Optimized pharmacological control over the AAV-Gene-Switch vector for regulable gene therapy
| Autor: | Enrique Garea-Rodriguez, Sebastian Kügler, Marcel M. van Gaalen, Shi Cheng, Mathias Bähr |
|---|---|
| Přispěvatelé: | Cheng, Shi [0000-0003-4529-5546], Apollo - University of Cambridge Repository |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Drug
media_common.quotation_subject Genetic enhancement Transgene mifepristone QH426-470 Pharmacology 03 medical and health sciences 0302 clinical medicine Pharmacokinetics Neurotrophic factors Genetics Glial cell line-derived neurotrophic factor Medicine Molecular Biology 030304 developmental biology media_common 0303 health sciences QH573-671 biology business.industry AAV Mifepristone GDNF 3. Good health ritonavir 030220 oncology & carcinogenesis biology.protein Gene-Switch Parkinson’s disease Molecular Medicine Ritonavir Original Article Cytology business medicine.drug alpha-1 acid glycoprotein |
| Zdroj: | Molecular Therapy. Methods & Clinical Development Molecular Therapy: Methods & Clinical Development, Vol 23, Iss, Pp 1-10 (2021) |
| ISSN: | 2329-0501 |
| Popis: | 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. Graphical abstract Regulable gene therapy may enable personalized genetic medicines. We demonstrate optimized pharmacological control over expression of the neurotrophic factor GDNF from an AAV-Gene-Switch vector. This work substantially advances our understanding of how to gain external control over a regulable vector for treatment of Parkinson’s disease. |
| Databáze: | OpenAIRE |
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