title: Specific transfection of inflamed brain by macrophages: a new therapeutic strategy for neurodegenerative diseases.
abstract: The ability to precisely upregulate genes in inflamed brain holds great therapeutic promise. Here we report a novel class of vectors, genetically modified macrophages that carry reporter and therapeutic genes to neural cells. Systemic administration of macrophages transfected ex vivo with a plasmid DNA (pDNA) encoding a potent antioxidant enzyme, catalase, produced month-long expression levels of catalase in the brain resulting in three-fold reductions in inflammation and complete neuroprotection in mouse models of Parkinson's disease (PD). This resulted in significant improvements in motor functions in PD mice. Mechanistic studies revealed that transfected macrophages secreted extracellular vesicles, exosomes, packed with catalase genetic material, pDNA and mRNA, active catalase, and NF-κb, a transcription factor involved in the encoded gene expression. Exosomes efficiently transfer their contents to contiguous neurons resulting in de novo protein synthesis in target cells. Thus, genetically modified macrophages serve as a highly efficient system for reproduction, packaging, and targeted gene and drug delivery to treat inflammatory and neurodegenerative disorders.
authors.affiliation: Department of Pharmaceutical Sciences, Center for Drug Delivery and Nanomedicine, University of Nebraska Medical Center, Omaha, Nebraska, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Haney
authors.forename: Yuling
authors.initials: Y
authors.lastname: Zhao
authors.forename: Emily B
authors.initials: EB
authors.lastname: Harrison
authors.forename: Vivek
authors.initials: V
authors.lastname: Mahajan
authors.forename: Shaheen
authors.initials: S
authors.lastname: Ahmed
authors.forename: Zhijian
authors.initials: Z
authors.lastname: He
authors.forename: Poornima
authors.initials: P
authors.lastname: Suresh
authors.forename: Shawn D
authors.initials: SD
authors.lastname: Hingtgen
authors.forename: Natalia L
authors.initials: NL
authors.lastname: Klyachko
authors.forename: R Lee
authors.initials: RL
authors.lastname: Mosley
authors.forename: Howard E
authors.initials: HE
authors.lastname: Gendelman
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Kabanov
authors.forename: Elena V
authors.initials: EV
authors.lastname: Batrakova
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000473:pathology*; D002374:Catalase / Q000235:genetics / Q000627:therapeutic use; D002460:Cell Line; D004195:Disease Models, Animal; D055354:Exosomes / Q000187:drug effects / Q000378:metabolism; D017930:Genes, Reporter; D015316:Genetic Therapy; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D007700:Kinetics; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D019636:Neurodegenerative Diseases / Q000628:therapy*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D010300:Parkinson Disease / Q000473:pathology / Q000628:therapy; D014018:Tissue Distribution / Q000187:drug effects; D014162:Transfection / Q000379:methods*
chemical_list: D000893:Anti-Inflammatory Agents; D018696:Neuroprotective Agents; D049452:Green Fluorescent Proteins; D002374:Catalase