Gaucher Disease is an inherited metabolic disorder caused by mutations in the GBA1 gene. It is the most common lysosomal storage disease and can manifest with severe neurodegeneration and visceral pathology. The most acute neuronopathic form (nGD), for which there are no curative therapeutic options, is characterised by devastating neuropathology and death during infancy. In this study, we investigated the therapeutic benefit of systemically delivered AAV9 vectors expressing the human GBA1 gene at two different doses comparing a neuronal-selective promoter with the ubiquitous chicken-β-actin promoter, on survival, neurodegeneration, motor function, biochemical markers, and visceral pathology. 

High dose gene therapy resulted in extended life span of knock-out mice, normalisation of neuropathological markers and increased enzymatic activity in brain and visceral organs. While supraphysiological expression of glucosylcerebrosidase (GCase) was beneficial in ameliorating the neuropathology, signs of inflammation were present in the viscera of mice treated with the ubiquitous vectors, suggesting that elevated GCase expression may promote inflammation and have deleterious effects in the viscera. We further evaluated the effect of sustained high-levels expression of GCase driven by the CAG promoter in a 1-year long-term study. Our long-term study showed that sustained GCase expression does not fully reverse the brain pathology, as demonstrated by the signs of hyperactivity in the 1-year-old mice treated with CAG.hGBA.

Our results highlight the importance of a careful evaluation of the promoter sequence used in gene delivery vectors, suggesting a neuron-targeted therapy leading to lower GCase expression in the viscera, might be the optimal therapeutic strategy for nGD.