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Transgene distribution and immune response after ultrasound delivery of rAAV9 and PHP.B to the brain in a mouse model of amyloidosis
Efficient disease-modifying treatments for Alzheimer disease, the most common form of dementia, have yet to be established. Gene therapy has the potential to provide the long-term production of therapeutic in the brain following a single administration. However, the blood-brain barrier poses a chall...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society of Gene & Cell Therapy
2021
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8560718/ https://www.ncbi.nlm.nih.gov/pubmed/34761053 http://dx.doi.org/10.1016/j.omtm.2021.10.001 |
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author | Kofoed, Rikke Hahn Heinen, Stefan Silburt, Joseph Dubey, Sonam Dibia, Chinaza Lilian Maes, Miriam Simpson, Elizabeth M. Hynynen, Kullervo Aubert, Isabelle |
author_facet | Kofoed, Rikke Hahn Heinen, Stefan Silburt, Joseph Dubey, Sonam Dibia, Chinaza Lilian Maes, Miriam Simpson, Elizabeth M. Hynynen, Kullervo Aubert, Isabelle |
author_sort | Kofoed, Rikke Hahn |
collection | PubMed |
description | Efficient disease-modifying treatments for Alzheimer disease, the most common form of dementia, have yet to be established. Gene therapy has the potential to provide the long-term production of therapeutic in the brain following a single administration. However, the blood-brain barrier poses a challenge for gene delivery to the adult brain. We investigated the transduction efficiency and immunological response following non-invasive gene-delivery strategies to the brain of a mouse model of amyloidosis. Two emerging technologies enabling gene delivery across the blood-brain barrier were used to establish the minimal vector dosage required to reach the brain: (1) focused ultrasound combined with intravenous microbubbles, which increases the permeability of the blood-brain barrier at targeted sites and (2) the recombinant adeno-associated virus (rAAV)-based capsid named rAAV-PHP.B. We found that equal intravenous dosages of rAAV9 combined with focused ultrasound, or rAAV-PHP.B, were required for brain gene delivery. In contrast to rAAV9, focused ultrasound did not decrease the rAAV-PHP.B dosage required to transduce brain cells in a mouse model of amyloidosis. The non-invasive rAAV delivery to the brain using rAAV-PHP.B or rAAV9 with focused ultrasound triggered an immune reaction including major histocompatibility complex class II expression, complement system and microglial activation, and T cell infiltration. |
format | Online Article Text |
id | pubmed-8560718 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Society of Gene & Cell Therapy |
record_format | MEDLINE/PubMed |
spelling | pubmed-85607182021-11-09 Transgene distribution and immune response after ultrasound delivery of rAAV9 and PHP.B to the brain in a mouse model of amyloidosis Kofoed, Rikke Hahn Heinen, Stefan Silburt, Joseph Dubey, Sonam Dibia, Chinaza Lilian Maes, Miriam Simpson, Elizabeth M. Hynynen, Kullervo Aubert, Isabelle Mol Ther Methods Clin Dev Original Article Efficient disease-modifying treatments for Alzheimer disease, the most common form of dementia, have yet to be established. Gene therapy has the potential to provide the long-term production of therapeutic in the brain following a single administration. However, the blood-brain barrier poses a challenge for gene delivery to the adult brain. We investigated the transduction efficiency and immunological response following non-invasive gene-delivery strategies to the brain of a mouse model of amyloidosis. Two emerging technologies enabling gene delivery across the blood-brain barrier were used to establish the minimal vector dosage required to reach the brain: (1) focused ultrasound combined with intravenous microbubbles, which increases the permeability of the blood-brain barrier at targeted sites and (2) the recombinant adeno-associated virus (rAAV)-based capsid named rAAV-PHP.B. We found that equal intravenous dosages of rAAV9 combined with focused ultrasound, or rAAV-PHP.B, were required for brain gene delivery. In contrast to rAAV9, focused ultrasound did not decrease the rAAV-PHP.B dosage required to transduce brain cells in a mouse model of amyloidosis. The non-invasive rAAV delivery to the brain using rAAV-PHP.B or rAAV9 with focused ultrasound triggered an immune reaction including major histocompatibility complex class II expression, complement system and microglial activation, and T cell infiltration. American Society of Gene & Cell Therapy 2021-10-08 /pmc/articles/PMC8560718/ /pubmed/34761053 http://dx.doi.org/10.1016/j.omtm.2021.10.001 Text en © 2021 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 Kofoed, Rikke Hahn Heinen, Stefan Silburt, Joseph Dubey, Sonam Dibia, Chinaza Lilian Maes, Miriam Simpson, Elizabeth M. Hynynen, Kullervo Aubert, Isabelle Transgene distribution and immune response after ultrasound delivery of rAAV9 and PHP.B to the brain in a mouse model of amyloidosis |
title | Transgene distribution and immune response after ultrasound delivery of rAAV9 and PHP.B to the brain in a mouse model of amyloidosis |
title_full | Transgene distribution and immune response after ultrasound delivery of rAAV9 and PHP.B to the brain in a mouse model of amyloidosis |
title_fullStr | Transgene distribution and immune response after ultrasound delivery of rAAV9 and PHP.B to the brain in a mouse model of amyloidosis |
title_full_unstemmed | Transgene distribution and immune response after ultrasound delivery of rAAV9 and PHP.B to the brain in a mouse model of amyloidosis |
title_short | Transgene distribution and immune response after ultrasound delivery of rAAV9 and PHP.B to the brain in a mouse model of amyloidosis |
title_sort | transgene distribution and immune response after ultrasound delivery of raav9 and php.b to the brain in a mouse model of amyloidosis |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8560718/ https://www.ncbi.nlm.nih.gov/pubmed/34761053 http://dx.doi.org/10.1016/j.omtm.2021.10.001 |
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