title: Engineered Mesenchymal Cells Improve Passive Immune Protection Against Lethal Venezuelan Equine Encephalitis Virus Exposure.
abstract: : Mesenchymal stromal cells (MSCs) are being exploited as gene delivery vectors for various disease and injury therapies. We provide proof-of-concept that engineered MSCs can provide a useful, effective platform for protection against infectious disease. Venezuelan equine encephalitis virus (VEEV) is a mosquito-borne pathogen affecting humans and equines and can be used in bio-warfare. No licensed vaccine or antiviral agent currently exists to combat VEEV infection in humans. Direct antibody administration (passive immunity) is an effective, but short-lived, method of providing immediate protection against a pathogen. We compared the protective efficacy of human umbilical cord perivascular cells (HUCPVCs; a rich source of MSCs), engineered with a transgene encoding a humanized VEEV-neutralizing antibody (anti-VEEV), to the purified antibody. In athymic mice, the anti-VEEV antibody had a half-life of 3.7 days, limiting protection to 2 or 3 days after administration. In contrast, engineered HUCPVCs generated protective anti-VEEV serum titers for 21-38 days after a single intramuscular injection. At 109 days after transplantation, 10% of the mice still had circulating anti-VEEV antibody. The mice were protected against exposure to a lethal dose of VEEV by an intramuscular pretreatment injection with engineered HUCPVCs 24 hours or 10 days before exposure, demonstrating both rapid and prolonged immune protection. The present study is the first to describe engineered MSCs as gene delivery vehicles for passive immunity and supports their utility as antibody delivery vehicles for improved, single-dose prophylaxis against endemic and intentionally disseminated pathogens.
  
  
  
  Direct injection of monoclonal antibodies (mAbs) is an important strategy to immediately protect the recipient from a pathogen. This strategy is critical during natural outbreaks or after the intentional release of bio-weapons. Vaccines require weeks to become effective, which is not practical for first responders immediately deployed to an infected region. However, mAb recipients often require booster shots to maintain protection, which is expensive and impractical once the first responders have been deployed. The present study has shown, for the first time, that mesenchymal stromal cells are effective gene delivery vehicles that can significantly improve mAb-mediated immune protection in a single, intramuscular dose of engineered cells. Such a cell-based delivery system can provide extended life-saving protection in the event of exposure to biological threats using a more practical, single-dose regimen.
authors.affiliation: Bio-Threat Defence Section, Defence Research and Development Canada, Suffield Research Centre, Ralston, Alberta, Canada Aurora BioSolutions Inc., Medicine Hat, Alberta, Canada.
authors.forename: Lorena R
authors.initials: LR
authors.lastname: Braid
authors.affiliation: Bio-Threat Defence Section, Defence Research and Development Canada, Suffield Research Centre, Ralston, Alberta, Canada wei-gang.hu@drdc-rddc.gc.ca.
authors.forename: Wei-Gang
authors.initials: WG
authors.lastname: Hu
authors.affiliation: Institute of Biomaterials and Bioengineering, University of Toronto, Toronto, Ontario, Canada Tissue Regeneration Therapeutics, Inc., Toronto, Ontario, Canada.
authors.forename: John E
authors.initials: JE
authors.lastname: Davies
authors.affiliation: Bio-Threat Defence Section, Defence Research and Development Canada, Suffield Research Centre, Ralston, Alberta, Canada.
authors.forename: Les P
authors.initials: LP
authors.lastname: Nagata
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D057134:Antibodies, Neutralizing / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D004666:Encephalitis Virus, Venezuelan Equine / Q000276:immunology / Q000472:pathogenicity*; D004685:Encephalomyelitis, Venezuelan Equine / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005838:Genotype; D006207:Half-Life; D054884:Host-Pathogen Interactions; D006801:Humans; D007273:Injections, Intramuscular; D059630:Mesenchymal Stem Cells / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010641:Phenotype; D055550:Protein Stability; D014162:Transfection; D014470:Umbilical Cord / Q000166:cytology*; D014765:Viral Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology* / Q000493:pharmacokinetics
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing; D014765:Viral Vaccines
keywords: Cell therapy; Gene therapy; Mesenchymal stromal cells; Passive immunity; Prophylaxis; Venezuelan equine encephalitis virus