Optimized pharmacological control over the AAV-Gene-Switch vector for regulable gene therapy.
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Publication Date
2021-12-10Journal Title
Mol Ther Methods Clin Dev
ISSN
2329-0501
Publisher
Elsevier BV
Volume
23
Pages
1-10
Language
eng
Type
Article
This Version
VoR
Physical Medium
Electronic-eCollection
Metadata
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Cheng, S., van Gaalen, M. M., Bähr, M., Garea-Rodriguez, E., & Kügler, S. (2021). Optimized pharmacological control over the AAV-Gene-Switch vector for regulable gene therapy.. Mol Ther Methods Clin Dev, 23 1-10. https://doi.org/10.1016/j.omtm.2021.07.007
Abstract
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.
Identifiers
External DOI: https://doi.org/10.1016/j.omtm.2021.07.007
This record's URL: https://www.repository.cam.ac.uk/handle/1810/329915
Rights
Attribution-NonCommercial-NoDerivatives 4.0 International
Licence URL: https://creativecommons.org/licenses/by-nc-nd/4.0/
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