The pathobiology of Parkinson's disease (PD) is associated with the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) projecting to the striatum. Currently, there are no treatments that can halt or reverse the course of PD; only palliative therapies, such as replacement strategies for missing neurotransmitters, exist. Thus, the successful brain delivery of neurotrophic factors that promote neuronal survival and reverse the disease progression is crucial. We demonstrated earlier systemically administered autologous macrophages can deliver nanoformulated antioxidant, catalase, to the SNpc providing potent anti-inflammatory effects in PD mouse models. Here we evaluated genetically-modified macrophages for active targeted brain delivery of glial cell-line derived neurotropic factor (GDNF). To capitalize on the beneficial properties afforded by alternatively activated macrophages, transfected with GDNF-encoded pDNA cells were further differentiated toward regenerative M2 phenotype. A systemic administration of GDNF-expressing macrophages significantly ameliorated neurodegeneration and neuroinflammation in PD mice. Behavioral studies confirmed neuroprotective effects of the macrophage-based drug delivery system. One of the suggested mechanisms of therapeutic effects is the release of exosomes containing the expressed neurotropic factor followed by the efficient GDNF transfer to target neurons. Such formulations can serve as a new technology based on cell-mediated active delivery of therapeutic proteins that attenuate and reverse progression of PD, and ultimately provide hope for those patients who are already significantly disabled by the disease.
Citation: Zhao Y, Haney MJ, Gupta R, Bohnsack JP, He Z, et al. (2014) GDNF-Transfected Macrophages Produce Potent Neuroprotective Effects in Parkinson's Disease Mouse Model. PLoS ONE 9(9): e106867. doi:10.1371/journal.pone.0106867
Editor: Tsuneya Ikezu, Boston University School of Medicine, United States of America
Received: May 27, 2014; Accepted: August 9, 2014; Published: September 17, 2014
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files.
Funding: This study was supported by the grants of the US National Institutes of Health 1R01 NS057748 (to EVB), RR021937 and R01 CA116591 (to AVK), US Department of Defense Award No. W81XWH-09-1-0386 (to AVK) and W81XWH11-1-0770 (to AVK), and the Russian Ministry of Science and Education No. 02.740.11.5231 and No. 11.G34.31.0004 (to AVK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Model Yuling Zhao, Matthew J. Haney, Richa Gupta, John P. Bohnsack, Zhijian He, Alexander V. Kabanov, Elena V. Batrakova
Sep. 17, 2014
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