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

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 t...

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Main Authors:	Evan Woodley, Karlaina J.L. Osmon, Patrick Thompson, Christopher Richmond, Zhilin Chen, Steven J. Gray, Jagdeep S. Walia
Format:	Article
Language:	English
Published:	Elsevier 2019-03-01
Series:	Molecular Therapy: Methods & Clinical Development
Online Access:	http://www.sciencedirect.com/science/article/pii/S2329050118301074

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spelling	doaj-81b1255349f54990b54a557a880e9f602020-11-25T00:32:44ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012019-03-01124757Efficacy of a Bicistronic Vector for Correction of Sandhoff Disease in a Mouse ModelEvan Woodley0Karlaina J.L. Osmon1Patrick Thompson2Christopher Richmond3Zhilin Chen4Steven J. Gray5Jagdeep S. Walia6Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, CanadaCentre for Neuroscience Studies, Queen’s University, Kingston, ON, CanadaDepartment of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, CanadaDepartment of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, CanadaMedical Genetics/Departments of Pediatrics, Queen’s University, Kingston, ON, CanadaGene Therapy Center, University of North Carolina, Chapel Hill, NC, USA; Department of Pediatrics; UT Southwestern Medical Center, Dallas, TX, USADepartment of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada; Centre for Neuroscience Studies, Queen’s University, Kingston, ON, Canada; Medical Genetics/Departments of Pediatrics, Queen’s University, Kingston, ON, Canada; Corresponding author: Jagdeep S. Walia, Queen’s University, 76 Stuart Street, Armstrong 4, Kingston General Hospital, Kingston, ON K7L 2V7, Canada.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, hexosaminidasehttp://www.sciencedirect.com/science/article/pii/S2329050118301074
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Evan Woodley Karlaina J.L. Osmon Patrick Thompson Christopher Richmond Zhilin Chen Steven J. Gray Jagdeep S. Walia
spellingShingle	Evan Woodley Karlaina J.L. Osmon Patrick Thompson Christopher Richmond Zhilin Chen Steven J. Gray Jagdeep S. Walia Efficacy of a Bicistronic Vector for Correction of Sandhoff Disease in a Mouse Model Molecular Therapy: Methods & Clinical Development
author_facet	Evan Woodley Karlaina J.L. Osmon Patrick Thompson Christopher Richmond Zhilin Chen Steven J. Gray Jagdeep S. Walia
author_sort	Evan Woodley
title	Efficacy of a Bicistronic Vector for Correction of Sandhoff Disease in a Mouse Model
title_short	Efficacy of a Bicistronic Vector for Correction of Sandhoff Disease in a Mouse Model
title_full	Efficacy of a Bicistronic Vector for Correction of Sandhoff Disease in a Mouse Model
title_fullStr	Efficacy of a Bicistronic Vector for Correction of Sandhoff Disease in a Mouse Model
title_full_unstemmed	Efficacy of a Bicistronic Vector for Correction of Sandhoff Disease in a Mouse Model
title_sort	efficacy of a bicistronic vector for correction of sandhoff disease in a mouse model
publisher	Elsevier
series	Molecular Therapy: Methods & Clinical Development
issn	2329-0501
publishDate	2019-03-01
description	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
url	http://www.sciencedirect.com/science/article/pii/S2329050118301074
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Efficacy of a Bicistronic Vector for Correction of Sandhoff Disease in a Mouse Model

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