Comparison of different promoters to improve AAV vector-mediated gene therapy for neuronopathic Gaucher disease.
Giulia MassaroAmy F GeardHemanth R NelvagalKatrina GoreNadine K ClemoSimon N WaddingtonAhad A RahimPublished in: Human molecular genetics (2024)
Gaucher Disease (GD) is an inherited metabolic disorder caused by mutations in the GBA1 gene. It 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 ubiquitous promoters. 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 high levels of enzymatic activity in the brain but lower GCase expression in the viscera, might be the optimal therapeutic strategy for nGD.
Keyphrases
- gene therapy
- genome wide
- copy number
- dna methylation
- genome wide identification
- transcription factor
- gene expression
- endothelial cells
- poor prognosis
- replacement therapy
- early onset
- liver failure
- insulin resistance
- drug induced
- resting state
- body mass index
- prognostic factors
- skeletal muscle
- weight gain
- metabolic syndrome
- long non coding rna
- smoking cessation
- high speed
- amino acid