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Cerebral Organoids: A Human Model for AAV Capsid Selection and Therapeutic Transgene Efficacy in the Brain

The development of gene therapies for central nervous system disorders is challenging because it is difficult to translate preclinical data from current in vitro and in vivo models to the clinic. Therefore, we developed induced pluripotent stem cell (iPSC)-derived cerebral organoids as a model for r...

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Autores principales: Depla, Josse A., Sogorb-Gonzalez, Marina, Mulder, Lance A., Heine, Vivi M., Konstantinova, Pavlina, van Deventer, Sander J., Wolthers, Katja C., Pajkrt, Dasja, Sridhar, Adithya, Evers, Melvin M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327852/
https://www.ncbi.nlm.nih.gov/pubmed/32637448
http://dx.doi.org/10.1016/j.omtm.2020.05.028
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author Depla, Josse A.
Sogorb-Gonzalez, Marina
Mulder, Lance A.
Heine, Vivi M.
Konstantinova, Pavlina
van Deventer, Sander J.
Wolthers, Katja C.
Pajkrt, Dasja
Sridhar, Adithya
Evers, Melvin M.
author_facet Depla, Josse A.
Sogorb-Gonzalez, Marina
Mulder, Lance A.
Heine, Vivi M.
Konstantinova, Pavlina
van Deventer, Sander J.
Wolthers, Katja C.
Pajkrt, Dasja
Sridhar, Adithya
Evers, Melvin M.
author_sort Depla, Josse A.
collection PubMed
description The development of gene therapies for central nervous system disorders is challenging because it is difficult to translate preclinical data from current in vitro and in vivo models to the clinic. Therefore, we developed induced pluripotent stem cell (iPSC)-derived cerebral organoids as a model for recombinant adeno-associated virus (rAAV) capsid selection and for testing efficacy of AAV-based gene therapy in a human context. Cerebral organoids are physiological 3D structures that better recapitulate the human brain compared with 2D cell lines. To validate the model, we compared the transduction efficiency and distribution of two commonly used AAV serotypes (rAAV5 and rAAV9). In cerebral organoids, transduction with rAAV5 led to higher levels of vector DNA, transgenic mRNA, and protein expression as compared with rAAV9. The superior transduction of rAAV5 was replicated in iPSC-derived neuronal cells. Furthermore, rAAV5-mediated delivery of a human sequence-specific engineered microRNA to cerebral organoids led to a lower expression of its target ataxin-3. Our studies provide a new tool for selecting and deselecting AAV serotypes, and for demonstrating therapeutic efficacy of transgenes in a human context. Implementing cerebral organoids during gene therapy development could reduce the usage of animal models and improve translation to the clinic.
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spelling pubmed-73278522020-07-06 Cerebral Organoids: A Human Model for AAV Capsid Selection and Therapeutic Transgene Efficacy in the Brain Depla, Josse A. Sogorb-Gonzalez, Marina Mulder, Lance A. Heine, Vivi M. Konstantinova, Pavlina van Deventer, Sander J. Wolthers, Katja C. Pajkrt, Dasja Sridhar, Adithya Evers, Melvin M. Mol Ther Methods Clin Dev Article The development of gene therapies for central nervous system disorders is challenging because it is difficult to translate preclinical data from current in vitro and in vivo models to the clinic. Therefore, we developed induced pluripotent stem cell (iPSC)-derived cerebral organoids as a model for recombinant adeno-associated virus (rAAV) capsid selection and for testing efficacy of AAV-based gene therapy in a human context. Cerebral organoids are physiological 3D structures that better recapitulate the human brain compared with 2D cell lines. To validate the model, we compared the transduction efficiency and distribution of two commonly used AAV serotypes (rAAV5 and rAAV9). In cerebral organoids, transduction with rAAV5 led to higher levels of vector DNA, transgenic mRNA, and protein expression as compared with rAAV9. The superior transduction of rAAV5 was replicated in iPSC-derived neuronal cells. Furthermore, rAAV5-mediated delivery of a human sequence-specific engineered microRNA to cerebral organoids led to a lower expression of its target ataxin-3. Our studies provide a new tool for selecting and deselecting AAV serotypes, and for demonstrating therapeutic efficacy of transgenes in a human context. Implementing cerebral organoids during gene therapy development could reduce the usage of animal models and improve translation to the clinic. American Society of Gene & Cell Therapy 2020-06-01 /pmc/articles/PMC7327852/ /pubmed/32637448 http://dx.doi.org/10.1016/j.omtm.2020.05.028 Text en © 2020 The Author(s) http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Depla, Josse A.
Sogorb-Gonzalez, Marina
Mulder, Lance A.
Heine, Vivi M.
Konstantinova, Pavlina
van Deventer, Sander J.
Wolthers, Katja C.
Pajkrt, Dasja
Sridhar, Adithya
Evers, Melvin M.
Cerebral Organoids: A Human Model for AAV Capsid Selection and Therapeutic Transgene Efficacy in the Brain
title Cerebral Organoids: A Human Model for AAV Capsid Selection and Therapeutic Transgene Efficacy in the Brain
title_full Cerebral Organoids: A Human Model for AAV Capsid Selection and Therapeutic Transgene Efficacy in the Brain
title_fullStr Cerebral Organoids: A Human Model for AAV Capsid Selection and Therapeutic Transgene Efficacy in the Brain
title_full_unstemmed Cerebral Organoids: A Human Model for AAV Capsid Selection and Therapeutic Transgene Efficacy in the Brain
title_short Cerebral Organoids: A Human Model for AAV Capsid Selection and Therapeutic Transgene Efficacy in the Brain
title_sort cerebral organoids: a human model for aav capsid selection and therapeutic transgene efficacy in the brain
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327852/
https://www.ncbi.nlm.nih.gov/pubmed/32637448
http://dx.doi.org/10.1016/j.omtm.2020.05.028
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