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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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society of Gene & Cell Therapy
2018
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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. |
format | Online Article Text |
id | pubmed-6279944 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | American Society of Gene & Cell Therapy |
record_format | MEDLINE/PubMed |
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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