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

Evan Woodley, Karlaina J.L. Osmon, Patrick Thompson, Christopher Richmond, Zhilin Chen, Steven James Gray, Jagdeep S. Walia

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


GM2 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 HEXA gene and HEXB gene, respectively. The HEXA and HEXB 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 × 1013 vg/kg) of systemically delivered single-stranded adeno-associated virus 9 expressing both human HEXB and human HEXA 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 GM2 ganglioside buildup. This is a proof-of-concept study showing the “correction efficacy” of a bicistronic AAV9 vector delivered intravenously for GM2 gangliosidoses. Further studies with higher doses are warranted.

Original languageEnglish (US)
Pages (from-to)47-57
Number of pages11
JournalMolecular Therapy - Methods and Clinical Development
StatePublished - Mar 15 2019


  • AAV9
  • Sandhoff disease
  • Tay-Sachs disease
  • gene therapy
  • hexosaminidase

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics


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