Nogo: A Promising Target for New Gene Therapies

Wed, 06/29/2016 - 15:31

Nogo is a neurite outgrowth inhibitor protein that plays an important role during central nervous system (CNS) development as well as in endoplasmic reticulum signaling regulation. Studies using Nogo antibodies have revealed Nogo proteins regulate precursor migration, neurite growth and branching in the developing CNS. In addition, Nogo serves as a negative regulator of neuronal growth in the adult CNS, causing wiring stabilization but greatly limiting any regeneration abilities (Schwab, 2010).

There are three Nogo isoforms; Nogo-A, Nogo-B and Nogo-C. Although Nogo-A was the first identified isoform and is the most widely studied, all three isoforms have shown significant potential as targets for a variety of new gene therapies.

A number of recent studies have shown that inhibition using monoclonal Nogo-A antibodies or knockdown using Nogo-A siRNA may lead to neural growth and potentially even CNS regeneration. For example, researchers found that Nogo-A inhibition promoted neuronal maturity in PC-12 cells with no observed negative effects on cell viability (Yazdi et al., 2016), while Nogo receptor knockdown using siRNA improved neurite outgrowth (Ding et al., 2016). In another recent study, Nogo-A knockdown was found to promote functional recovery after spinal cord injury (Liu et al., 2016). Finally, Nogo-A neutralization was shown to improve graft function during cell transplantation therapies in a rat model for Parkinson’s Disease (Seiler et al., 2016). Together these findings suggest that blocking Nogo-A signaling may open a whole new world of CNS injury and neurodegenerative disease treatments.

Nogo antibody

Nogo antibody Nogo antibody

Immunoflourescence analysis of Nogo-A antibody (AF3515) in rat cortical stem cells.

Immunoflourescence analysis of Nogo-A antibody (MAB3098) in rat embryo.

IHC analysis of Nogo antibody (NB100-56681) in human testis

Meanwhile, Nogo-B has been identified as a useful indicator of liver cirrhosis (Men et al., 2015) and a novel regulator of hepatic fibrosis (Zhang et al., 2011). Therefore, Nogo-B inhibition is hypothesized to serve as a potential therapeutic target in both liver fibrosis and cirrhosis.

Similar to Nogo-A, Nogo-C has been identified as a neurite growth inhibitor sufficient to delay nerve regeneration after CNS trauma (Kim et al., 2003). This would indicate that Nogo-C may be another potential target for gene therapies.

Novus Biologicals offers a wide variety of Nogo antibodies and Nogo Receptor antibodies that are helping advance research on neuroregeneration, cancer and hepatic cirrhosis/fibrosis. For example, Novus’ Nogo‑A antibody (AF3098) to study traumatic brain injury in rat models (Chao et al., 2012). In another study, Novus’ Nogo Receptor antibody (AF1440) to investigate Nogo localization in the developing spinal cord (Wang et al., 2010).

Schwab ME.  Functions of Nogo proteins and their receptors in the nervous system. Nat Rev Neurosci. 2010 Dec;11(12):799-811. [PMID: 21045861]

Yazdi IK, Taghipour N, Hmaidan S, Palomba R, Scaria S, Munoz A, Boone TB, Tasciotti E.
Antibody-mediated inhibition of Nogo-A signaling promotes neurite growth in PC-12 cells. J Tissue Eng. 2016 Jan 28;7:2041731416629767. [PMID: 27027860]

Ding SH, Bao YH, Shen JH, Gao GY, Pan YH, Luo QZ, Jiang JY. Improved neurite outgrowth on central nervous system myelin substrate by siRNA-mediated knockdown of Nogo receptor. Chin J Traumatol. 2016 Feb 1;19(1):16-24. [PMID: 27033267]

Liu GM, Luo YG, Li J, Xu K. Knockdown of Nogo gene by short hairpin RNA interference promotes functional recovery of spinal cord injury in a rat model. Mol Med Rep. 2016 Mar 30. [PMID: 27035338]

Seiler S, Di Santo S2, Widmer HR. Nogo-A Neutralization Improves Graft Function in a Rat Model of Parkinson's Disease. Front Cell Neurosci. 2016 Apr 5;10:87. [PMID: 27092052]

Men R, Wen M, Dan X, Zhu Y, Wang W, Li J, Wu W, Liu X, Yang L. Nogo-B: A potential indicator for hepatic cirrhosis and regulator in hepatic stellate cell activation. Hepatol Res. 2015 Jan;45(1):113-22. [PMID: 24606149]

Zhang D, Utsumi T, Huang HC, Gao L, Sangwung P, Chung C, Shibao K, Okamoto K, Yamaguchi K, Groszmann RJ, Jozsef L, Hao Z, Sessa WC, Iwakiri Y. Reticulon 4B (Nogo-B) is a novel regulator of hepatic fibrosis. Hepatology. 2011 Apr;53(4):1306-15. [PMID: 21480333]

Kim JE, Bonilla IE, Qiu D, Strittmatter SM. Nogo-C is sufficient to delay nerve regeneration. Mol Cell Neurosci. 2003 Jul;23(3):451-9. [PMID: 12837628]

Chao PK, Lu KT, Jhu JY, Wo YY, Huang TC, Ro LS, Yang YL. Indomethacin protects rats from neuronal damage induced by traumatic brain injury and suppresses hippocampal IL-1β release through the inhibition of Nogo-A expression. J Neuroinflammation. 2012 Jun 7;9:121. [PMID: 22676811]

Wang J, Wang L, Zhao H, Chan SO.  Localization of an axon growth inhibitory molecule Nogo and its receptor in the spinal cord of mouse embryos. Brain Res. 2010 Jan 8;1306:8-17. [PMID: 19833111]

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