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An AAV capsid increases transduction of striatum and a ChAT promoter allows selective cholinergic neuron transduction
Adeno-associated virus (AAV) vectors are currently the most efficient option for intracranial gene therapies to treat neurodegenerative disease. Increased efficacy and safety will depend upon robust and specific expression of therapeutic genes into target cell-types within the human brain. In this s...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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American Society of Gene & Cell Therapy
2023
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10285237/ https://www.ncbi.nlm.nih.gov/pubmed/37359416 http://dx.doi.org/10.1016/j.omtm.2023.05.001 |
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author | Santoscoy, Miguel C. Espinoza, Paula De La Cruz, Demitri Mahamdeh, Mohammed Starr, Jacqueline R. Patel, Nikita Maguire, Casey A. |
author_facet | Santoscoy, Miguel C. Espinoza, Paula De La Cruz, Demitri Mahamdeh, Mohammed Starr, Jacqueline R. Patel, Nikita Maguire, Casey A. |
author_sort | Santoscoy, Miguel C. |
collection | PubMed |
description | Adeno-associated virus (AAV) vectors are currently the most efficient option for intracranial gene therapies to treat neurodegenerative disease. Increased efficacy and safety will depend upon robust and specific expression of therapeutic genes into target cell-types within the human brain. In this study, we set out with two objectives: (1) to identify capsids with broader transduction of the striatum upon intracranial injection in mice and (2) to test a truncated human choline acetyltransferase (ChAT) promoter that would allow efficient and selective transduction of cholinergic neurons. We compared AAV9 and an engineered capsid, AAV-S, to mediate widespread reporter gene expression throughout the striatum. We observed that AAV-S transduced a significantly greater area of the injected hemisphere primarily in the rostral direction compared with AAV9 (CAG promoter). We tested AAV9 vectors packaging a reporter gene expression cassette driven by either the ChAT or CAG promoter. Specificity of transgene expression of ChAT neurons over other cells was 7-fold higher, and efficiency was 3-fold higher for the ChAT promoter compared with the CAG promoter. The AAV-ChAT transgene expression cassette should be a useful tool for the study of cholinergic neurons in mice, and the broader transduction area of AAV-S warrants further evaluation of this capsid. |
format | Online Article Text |
id | pubmed-10285237 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Society of Gene & Cell Therapy |
record_format | MEDLINE/PubMed |
spelling | pubmed-102852372023-06-23 An AAV capsid increases transduction of striatum and a ChAT promoter allows selective cholinergic neuron transduction Santoscoy, Miguel C. Espinoza, Paula De La Cruz, Demitri Mahamdeh, Mohammed Starr, Jacqueline R. Patel, Nikita Maguire, Casey A. Mol Ther Methods Clin Dev Original Article Adeno-associated virus (AAV) vectors are currently the most efficient option for intracranial gene therapies to treat neurodegenerative disease. Increased efficacy and safety will depend upon robust and specific expression of therapeutic genes into target cell-types within the human brain. In this study, we set out with two objectives: (1) to identify capsids with broader transduction of the striatum upon intracranial injection in mice and (2) to test a truncated human choline acetyltransferase (ChAT) promoter that would allow efficient and selective transduction of cholinergic neurons. We compared AAV9 and an engineered capsid, AAV-S, to mediate widespread reporter gene expression throughout the striatum. We observed that AAV-S transduced a significantly greater area of the injected hemisphere primarily in the rostral direction compared with AAV9 (CAG promoter). We tested AAV9 vectors packaging a reporter gene expression cassette driven by either the ChAT or CAG promoter. Specificity of transgene expression of ChAT neurons over other cells was 7-fold higher, and efficiency was 3-fold higher for the ChAT promoter compared with the CAG promoter. The AAV-ChAT transgene expression cassette should be a useful tool for the study of cholinergic neurons in mice, and the broader transduction area of AAV-S warrants further evaluation of this capsid. American Society of Gene & Cell Therapy 2023-05-09 /pmc/articles/PMC10285237/ /pubmed/37359416 http://dx.doi.org/10.1016/j.omtm.2023.05.001 Text en © 2023 The Author(s) https://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 | Original Article Santoscoy, Miguel C. Espinoza, Paula De La Cruz, Demitri Mahamdeh, Mohammed Starr, Jacqueline R. Patel, Nikita Maguire, Casey A. An AAV capsid increases transduction of striatum and a ChAT promoter allows selective cholinergic neuron transduction |
title | An AAV capsid increases transduction of striatum and a ChAT promoter allows selective cholinergic neuron transduction |
title_full | An AAV capsid increases transduction of striatum and a ChAT promoter allows selective cholinergic neuron transduction |
title_fullStr | An AAV capsid increases transduction of striatum and a ChAT promoter allows selective cholinergic neuron transduction |
title_full_unstemmed | An AAV capsid increases transduction of striatum and a ChAT promoter allows selective cholinergic neuron transduction |
title_short | An AAV capsid increases transduction of striatum and a ChAT promoter allows selective cholinergic neuron transduction |
title_sort | aav capsid increases transduction of striatum and a chat promoter allows selective cholinergic neuron transduction |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10285237/ https://www.ncbi.nlm.nih.gov/pubmed/37359416 http://dx.doi.org/10.1016/j.omtm.2023.05.001 |
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