Selection of an Efficient AAV Vector for Robust CNS Transgene Expression

Adeno-associated virus (AAV) capsid libraries have generated improved transgene delivery vectors. We designed an AAV library construct, iTransduce, that combines a peptide library on the AAV9 capsid with a Cre cassette to enable sensitive detection of transgene expression. After only two selection r...

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Autores principales: Hanlon, Killian S., Meltzer, Jonah C., Buzhdygan, Tetyana, Cheng, Ming J., Sena-Esteves, Miguel, Bennett, Rachel E., Sullivan, Timothy P., Razmpour, Roshanak, Gong, Yi, Ng, Carrie, Nammour, Josette, Maiz, Daniela, Dujardin, Simon, Ramirez, Servio H., Hudry, Eloise, Maguire, Casey A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2019
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6881693/
https://www.ncbi.nlm.nih.gov/pubmed/31788496
http://dx.doi.org/10.1016/j.omtm.2019.10.007
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author Hanlon, Killian S.
Meltzer, Jonah C.
Buzhdygan, Tetyana
Cheng, Ming J.
Sena-Esteves, Miguel
Bennett, Rachel E.
Sullivan, Timothy P.
Razmpour, Roshanak
Gong, Yi
Ng, Carrie
Nammour, Josette
Maiz, Daniela
Dujardin, Simon
Ramirez, Servio H.
Hudry, Eloise
Maguire, Casey A.
author_facet Hanlon, Killian S.
Meltzer, Jonah C.
Buzhdygan, Tetyana
Cheng, Ming J.
Sena-Esteves, Miguel
Bennett, Rachel E.
Sullivan, Timothy P.
Razmpour, Roshanak
Gong, Yi
Ng, Carrie
Nammour, Josette
Maiz, Daniela
Dujardin, Simon
Ramirez, Servio H.
Hudry, Eloise
Maguire, Casey A.
author_sort Hanlon, Killian S.
collection PubMed
description Adeno-associated virus (AAV) capsid libraries have generated improved transgene delivery vectors. We designed an AAV library construct, iTransduce, that combines a peptide library on the AAV9 capsid with a Cre cassette to enable sensitive detection of transgene expression. After only two selection rounds of the library delivered intravenously in transgenic mice carrying a Cre-inducible fluorescent protein, we flow sorted fluorescent cells from brain, and DNA sequencing revealed two dominant capsids. One of the capsids, termed AAV-F, mediated transgene expression in the brain cortex more than 65-fold (astrocytes) and 171-fold (neurons) higher than the parental AAV9. High transduction efficiency was sex-independent and sustained in two mouse strains (C57BL/6 and BALB/c), making it a highly useful capsid for CNS transduction of mice. Future work in large animal models will test the translation potential of AAV-F.
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spelling pubmed-68816932019-11-29 Selection of an Efficient AAV Vector for Robust CNS Transgene Expression Hanlon, Killian S. Meltzer, Jonah C. Buzhdygan, Tetyana Cheng, Ming J. Sena-Esteves, Miguel Bennett, Rachel E. Sullivan, Timothy P. Razmpour, Roshanak Gong, Yi Ng, Carrie Nammour, Josette Maiz, Daniela Dujardin, Simon Ramirez, Servio H. Hudry, Eloise Maguire, Casey A. Mol Ther Methods Clin Dev Article Adeno-associated virus (AAV) capsid libraries have generated improved transgene delivery vectors. We designed an AAV library construct, iTransduce, that combines a peptide library on the AAV9 capsid with a Cre cassette to enable sensitive detection of transgene expression. After only two selection rounds of the library delivered intravenously in transgenic mice carrying a Cre-inducible fluorescent protein, we flow sorted fluorescent cells from brain, and DNA sequencing revealed two dominant capsids. One of the capsids, termed AAV-F, mediated transgene expression in the brain cortex more than 65-fold (astrocytes) and 171-fold (neurons) higher than the parental AAV9. High transduction efficiency was sex-independent and sustained in two mouse strains (C57BL/6 and BALB/c), making it a highly useful capsid for CNS transduction of mice. Future work in large animal models will test the translation potential of AAV-F. American Society of Gene & Cell Therapy 2019-10-23 /pmc/articles/PMC6881693/ /pubmed/31788496 http://dx.doi.org/10.1016/j.omtm.2019.10.007 Text en © 2019 The Author(s) 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
Hanlon, Killian S.
Meltzer, Jonah C.
Buzhdygan, Tetyana
Cheng, Ming J.
Sena-Esteves, Miguel
Bennett, Rachel E.
Sullivan, Timothy P.
Razmpour, Roshanak
Gong, Yi
Ng, Carrie
Nammour, Josette
Maiz, Daniela
Dujardin, Simon
Ramirez, Servio H.
Hudry, Eloise
Maguire, Casey A.
Selection of an Efficient AAV Vector for Robust CNS Transgene Expression
title Selection of an Efficient AAV Vector for Robust CNS Transgene Expression
title_full Selection of an Efficient AAV Vector for Robust CNS Transgene Expression
title_fullStr Selection of an Efficient AAV Vector for Robust CNS Transgene Expression
title_full_unstemmed Selection of an Efficient AAV Vector for Robust CNS Transgene Expression
title_short Selection of an Efficient AAV Vector for Robust CNS Transgene Expression
title_sort selection of an efficient aav vector for robust cns transgene expression
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6881693/
https://www.ncbi.nlm.nih.gov/pubmed/31788496
http://dx.doi.org/10.1016/j.omtm.2019.10.007
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