title: GDNF-transfected macrophages produce potent neuroprotective effects in Parkinson's disease mouse model.
abstract: 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.
authors.affiliation: Center for Nanotechnology in Drug Delivery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Yuling
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Center for Nanotechnology in Drug Delivery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Haney
authors.affiliation: Center for Nanotechnology in Drug Delivery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Richa
authors.initials: R
authors.lastname: Gupta
authors.affiliation: Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: John P
authors.initials: JP
authors.lastname: Bohnsack
authors.affiliation: Center for Nanotechnology in Drug Delivery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Zhijian
authors.initials: Z
authors.lastname: He
authors.affiliation: Center for Nanotechnology in Drug Delivery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Department of Chemical Enzymology, Faculty of Chemistry, M.V. Lomonosov Moscow State University, Moscow, Russia.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Kabanov
authors.affiliation: Center for Nanotechnology in Drug Delivery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America; Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Batrakova
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D004195:Disease Models, Animal; D005260:Female; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D010300:Parkinson Disease / Q000628:therapy*
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor