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Secreted therapeutics: monitoring durability of microRNA-based gene therapies in the central nervous system
The preclinical development of microRNA-based gene therapies for inherited neurodegenerative diseases is accompanied by translational challenges. Due to the inaccessibility of the brain to periodically evaluate therapy effects, accessible and reliable biomarkers indicative of dosing, durability and...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093922/ https://www.ncbi.nlm.nih.gov/pubmed/34704020 http://dx.doi.org/10.1093/braincomms/fcab054 |
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author | Sogorb-Gonzalez, Marina Vendrell-Tornero, Carlos Snapper, Jolanda Stam, Anouk Keskin, Sonay Miniarikova, Jana Spronck, Elisabeth A de Haan, Martin Nieuwland, Rienk Konstantinova, Pavlina van Deventer1, Sander J Evers, Melvin M Vallès, Astrid |
author_facet | Sogorb-Gonzalez, Marina Vendrell-Tornero, Carlos Snapper, Jolanda Stam, Anouk Keskin, Sonay Miniarikova, Jana Spronck, Elisabeth A de Haan, Martin Nieuwland, Rienk Konstantinova, Pavlina van Deventer1, Sander J Evers, Melvin M Vallès, Astrid |
author_sort | Sogorb-Gonzalez, Marina |
collection | PubMed |
description | The preclinical development of microRNA-based gene therapies for inherited neurodegenerative diseases is accompanied by translational challenges. Due to the inaccessibility of the brain to periodically evaluate therapy effects, accessible and reliable biomarkers indicative of dosing, durability and therapeutic efficacy in the central nervous system are very much needed. This is particularly important for viral vector-based gene therapies, in which a one-time administration results in long-term expression of active therapeutic molecules in the brain. Recently, extracellular vesicles have been identified as carriers of RNA species, including microRNAs, and proteins in all biological fluids, whilst becoming potential sources of biomarkers for diagnosis. In this study, we investigated the secretion and potential use of circulating miRNAs associated with extracellular vesicles as suitable sources to monitor the expression and durability of gene therapies in the brain. Neuronal cells derived from induced pluripotent stem cells were treated with adeno-associated viral vector serotype 5 carrying an engineered microRNA targeting huntingtin or ataxin3 gene sequences, the diseases-causing genes of Huntington disease and spinocerebellar ataxia type 3, respectively. After treatment, the secretion of mature engineered microRNA molecules was confirmed, with extracellular microRNA levels correlating with viral dose and cellular microRNA expression in neurons. We further investigated the detection of engineered microRNAs over time in the CSF of non-human primates after a single intrastriatal injection of adeno-associated viral vector serotype 5 carrying a huntingtin-targeting engineered microRNA. Quantifiable engineered microRNA levels enriched in extracellular vesicles were detected in the CSF up to two years after brain infusion. Altogether, these results confirm the long-term expression of adeno-associated viral vector serotype 5-delivered microRNAs and support the use of extracellular vesicle-associated microRNAs as novel translational pharmacokinetic markers in ongoing clinical trials of gene therapies for neurodegenerative diseases. |
format | Online Article Text |
id | pubmed-8093922 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-80939222021-12-11 Secreted therapeutics: monitoring durability of microRNA-based gene therapies in the central nervous system Sogorb-Gonzalez, Marina Vendrell-Tornero, Carlos Snapper, Jolanda Stam, Anouk Keskin, Sonay Miniarikova, Jana Spronck, Elisabeth A de Haan, Martin Nieuwland, Rienk Konstantinova, Pavlina van Deventer1, Sander J Evers, Melvin M Vallès, Astrid Brain Commun Original Article The preclinical development of microRNA-based gene therapies for inherited neurodegenerative diseases is accompanied by translational challenges. Due to the inaccessibility of the brain to periodically evaluate therapy effects, accessible and reliable biomarkers indicative of dosing, durability and therapeutic efficacy in the central nervous system are very much needed. This is particularly important for viral vector-based gene therapies, in which a one-time administration results in long-term expression of active therapeutic molecules in the brain. Recently, extracellular vesicles have been identified as carriers of RNA species, including microRNAs, and proteins in all biological fluids, whilst becoming potential sources of biomarkers for diagnosis. In this study, we investigated the secretion and potential use of circulating miRNAs associated with extracellular vesicles as suitable sources to monitor the expression and durability of gene therapies in the brain. Neuronal cells derived from induced pluripotent stem cells were treated with adeno-associated viral vector serotype 5 carrying an engineered microRNA targeting huntingtin or ataxin3 gene sequences, the diseases-causing genes of Huntington disease and spinocerebellar ataxia type 3, respectively. After treatment, the secretion of mature engineered microRNA molecules was confirmed, with extracellular microRNA levels correlating with viral dose and cellular microRNA expression in neurons. We further investigated the detection of engineered microRNAs over time in the CSF of non-human primates after a single intrastriatal injection of adeno-associated viral vector serotype 5 carrying a huntingtin-targeting engineered microRNA. Quantifiable engineered microRNA levels enriched in extracellular vesicles were detected in the CSF up to two years after brain infusion. Altogether, these results confirm the long-term expression of adeno-associated viral vector serotype 5-delivered microRNAs and support the use of extracellular vesicle-associated microRNAs as novel translational pharmacokinetic markers in ongoing clinical trials of gene therapies for neurodegenerative diseases. Oxford University Press 2021-04-01 /pmc/articles/PMC8093922/ /pubmed/34704020 http://dx.doi.org/10.1093/braincomms/fcab054 Text en © The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by/4.0/), which permits non-commercial reuse, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Original Article Sogorb-Gonzalez, Marina Vendrell-Tornero, Carlos Snapper, Jolanda Stam, Anouk Keskin, Sonay Miniarikova, Jana Spronck, Elisabeth A de Haan, Martin Nieuwland, Rienk Konstantinova, Pavlina van Deventer1, Sander J Evers, Melvin M Vallès, Astrid Secreted therapeutics: monitoring durability of microRNA-based gene therapies in the central nervous system |
title | Secreted therapeutics: monitoring durability of microRNA-based gene therapies in the central nervous system |
title_full | Secreted therapeutics: monitoring durability of microRNA-based gene therapies in the central nervous system |
title_fullStr | Secreted therapeutics: monitoring durability of microRNA-based gene therapies in the central nervous system |
title_full_unstemmed | Secreted therapeutics: monitoring durability of microRNA-based gene therapies in the central nervous system |
title_short | Secreted therapeutics: monitoring durability of microRNA-based gene therapies in the central nervous system |
title_sort | secreted therapeutics: monitoring durability of microrna-based gene therapies in the central nervous system |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093922/ https://www.ncbi.nlm.nih.gov/pubmed/34704020 http://dx.doi.org/10.1093/braincomms/fcab054 |
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