Assessing the potential of rAAV9 systemic gene therapy for GM2 gangliosidoses using a Sandhoff mouse model

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Altaleb, Naderah
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Nature Publishing Group
The infantile GM2 gangliosidoses are severe neurodegenerative disorders, caused by a defect in the β-hexosaminidase system. They are characterized by lysosomal accumulation of the substrate, GM2 ganglioside, which results in severe neuronal damage and death in the early years of life. Sandhoff mice deficient in both major hexosaminidase isozymes, Hex A and Hex B, mimic the disease severity in the human condition including the motor deterioration, histopathological findings, and premature death. To investigate the utility of systemic adeno-associated virus 9 (AAV9)-based gene delivery in treating GM2 gangliosidoses, we evaluated the therapeutic outcome of a single intravenous injection of recombinant AAV9 encoding the complementing Hexb gene in a Sandhoff mouse model. We showed prolonged survival, preserved motor function, and reduced GM2 ganglioside accumulation as well as inflammation when systemic AAV9 therapy was administered to 1-2 days old mice. However, the formation of liver or lung tumours accompanied the positive therapeutic effect.
Gene therapy, GM2 gangliosidoses, AAV9
Walia, J. S.; Altaleb, N.; Bello, A.; Kruck, C.; LaFave, M. C.; Varshney, G. K.; Burgess, S. M.; Chowdhury, B.; Hurlbut, D.; Hemming, R.; Kobinger, G. P.; Triggs-Raine, B. Long-Term Correction of Sandhoff Disease Following Intravenous Delivery of rAAV9 to Mouse Neonates. Mol Ther 2015.