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Sci Rep. 2017 Sep 5;7(1):10529. doi: 10.1038/s41598-017-10987-7.

RGMa inhibition with human monoclonal antibodies promotes regeneration, plasticity and repair, and attenuates neuropathic pain after spinal cord injury.

Author information

1
Krembil Research Institute, Division of Genetics and Development, Krembil Discovery Tower, Toronto ON, M5T 2S8, Canada. amothe@uhnres.utoronto.ca.
2
Toronto Western Hospital, University Health Network, Toronto ON, M5T 2S8, Canada. amothe@uhnres.utoronto.ca.
3
Krembil Research Institute, Division of Genetics and Development, Krembil Discovery Tower, Toronto ON, M5T 2S8, Canada.
4
Toronto Western Hospital, University Health Network, Toronto ON, M5T 2S8, Canada.
5
AbbVie Bioresearch Center, Worcester MA, 01605, USA.
6
Neuroscience Research, Research and Development, AbbVie Deutschland GmbH & Co. KG, Knollstrasse, Ludwigshafen, 67061, Germany.
7
Department of Ophthalmology and Vision Science, University of Toronto, Toronto ON, M5S 3H6, Canada.
8
Krembil Research Institute, Division of Genetics and Development, Krembil Discovery Tower, Toronto ON, M5T 2S8, Canada. charles.tator@uhn.ca.
9
Toronto Western Hospital, University Health Network, Toronto ON, M5T 2S8, Canada. charles.tator@uhn.ca.
10
Department of Surgery, Division of Neurosurgery, University of Toronto, Toronto ON, M5S 3H6, Canada. charles.tator@uhn.ca.

Abstract

Traumatic spinal cord injury (SCI) causes a cascade of degenerative events including cell death, axonal damage, and the upregulation of inhibitory molecules which prevent regeneration and limit recovery. Repulsive guidance molecule A (RGMa) is a potent neurite growth inhibitor in the central nervous system, exerting its repulsive activity by binding the Neogenin receptor. Here, we show for the first time that inhibitory RGMa is markedly upregulated in multiple cell types after clinically relevant impact-compression SCI in rats, and importantly, also in the injured human spinal cord. To neutralize inhibitory RGMa, clinically relevant human monoclonal antibodies were systemically administered after acute SCI, and were detected in serum, cerebrospinal fluid, and in the injured tissue. Rats treated with RGMa blocking antibodies showed significantly improved recovery of motor function and gait. Furthermore, RGMa blocking antibodies promoted neuronal survival, and enhanced the plasticity of descending serotonergic pathways and corticospinal tract axonal regeneration. RGMa antibody also attenuated neuropathic pain responses, which was associated with fewer activated microglia and reduced CGRP expression in the dorsal horn caudal to the lesion. These results show the therapeutic potential of the first human RGMa antibody for SCI and uncovers a new role for the RGMa/Neogenin pathway on neuropathic pain.

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