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

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.

Glial Cell-Axonal Growth Cone Interactions in Neurodevelopment and Regeneration

“…Furthermore, intrathecal administration of an antibody against RGMa in a rat SCI model promoted axonal growth and functional recovery, which may be attributed to invasion of microglia and/or macrophages in the site of injury (Hata et al, 2006). Another group developed a systemically administered, human monoclonal antibody against the N-terminus of RGMa, which both neutralized RGMa as well as prevented the RGMa receptor Neogenin from associating with lipid rafts, which is essential for its downstream functions (Mothe et al, 2017). The authors demonstrated that this treatment promoted neuron survival, corticospinal tract axonal regeneration, and improvement in motor function and gait.…”

Polycaprolactone electrospun fiber scaffold loaded with iPSCs-NSCs and ASCs as a novel tissue engineering scaffold for the treatment of spinal cord injury

“…SCI is a common central nervous system disorder characterized by destruction or dysfunction of spinal cord caused by trauma or other causes. [42][43][44] SCI can cause a variety of complications that lead to irreversible loss of sensory and motor functions. Recently, the incidence of SCI showed a significant upward trend especially in developing countries, and this is a heavy burden for the patients' family and society.…”

Promoting functions of microRNA-29a/199B in neurological recovery in rats with spinal cord injury through inhibition of the RGMA/STAT3 axis

“…miR-29a and miR-199B target RGMA and suppress the STAT3 signaling pathway RGMA has been noted to be upregulated in SCI rats and suppressed neurological recovery [10], and STAT3 signaling activation was suggested to inhibit nerve regeneration and repair [21]. Interestingly, either miR-29a or Fig.…”