AAV-mediated GBA1 and GDNF rescue neurological defects in a murine model of neuronopathic Gaucher disease.

Neuropathic Gaucher disease (nGD) is a life-threatening disease that progresses rapidly and is caused by a glucosylceramidase beta 1 (GBA1) mutation, which encodes the lysosomal hydrolase β-glucocerebrosidase (GCase). Nerve damage in nGD, associated with stunted growth and development, arises from the degeneration and death of nervous system cells, which is often irreversible. Approved therapies effectively reduce the substrate burden outside the central nervous system (CNS) through augmenting mutant enzyme activity with pharmacologic recombinant GCase or by inhibiting glucocerebroside synthesis. However, these therapies do not provide neuroprotection. In this study, we developed a novel double-gene therapy based on adeno-associated virus (AAV), AAV9-GBA1-GDNF, which stably expresses human GBA1 and glial derived neurotrophic factor (GDNF) over the long term. Pathological, molecular, and proteomic tests in the nGD model confirmed that the early stages of the disease are characterized by GBA1 deficiency, loss of neuronal function, and even neuronal death. After treatment with AAV9-GBA1-GDNF, the lifespan of nGD mice was extended, and weight, brain development, and motor ability were recovered. Additionally, GBA1 and GDNF additively prevented irreversible neuronal death by activating the AKT/GSK3β pathway. These findings offer potential therapeutic strategies for nGD and other neurodegenerative diseases associated with lysosomal dysfunction.