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dc.contributor.authorCheng, Shi
dc.contributor.authorvan Gaalen, Marcel M
dc.contributor.authorBähr, Mathias
dc.contributor.authorGarea-Rodriguez, Enrique
dc.contributor.authorKügler, Sebastian
dc.date.accessioned2021-10-26T23:30:23Z
dc.date.available2021-10-26T23:30:23Z
dc.date.issued2021-12-10
dc.identifier.issn2329-0501
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/329915
dc.description.abstractGene 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.
dc.format.mediumElectronic-eCollection
dc.languageeng
dc.publisherElsevier BV
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.titleOptimized pharmacological control over the AAV-Gene-Switch vector for regulable gene therapy.
dc.typeArticle
prism.endingPage10
prism.publicationDate2021
prism.publicationNameMol Ther Methods Clin Dev
prism.startingPage1
prism.volume23
dc.identifier.doi10.17863/CAM.77358
dcterms.dateAccepted2021-07-30
rioxxterms.versionofrecord10.1016/j.omtm.2021.07.007
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2021-12
dc.contributor.orcidCheng, Shi [0000-0003-4529-5546]
dc.identifier.eissn2329-0501
rioxxterms.typeJournal Article/Review
cam.issuedOnline2021-08-08


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Attribution-NonCommercial-NoDerivatives 4.0 International
Except where otherwise noted, this item's licence is described as Attribution-NonCommercial-NoDerivatives 4.0 International