title: Targeted gene therapy to antigen-presenting cells in the central nervous system using hematopoietic stem cells.
abstract: BACKGROUND
  Hematopoietic stem cells (HSC) have been previously used as vectors for gene therapy of systemic disease. The effectiveness of HSC-mediated gene therapy largely depends on efficient gene delivery into long-term repopulating progenitors and targeted transgene expression in an appropriate progeny of the transduced pluripotent HSCs. In the present study, we examined the feasibility of using HSC transduced with self-inactivating (SIN) lentiviral vectors for the delivery of gene therapy to the central nervous system (CNS).
  
  
  METHODS
  We constructed two SIN lentiviral vectors, EF.GFP and DR.GFP, to express the green fluorescent protein (GFP) gene controlled solely by the promoter of either a housekeeping gene EF-1alpha or the human HLA-DRalpha gene, which is selectively expressed in antigen-presenting cells.
  
  
  RESULTS
  We demonstrated that both vectors efficiently transduced human pluripotent CD34+ cells capable of engrafting NOD/SCID mice. Only the DR.GFP vector mediated transgene expression in the murine CNS containing human HLA-DR+ cells. These cells express surface markers characteristic of resident CNS microglia. Furthermore, human dendritic cells derived from transduced and engrafted human cells potently stimulated allogeneic T cell proliferation.
  
  
  CONCLUSIONS
  The present study demonstrated successful targeting of transgene expression to CNS microglia after stable gene transduction of pluripotent HSC.
authors.affiliation: Section of Neurosurgery, The University of Chicago Pritzker School of Medicine, USA. mlesniak@syrgery.bsd.uchicago.edu
authors.forename: Maciej S
authors.initials: MS
authors.lastname: Lesniak
authors.forename: Erin
authors.initials: E
authors.lastname: Kelleher
authors.forename: Drew
authors.initials: D
authors.lastname: Pardoll
authors.forename: Yan
authors.initials: Y
authors.lastname: Cui
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000378:metabolism; D002525:Cerebellar Cortex / Q000166:cytology / Q000276:immunology; D002540:Cerebral Cortex / Q000166:cytology / Q000276:immunology; D003673:Defective Viruses / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005240:Feasibility Studies; D005786:Gene Expression Regulation; D005802:Genes, MHC Class II; D017930:Genes, Reporter; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000627:therapeutic use*; D049452:Green Fluorescent Proteins / Q000235:genetics; D006684:HLA-DR Antigens / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation; D006624:Hippocampus / Q000166:cytology / Q000276:immunology; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D017628:Microglia / Q000276:immunology* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics; D013047:Specific Pathogen-Free Organisms; D013601:T-Lymphocytes / Q000276:immunology; D014157:Transcription Factors / Q000235:genetics; D019076:Transgenes; D014183:Transplantation, Heterologous
chemical_list: D006684:HLA-DR Antigens; D009687:Nuclear Proteins; D014157:Transcription Factors; D049452:Green Fluorescent Proteins