Molecular Therapy: Methods & Clinical Development (Mar 2019)

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 J. Gray,
  • Jagdeep S. Walia

Journal volume & issue
Vol. 12
pp. 47 – 57

Abstract

Read online

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. Keywords: Sandhoff disease, Tay-Sachs disease, AAV9, gene therapy, hexosaminidase