For inherited
genetic diseases, fetal gene therapy offers the potential of prophylaxis against early, irreversible and lethal pathological change. To explore this, we studied neuronopathic
Gaucher disease (nGD), caused by mutations in GBA. In adult patients, the milder form presents with
hepatomegaly,
splenomegaly and occasional lung and
bone disease; this is managed, symptomatically, by
enzyme replacement therapy. The acute childhood lethal form of nGD is untreatable since
enzyme cannot cross the blood-brain barrier. Patients with nGD exhibit signs consistent with hindbrain neurodegeneration, including neck hyperextension,
strabismus and, often, fatal apnea1. We selected a mouse model of nGD carrying a loxP-flanked
neomycin disruption of Gba plus
Cre recombinase regulated by the keratinocyte-specific K14 promoter. Exclusive skin expression of Gba prevents fatal neonatal
dehydration. Instead, mice develop fatal neurodegeneration within 15 days2. Using this model, fetal intracranial injection of adeno-associated virus (AAV) vector reconstituted neuronal
glucocerebrosidase expression. Mice lived for up to at least 18 weeks, were fertile and fully mobile. Neurodegeneration was abolished and
neuroinflammation ameliorated. Neonatal intervention also rescued mice but less effectively. As the next step to clinical translation, we also demonstrated the feasibility of ultrasound-guided global AAV gene transfer to fetal macaque brains.