Delivery of Glucosylceramidase Beta Gene Using AAV9 Vector Therapy as a Treatment Strategy in Mouse Models of Gaucher Disease

Abstract

Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by mutations in the GBA gene. Enzyme replacement treatment is the most effective therapy available for type 1 GD patients, but it is very expensive and does not improve neurologic outcomes in type 2 and 3 GD patients. This study evaluated the effectiveness of an adeno-associated virus 9 (AAV9) vector expressing the Gba gene delivered systemically in GD mouse models. To detect the therapeutic effects of the AAV9-mediated Gba transfer on the systemic symptoms of GD, an inducible whole-body Gba knockout mouse was developed in which tamoxifen effectively induced whole-body Gba gene deletion, and the mice displayed systemic symptoms of GD. The AAV9-CMV-Gba vector, with the expression of Gba driven by the universal CMV promoter, restored GCase activity in multiple organs and prolonged the lifespan in tamoxifen-induced GD mice after intravenous injection. Mice with brain-specific Gba deletion were also included in this study as a model of neuropathic GD (nGD) and injected intraperitoneally on postnatal day 5 with the AAV9-SYN-Gba vector; this improved the GCase activity, ameliorated the neuropathological changes and extended the mean lifespan two-fold. This study demonstrates that AAV9-mediated gene transfer is a potentially effective treatment for GD.

Fetal gene therapy for neurodegenerative lysosomal storage diseases

“…14 Gene therapy in mouse models of GD has been reported, previously. Both ex vivo lentiviral 15 and in vivo AAV-mediated 16,17 gene therapies have shown an improvement of the visceral phenotype. Massaro et al present, for the first time, a long-term amelioration of GD neuropathology after both central and systemic delivery of gene therapy.…”

“…A second group recently observed a reduction in GD neuropathology after systemic AAV9 gene therapy. 16 This therapeutic strategy is promising for nGD, for which enzyme replacement therapy is ineffective.…”

Systemic AAV9 gene therapy using the synapsin I promoter rescues a mouse model of neuronopathic Gaucher disease but with limited cross-correction potential to astrocytes

“…Systemic delivery of AAV9 in two different nGD mouse models has been already attempted by Du and colleagues ( 35 ). Intravenous injection of an AAV9.CMV.Gba vector expressing the murine wild-type gene was administered 30 days before tamoxifen induction to Gba(flox/flox),UBC-CreERT2 mice, resulting in extension of the life span and increased GCase activity in the brain, liver and spleen of treated mice.…”

Ablation of Zfhx4 results in early postnatal lethality by disrupting the respiratory center in mice

“…The brains were cut sagittally. Sections of the different tissues were stained with hematoxylin and eosin, as reported previously ( Xiao et al, 2016 ; Du et al, 2019 ).…”