Hoang Dao

Background:  Spinal cord injury is a devastating neurological condition that follows from significant trauma with symptoms such as paralysis, spasticity, and cardiovascular, bowel and sexual dysfunction.¹ Spinal cord injury (SCI) affects between 250,000 and 500,000 individuals every year with these people being two to five times more likely to die prematurely when compared to people without an SCI.¹ Current treatments consists of corticosteroids, cyclooxygenase inhibitors or non-steroidal anti-inflammatory drugs to decrease inflammation and edema.^2,3 There is no specific form of therapy that is considered a gold standard treatment of choice. One form of treatment being studied is the inhibition of Nogo receptor signaling. Neutralization of the myelin-enriched membrane protein Nogo-A by blocking antibodies, genetic deletion of Nogo-A or blocking Nogo receptors has been shown to increase axonal regeneration and promote recovery of function in spinal cord injuries.⁴

Objective(s):  explored the Nogo receptor and the multiple mechanisms of inhibition to determine the effects it has on spinal cord injury.

Search Methods: An online search in the PubMed database was conducted from 2017-2023 using the following keywords: “spinal cord injuries”, “Nogo proteins”, “Nogo receptors”, and “Nogo receptor 1”.

Results: Studies showed that lateral olfactory tract usher substance (LOTUS), which is a Nogo receptor (NgR) antagonist, promotes neurite outgrowth by NgR signaling.⁵ The LOTUS-expressing mice had a statistically significant increase in hindlimb recovery after SCI when compared to control mice. Another form of Nogo receptor inhibition was the Nogo receptor decoy (NgR1-Fc, AXER-204).⁶ This study showed that NgR1-Fc treatment was effective in promoting fiber growth caudal to the lesion and improved neurological function.⁶ Intrathecal NgR1-Fc (AXER-204) was found to have no safety concerns in rats or monkeys for intrathecal administration.⁶ Another method to target the Nogo receptor is anti-Nogo-A antibodies. Intrathecal administration of anti-Nogo-A antibody led to decreased abnormal electromyography (EMG) high-frequency activity in the external urethral sphincter. Abnormal EMG activity represented dyssynergistic contraction of the EUS.⁷ The anti-Nogo-A antibody treatment was found to have improved key urodynamic and electrophysiological parameters that led to increased recovery of the physiological EUS function during voiding.⁷ An in-man clinical study of anti-Nogo-A antibodies (ATI355) found that ATI355 is well tolerated in treatment of acute SCI, with i.t. bolus injections being the preferred method of administration.⁸ I.t. dosing allows one to bypass the blood brain barrier and helps improve tolerability by allowing smaller doses to be delivered than would be given intravenously. ⁸

Conclusion: Studies have found that inhibition of the Nogo receptor could help in promoting functional and neurological recovery after SCI. Other forms such as LOTUS or NgR-Fc, AXER-204 were shown to improve motor and neurological function. With the in-man clinical study of anti-Nogo-A antibodies showing effectiveness and being tolerated by the patients, ATI355 could undergo large-scale, randomized trials to examine the true efficacy in improving neurological recovery after spinal cord injury. One consideration to investigate in the future is how these treatments will interact with other drugs as these trauma patients will likely be receiving treatment for other symptoms.

Works Cited

1. Quadri SA, Farooqui M, Ikram A, et al. Recent update on basic mechanisms of spinal cord injury. Neurosurg Rev. 2020;43(2):425-441. doi:10.1007/s10143-018-1008-3
2. Eli I, Lerner DP, Ghogawala Z. Acute Traumatic Spinal Cord Injury. Neurol Clin. 2021;39(2):471-488. doi:10.1016/j.ncl.2021.02.004
3. Sterner RC, Sterner RM. Immune response following traumatic spinal cord injury: Pathophysiology and therapies. Front Immunol. 2023;13:1084101. Published 2023 Jan 6. doi:10.3389/fimmu.2022.1084101
4. Schneider MP, Sartori AM, Ineichen BV, et al. Anti-Nogo-A Antibodies As a Potential Causal Therapy for Lower Urinary Tract Dysfunction after Spinal Cord Injury. J Neurosci. 2019;39(21):4066-4076. doi:10.1523/JNEUROSCI.3155-18.2019
5. Ito S, Nagoshi N, Tsuji O, et al. LOTUS Inhibits Neuronal Apoptosis and Promotes Tract Regeneration in Contusive Spinal Cord Injury Model Mice. eNeuro. 2018;5(5):ENEURO.0303-18.2018. Published 2018 Dec 14. doi:10.1523/ENEURO.0303-18.2018
6. Wang X, Zhou T, Maynard GD, et al. Nogo receptor decoy promotes recovery and corticospinal growth in non-human primate spinal cord injury. Brain. 2020;143(6):1697-1713. doi:10.1093/brain/awaa116
7. Schneider MP, Sartori AM, Ineichen BV, et al. Anti-Nogo-A Antibodies As a Potential Causal Therapy for Lower Urinary Tract Dysfunction after Spinal Cord Injury. J Neurosci. 2019;39(21):4066-4076. doi:10.1523/JNEUROSCI.3155-18.2019
8. Kucher K, Johns D, Maier D, et al. First-in-Man Intrathecal Application of Neurite Growth-Promoting Anti-Nogo-A Antibodies in Acute Spinal Cord Injury. Neurorehabil Neural Repair. 2018;32(6-7):578-589. doi:10.1177/1545968318776371