Silencing Nogo-A promotes functional recovery in demyelinating disease.
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.
Yang
Yuhong
Y
Department of Neurology, Ohio State University Medical Center, Columbus, OH 43210, USA.
Liu
Yue
Y
Wei
Ping
P
Peng
Haiyan
H
Winger
Ryan
R
Hussain
Rehana Z
RZ
Ben
Li-Hong
LH
Cravens
Petra D
PD
Gocke
Anne R
AR
Puttaparthi
Krishna
K
Racke
Michael K
MK
McTigue
Dana M
DM
Lovett-Racke
Amy E
AE
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
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