Regulation of human GDNF gene expression in nigral dopaminergic neurons using a new doxycycline-regulated NTS-polyplex nanoparticle system

Armando J. Espadas-Alvarez, Michael J. Bannon, Carlos E. Orozco-Barrios, Lourdes Escobedo-Sanchez, Jose Ayala-Davila, David Reyes-Corona, Guadalupe Soto-Rodriguez, Vicente Escamilla-Rivera, Andrea De Vizcaya-Ruiz, M. Eugenia Gutierrez-Castillo, America Padilla-Viveros, Daniel Martinez-Fong

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    Abstract

    © 2017 Elsevier Inc. The human glial-cell derived neurotrophic factor (hGDNF) gene transfer by neurotensin (NTS)-polyplex nanoparticles functionally restores the dopamine nigrostriatal system in experimental Parkinson's disease models. However, high levels of sustained expression of GDNF eventually can cause harmful effects. Herein, we report an improved NTS-polyplex nanoparticle system that enables regulation of hGDNF expression within dopaminergic neurons. We constructed NTS-polyplex nanoparticles containing a single bifunctional plasmid that codes for the reverse tetracycline-controlled transactivator advanced (rtTA-Adv) under the control of NBRE3x promoter, and for hGDNF under the control of tetracycline-response element (TRE). Another bifunctional plasmid contained the enhanced green fluorescent protein (GFP) gene. Transient transfection experiments in N1E-115-Nurr1 cells showed that doxycycline (100 ng/mL) activates hGDNF and GFP expression. Doxycycline (5 mg/kg, i.p.) administration in rats activated hGDNF expression only in transfected dopaminergic neurons, whereas doxycycline withdrawal silenced transgene expression. Our results offer a specific doxycycline-regulated system suitable for nanomedicine-based treatment of Parkinson's disease.
    Original languageAmerican English
    Pages (from-to)1363-1375
    Number of pages1225
    JournalNanomedicine: Nanotechnology, Biology, and Medicine
    DOIs
    StatePublished - 1 May 2017

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    Espadas-Alvarez, A. J., Bannon, M. J., Orozco-Barrios, C. E., Escobedo-Sanchez, L., Ayala-Davila, J., Reyes-Corona, D., Soto-Rodriguez, G., Escamilla-Rivera, V., De Vizcaya-Ruiz, A., Eugenia Gutierrez-Castillo, M., Padilla-Viveros, A., & Martinez-Fong, D. (2017). Regulation of human GDNF gene expression in nigral dopaminergic neurons using a new doxycycline-regulated NTS-polyplex nanoparticle system. Nanomedicine: Nanotechnology, Biology, and Medicine, 1363-1375. https://doi.org/10.1016/j.nano.2017.02.006