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 journalArticle

Abstract

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.

LanguageEnglish (US)
Pages47-57
Number of pages11
JournalMolecular Therapy - Methods and Clinical Development
Volume12
DOIs
StatePublished - Mar 15 2019

Fingerprint

Sandhoff Disease
Hexosaminidase A
GM2 Gangliosidosis
beta-N-Acetylhexosaminidases
Enzymes
G(M2) Ganglioside
Tay-Sachs Disease
Genes
Dependovirus
Brain
Neurodegenerative Diseases
Veins
Complementary DNA
Phenotype
Mutation
Survival
Serum

Keywords

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

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Efficacy of a Bicistronic Vector for Correction of Sandhoff Disease in a Mouse Model. / Woodley, Evan; Osmon, Karlaina J.L.; Thompson, Patrick; Richmond, Christopher; Chen, Zhilin; Gray, Steven James; Walia, Jagdeep S.

In: Molecular Therapy - Methods and Clinical Development, Vol. 12, 15.03.2019, p. 47-57.

Research output: Contribution to journalArticle

Woodley, Evan ; Osmon, Karlaina J.L. ; Thompson, Patrick ; Richmond, Christopher ; Chen, Zhilin ; Gray, Steven James ; Walia, Jagdeep S. / Efficacy of a Bicistronic Vector for Correction of Sandhoff Disease in a Mouse Model. In: Molecular Therapy - Methods and Clinical Development. 2019 ; Vol. 12. pp. 47-57.
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