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Silencing Nogo‐A promotes functional recovery in demyelinating disease
Author(s) -
Yang Yuhong,
Liu Yue,
Wei Ping,
Peng Haiyan,
Winger Ryan,
Hussain Rehana Z.,
Ben LiHong,
Cravens Petra D.,
Gocke Anne R.,
Puttaparthi Krishna,
Racke Michael K.,
McTigue Dana M.,
LovettRacke Amy E.
Publication year - 2010
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.21935
Subject(s) - gene silencing , small interfering rna , experimental autoimmune encephalomyelitis , multiple sclerosis , in vivo , myelin , flow cytometry , rna interference , in vitro , cancer research , microbiology and biotechnology , chemistry , immunology , biology , neuroscience , cell culture , transfection , rna , central nervous system , biochemistry , genetics , gene
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. Interpretation 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. ANN NEUROL 2010;67:498–507