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Publication Detail
Intravenously administered gene therapy for neuronopathic Gaucher disease
Gaucher disease is a lysosomal storage disorder caused by mutations in the GBA1 gene encoding the enzyme glucocerebrosidase (GCase). Deficiency of GCase causes the accumulation of its substrate glucosylceramide in both visceral organs and the brain. Enzyme replacement therapy is successfully used to ameliorate the visceral pathology, however there is no treatment available for the lethal neurodegeneration. This research focuses on Gaucher disease type II, the most acute neuronopathic form, in which the neuropathology results in death during early infancy. The aim of this project is to intravenously administer adeno-associated viral vector (AAV) based gene therapy to a GCase-deficient mouse model of acute neuronopathic Gaucher disease and assess improvement in lifespan, behaviour, brain and visceral pathology. The untreated Gba1 knock-out mice die 12-14 days after birth following severe neurodegeneration. The AAV vector carrying the functional human GBA1 gene under control of a ubiquitous promoter was intravenously administered to neonatal knock-out mice, with treated animals showing a significant increase in their lifespan (p=0.0081). Since the animals did not develop any evident pathological symptoms, they were sacrificed at 55 days of age for a short-term study. The neuropathology was ameliorated and several of the most affected areas of the brain were partially rescued. The analysis of liver, spleen, lung and heart tissues revealed promising improvements in the visceral pathology. A consequent long-term study was performed on 180-day-old treated mice, with the aim to compare intravenous and intracranial administration of the viral vector. In order to enhance the therapeutic effects of the treatment and improve gene expression in the central nervous system, a novel construct where the GBA1 gene is controlled by a neuron-specific promoter was administered to neonatal knock-out mice. The severe neurodegeneration was further rescued and the life span of treated animals increased. Together, these encouraging results demonstrate that gene therapy could provide an effective treatment for the neuronopathic form of Gaucher disease, for which therapeutic needs are currently unmet.
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