title: Silencing Nogo-A promotes functional recovery in demyelinating disease.
abstract: OBJECTIVE
  To determine if suppressing Nogo-A, an axonal inhibitory protein, will promote functional recovery in a murine model of multiple sclerosis (MS).
  
  
  METHODS
  A small interfering RNA was developed to specifically suppress Nogo-A (siRNA-NogoA). The siRNA-NogoA silencing effect was evaluated in vitro and in vivo via immunohistochemistry. The siRNA was administered intravenously in 2 models of experimental autoimmune encephalomyelitis (EAE). Axonal repair was measured by upregulation of GAP43. Enzyme-linked immunosorbent assay, flow cytometry, and (3)H-thymidine incorporation were used to determine immunological changes in myelin-specific T cells in mice with EAE.
  
  
  RESULTS
  The siRNA-NogoA suppressed Nogo-A expression in vitro and in vivo. Systemic administration of siRNA-NogoA ameliorated EAE and promoted axonal repair, as demonstrated by enhanced GAP43+ axons in the lesions. Myelin-specific T-cell proliferation and cytokine production were unchanged in the siRNA-NogoA-treated mice.
  
  
  CONCLUSIONS
  Silencing Nogo-A in EAE promotes functional recovery. The therapeutic benefit appears to be mediated by axonal growth and repair, and is not attributable to changes in the encephalitogenic capacity of the myelin-specific T cells. Silencing Nogo-A may be a therapeutic option for MS patients to prevent permanent functional deficits caused by immune-mediated axonal damage.
authors.affiliation: Department of Neurology, Ohio State University Medical Center, Columbus, OH 43210, USA.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Yang
authors.forename: Yue
authors.initials: Y
authors.lastname: Liu
authors.forename: Ping
authors.initials: P
authors.lastname: Wei
authors.forename: Haiyan
authors.initials: H
authors.lastname: Peng
authors.forename: Ryan
authors.initials: R
authors.lastname: Winger
authors.forename: Rehana Z
authors.initials: RZ
authors.lastname: Hussain
authors.forename: Li-Hong
authors.initials: LH
authors.lastname: Ben
authors.forename: Petra D
authors.initials: PD
authors.lastname: Cravens
authors.forename: Anne R
authors.initials: AR
authors.lastname: Gocke
authors.forename: Krishna
authors.initials: K
authors.lastname: Puttaparthi
authors.forename: Michael K
authors.initials: MK
authors.lastname: Racke
authors.forename: Dana M
authors.initials: DM
authors.lastname: McTigue
authors.forename: Amy E
authors.initials: AE
authors.lastname: Lovett-Racke
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005434:Flow Cytometry / Q000379:methods; D019922:GAP-43 Protein / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006023:Glycoproteins / Q000009:adverse effects; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D004676:Myelin Basic Protein / Q000235:genetics / Q000494:pharmacology; D009185:Myelin Proteins / Q000235:genetics / Q000378:metabolism*; D063308:Myelin-Oligodendrocyte Glycoprotein; D009447:Neuroblastoma; D000070798:Nogo Proteins; D010446:Peptide Fragments / Q000009:adverse effects / Q000235:genetics / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000627:therapeutic use*; D013116:Spinal Cord / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000494:pharmacology; D014162:Transfection / Q000379:methods
chemical_list: D019922:GAP-43 Protein; D006023:Glycoproteins; D004676:Myelin Basic Protein; D009185:Myelin Proteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D000070798:Nogo Proteins; D010446:Peptide Fragments; D034741:RNA, Small Interfering; C000603201:Rtn4 protein, mouse; C405722:myelin basic protein 1-11; C445081:myelin oligodendrocyte glycoprotein (35-55); D016753:Interleukin-10; C020922:4-O-methyl-12-O-tetradecanoylphorbol 13-acetate; D007371:Interferon-gamma; D013755:Tetradecanoylphorbol Acetate