The enzyme beta-glucocerebrosidase (GBA) is a housekeeping lysosomal enzyme that breaks down a membrane component, glucocerebroside, into a sugar (glucose) and a simpler fat molecule (ceramide). Gaucher’s disease is a rare autosomal recessive disorder caused by two faulty copies of the GBA gene that encodes glucocerebrosidase. The annual incidence is about 1 in 60,000. Type 1 Gaucher’s disease can be treated by regular enzyme replacement therapy. A rarer form of Gaucher’s disease is type 2, the neuronopathic (nGD) form, which usually leads to death before the age of two. The acute childhood lethal form of type 2 is untreatable with enzyme replacement therapy because the enzyme cannot cross the blood-brain barrier.
A mouse model of nGD develops fatal neurodegeneration and animals die at around two weeks of age. Using this model, the authors injected adeno-associated virus (AAV) vector encoding glucocerebrosidase into the foetal mouse brain in order to reconstitute neuronal glucocerebrosidase expression. The treated mice lived for at least 18 weeks after birth, neurodegeneration was abolished and neuroinflammation ameliorated. The figure shows the extent of astrogliosis using Glial Fibrillary Acid Protein (GFAP) a marker.
As the next step to clinical translation, the study also demonstrated the feasibility of ultrasound-guided global AAV gene transfer to foetal macaque brains. This work shows that for inherited genetic diseases like nGD, foetal gene therapy offers the potential for prophylaxis against the early, irreversible and lethal pathological changes.
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