Working copies of the gene were delivered directly into the brains of mouse fetuses before they were born.

In a new study, researchers worked to prevent an inherited condition called Gaucher disease which affects about 1 in 57,000.  The disease is caused by the buildup of fatty chemicals that would normally be broken down by the body. In mild cases of Gaucher disease, doctors can treat the child after birth with enzyme replacement therapies, but more severe forms are currently untreatable and often fatal. In these severe cases, treatment is needed as early as possible. So Simon Waddington and colleagues tested a way to administer gene therapy for the condition in mice before they were even born.

We spoke to Waddington about work.

ResearchGate: How successful was the gene therapy approach at treating Gaucher disease in your study?

Simon Waddington: It was good, but not perfect. We massively extended the lifespan of the mice, from 15 days to over 130 days or longer, but didn’t completely abolish the neuroinflammation. The intracranial gene therapy did not treat the visceral disease (because it was just fixing the neurodegeneration). The intravenous gene therapy completely abolished the visceral disease, which was an unexpected but welcome surprise.

RG: Can you briefly explain how the gene therapy approach you tested works?

Waddington: This was gene supplementation – delivering extra working copies of the glucocerebrosidase (GBA) gene, which encodes the lysosomal enzyme that is deficient in Gaucher's disease. We delivered the genes using a gene therapy vector, a delivery vehicle developed based on viral biology (viruses are great at delivering genetic material). The vector we used has a special property of being able to spread throughout the brain, even when injected intravenously.

RG: What’s significant about this study?

Waddington: The unique aspects of our study were the fact we delivered the therapeutic gene in utero to prevent the neurodegenerative disease from ever occurring. We demonstrated that this vector could be delivered, and result in widespread gene expression to the larger, non-human primate brain.

There are two major take-home points: First, we provide evidence that Gaucher Disease may be treatable, even curable, by gene therapy and that even the acute neuronopathic disease at the extreme end of the Gaucher Disease spectrum may be treatable. Second, we have performed several experiments to demonstrate the feasibility of fetal gene therapy that could be translated to humans.

RG: Do you think this will one day be attempted in humans? If so, when?

Waddington: I think that gene therapy for Gaucher Disease will be a clinical trial within five years. I’m less sure about fetal gene therapy. Fetal stem cell therapy clinical trials have been performed, and there is one already ongoing (BOOSTB4). There was also a really cool fetal protein therapy trial very recently. Probably the first fetal gene therapy would be for a disease where postnatal gene therapy has been attempted, but where there is good evidence that a fetal approach would be substantially better.

RG: Is there any reason that this wouldn’t work as well in humans that it does in mice?

Waddington: Yes – the main reason being that humans are bigger, so spread to the nervous system might not be as effective. However, the more recent clinical trials for haemophilia, spinal muscular atrophy etc. have translated well from mice to humans.

RG: What’s next for this research?

Waddington: We are working with Apollo Therapeutics to develop and optimize vectors for clinical translation postnatally.


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Image courtesy of Tatiana Vdb.