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

G(M2) 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...

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Autores principales: Woodley, Evan, Osmon, Karlaina J.L., Thompson, Patrick, Richmond, Christopher, Chen, Zhilin, Gray, Steven J., Walia, Jagdeep S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279944/
https://www.ncbi.nlm.nih.gov/pubmed/30534578
http://dx.doi.org/10.1016/j.omtm.2018.10.011
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author Woodley, Evan
Osmon, Karlaina J.L.
Thompson, Patrick
Richmond, Christopher
Chen, Zhilin
Gray, Steven J.
Walia, Jagdeep S.
author_facet Woodley, Evan
Osmon, Karlaina J.L.
Thompson, Patrick
Richmond, Christopher
Chen, Zhilin
Gray, Steven J.
Walia, Jagdeep S.
author_sort Woodley, Evan
collection PubMed
description G(M2) 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 × 10(13) 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 G(M2) ganglioside buildup. This is a proof-of-concept study showing the “correction efficacy” of a bicistronic AAV9 vector delivered intravenously for G(M2) gangliosidoses. Further studies with higher doses are warranted.
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spelling pubmed-62799442018-12-10 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 J. Walia, Jagdeep S. Mol Ther Methods Clin Dev Article G(M2) 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 × 10(13) 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 G(M2) ganglioside buildup. This is a proof-of-concept study showing the “correction efficacy” of a bicistronic AAV9 vector delivered intravenously for G(M2) gangliosidoses. Further studies with higher doses are warranted. American Society of Gene & Cell Therapy 2018-10-26 /pmc/articles/PMC6279944/ /pubmed/30534578 http://dx.doi.org/10.1016/j.omtm.2018.10.011 Text en © 2018. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Woodley, Evan
Osmon, Karlaina J.L.
Thompson, Patrick
Richmond, Christopher
Chen, Zhilin
Gray, Steven J.
Walia, Jagdeep S.
Efficacy of a Bicistronic Vector for Correction of Sandhoff Disease in a Mouse Model
title 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_short 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
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279944/
https://www.ncbi.nlm.nih.gov/pubmed/30534578
http://dx.doi.org/10.1016/j.omtm.2018.10.011
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