Efficacy of a Bicistronic Vector for Correction of Sandhoff Disease in a Mouse Model

• Published in: Molecular therapy. Methods & clinical development 2019-03, Vol.12, p.47-57
• Main Authors: Woodley, Evan, Osmon, Karlaina J L, Thompson, Patrick, Richmond, Christopher, Chen, Zhilin, Gray, Steven J, Walia, Jagdeep S
• Format: Article
• Language: English
• Subjects: Biochemical analysis; Deoxyribonucleic acid; Disease; DNA; Enzymatic activity; Enzymes; Fibroblasts; Ganglioside GM2; Gene therapy; Genotype & phenotype; Neonates; Neurodegeneration; Neurodegenerative diseases; Phenotypes; Secretion; Tay-Sachs disease; Vectors (Biology)
• ISSN: 2329-0501; 2329-0501
• DOI: 10.1016/j.omtm.2018.10.011

G gangliosidoses are a family of severe neurodegenerative disorders resulting from a deficiency in the β-hexosaminidase A enzyme. These disorders include Tay-Sachs disease and Sandhoff disease, caused by mutations in the gene and gene, respectively. The and genes are required to produce the α and β subunits of the β-hexosaminidase A enzyme, respectively. Using a Sandhoff disease mouse model, we tested for the first time the potential of a comparatively lower dose (2.04 × 10 vg/kg) of systemically delivered single-stranded adeno-associated virus 9 expressing both human and human cDNA under the control of a single promoter with a P2A-linked bicistronic vector design to correct the neurological phenotype. A bicistronic design allows maximal overexpression and secretion of the Hex A enzyme. Neonatal mice were injected with either this ssAAV9-HexB-P2A-HexA vector or a vehicle solution via the superficial temporal vein. An increase in survival of 56% compared with vehicle-injected controls and biochemical analysis of the brain tissue and serum revealed an increase in enzyme activity and a decrease in brain G ganglioside buildup. This is a proof-of-concept study showing the "correction efficacy" of a bicistronic AAV9 vector delivered intravenously for G gangliosidoses. Further studies with higher doses are warranted.