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Fetal Gene Therapy Prevents Lethal Neurodegenerative Disease

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Researchers have successfully prevented the development of a fatal neurodegenerative disorder, Gaucher disease, using fetal gene therapy, in mice. The study, published in Nature Medicine, highlights the potential of using this approach to combat lethal neurodegenerative diseases affecting newborns.

“Our study provides evidence that the visceral symptoms of “mild” – Type I Gaucher disease, namely hepatomegaly & splenomegaly, are amenable to treatment by gene therapy,” comments Simon Waddington, Professor of Gene Therapy, EGA Institute for Women’s Health, University College London, UK, corresponding author of the study.

What is Gaucher disease?

Gaucher disease is an inherited metabolic disorder whereby a specific type of lipid (glucocerebroside) cannot be degraded efficiently due to a lack of the enzyme glucocerebrosidase, which is caused by mutations in the gene (GBA) that controls the production of the enzyme. Glucocerebrosidase usually degrades and recycles glucocerebroside, however in Gaucher disease, the lipid accumulates in cells within the liver, spleen, bone marrow and nervous system. This build up results in numerous symptoms including: 
  • liver and spleen swelling
  • anemia
  • bone disease (leading to fractures and pain)
  • a susceptibility to bruising
  • seizure and brain damage

It is worth noting that there are three types of Gaucher disease, each with a range of symptoms – not all neuropathic. For those diagnosed with mild forms, the disease can usually be treated using enzyme replacement therapy – intravenous infusion of a modified version of the enzyme administered every two weeks to compensate for the lack of glucocerebrosidase. However, for the more severe forms of Gaucher – that can cause irreversible neurodegeneration – the condition is often lethal.   

Using a murine (mouse) model, the researchers delivered a viral vector in to the fetal brain via intracranial injection. This vector was engineered to ‘re-express’ GBA – the gene encoding glucocerebrosidase.

“We used an AAV9 vector to deliver the human glucocerebrosidase gene to mice. This vector has been shown to spread throughout the central nervous system when injected intracerebroventricularly, and to cross the blood brain barrier into the nervous system when delivered intravenously, early in life,” explains Waddington.

Neurodegeneration was abolished and neuroinflammation was notably reduced in those animals receiving the therapy. In addition, their lifespan was considerably longer than the untreated group.

As the results obtained in the murine model were so promising, the researchers performed a subsequent study using macaques (non-human primates) to determine the feasibility of delivering the transgene using a viral vector to an animal model with greater similarity to humans, enabling them to collect more accurate preclinical data.   

“We provide evidence that gene therapy early in life (in the neonatal or fetal period) could profoundly ameliorate the neurodegeneration manifest in the most severe end of the spectrum of Gaucher disease (also sometimes referred to as Type II).”

Waddington touches on next steps: “We are now working with Apollo Therapeutics to develop and optimize the vector system in order to treat Gaucher disease postnatally.”

Prof Simon Waddington was speaking to Laura Elizabeth Mason, Science Writer for Technology Networks.

Apollo Therapeutics is a drug discovery organization established to enable academic findings to be more effectively translated into future therapeutics.


Learning About Gaucher Disease. (2012). National Human Genome Research Institute, NIH. Retrieved from https://www.genome.gov/25521505/learning-about-gaucher-disease/#al-2
Giulia Massaro et al. Fetal gene therapy for neurodegenerative disease of infants. Nature Medicine. (2018). Available at:  https://www.nature.com/articles/s41591-018-0106-7