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Optimized pharmacological control over the AAV-Gene-Switch vector for regulable gene therapy
Gene therapy in its current design is an irreversible process. It cannot be stopped in case of unwanted side effects, nor can expression levels of therapeutics be adjusted to individual patient’s needs. Thus, the Gene-Switch (GS) system for pharmacologically regulable neurotrophic factor expression...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society of Gene & Cell Therapy
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426472/ https://www.ncbi.nlm.nih.gov/pubmed/34552998 http://dx.doi.org/10.1016/j.omtm.2021.07.007 |
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author | Cheng, Shi van Gaalen, Marcel M. Bähr, Mathias Garea-Rodriguez, Enrique Kügler, Sebastian |
author_facet | Cheng, Shi van Gaalen, Marcel M. Bähr, Mathias Garea-Rodriguez, Enrique Kügler, Sebastian |
author_sort | Cheng, Shi |
collection | PubMed |
description | Gene therapy in its current design is an irreversible process. It cannot be stopped in case of unwanted side effects, nor can expression levels of therapeutics be adjusted to individual patient’s needs. Thus, the Gene-Switch (GS) system for pharmacologically regulable neurotrophic factor expression was established for treatment of parkinsonian patients. Mifepristone, the synthetic steroid used to control transgene expression of the GS vector, is an approved clinical drug. However, pharmacokinetics and -dynamics of mifepristone vary considerably between different experimental animal species and depend on age and gender. In humans, but not in any other species, mifepristone binds to a high-affinity plasma carrier protein. We now demonstrate that the formulation of mifepristone can have robust impact on its ability to activate the GS system. Furthermore, we show that a pharmacological booster, ritonavir (Rtv), robustly enhances the pharmacological effect of mifepristone, and allows it to overcome gender- and species-specific pharmacokinetic and -dynamic issues. Most importantly, we demonstrate that the GS vector can be efficiently controlled by mifepristone in the presence of its human plasma carrier protein, α1-acid glycoprotein, in a “humanized” rat model. Thus, we have substantially improved the applicability of the GS vector toward therapeutic use in patients. |
format | Online Article Text |
id | pubmed-8426472 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Society of Gene & Cell Therapy |
record_format | MEDLINE/PubMed |
spelling | pubmed-84264722021-09-21 Optimized pharmacological control over the AAV-Gene-Switch vector for regulable gene therapy Cheng, Shi van Gaalen, Marcel M. Bähr, Mathias Garea-Rodriguez, Enrique Kügler, Sebastian Mol Ther Methods Clin Dev Original Article Gene therapy in its current design is an irreversible process. It cannot be stopped in case of unwanted side effects, nor can expression levels of therapeutics be adjusted to individual patient’s needs. Thus, the Gene-Switch (GS) system for pharmacologically regulable neurotrophic factor expression was established for treatment of parkinsonian patients. Mifepristone, the synthetic steroid used to control transgene expression of the GS vector, is an approved clinical drug. However, pharmacokinetics and -dynamics of mifepristone vary considerably between different experimental animal species and depend on age and gender. In humans, but not in any other species, mifepristone binds to a high-affinity plasma carrier protein. We now demonstrate that the formulation of mifepristone can have robust impact on its ability to activate the GS system. Furthermore, we show that a pharmacological booster, ritonavir (Rtv), robustly enhances the pharmacological effect of mifepristone, and allows it to overcome gender- and species-specific pharmacokinetic and -dynamic issues. Most importantly, we demonstrate that the GS vector can be efficiently controlled by mifepristone in the presence of its human plasma carrier protein, α1-acid glycoprotein, in a “humanized” rat model. Thus, we have substantially improved the applicability of the GS vector toward therapeutic use in patients. American Society of Gene & Cell Therapy 2021-08-08 /pmc/articles/PMC8426472/ /pubmed/34552998 http://dx.doi.org/10.1016/j.omtm.2021.07.007 Text en © 2021 The Authors 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 Cheng, Shi van Gaalen, Marcel M. Bähr, Mathias Garea-Rodriguez, Enrique Kügler, Sebastian Optimized pharmacological control over the AAV-Gene-Switch vector for regulable gene therapy |
title | Optimized pharmacological control over the AAV-Gene-Switch vector for regulable gene therapy |
title_full | Optimized pharmacological control over the AAV-Gene-Switch vector for regulable gene therapy |
title_fullStr | Optimized pharmacological control over the AAV-Gene-Switch vector for regulable gene therapy |
title_full_unstemmed | Optimized pharmacological control over the AAV-Gene-Switch vector for regulable gene therapy |
title_short | Optimized pharmacological control over the AAV-Gene-Switch vector for regulable gene therapy |
title_sort | optimized pharmacological control over the aav-gene-switch vector for regulable gene therapy |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426472/ https://www.ncbi.nlm.nih.gov/pubmed/34552998 http://dx.doi.org/10.1016/j.omtm.2021.07.007 |
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