Targeting repulsive guidance molecule A to promote regeneration and neuroprotection in multiple sclerosis

Elena Demicheva, Yi Fang Cui, Philip Bardwell, Stefan Barghorn, Martina Kron, Axel H. Meyer, Martin Schmidt, Björn Gerlach, Mary Leddy, Eve Barlow, Elizabeth O'Connor, Chee Ho Choi, Lili Huang, Geertruida M. Veldman, Horea Rus, Alireza P. Shabanzadeh, Nardos G. Tassew, Philippe P. Monnier, Thomas Müller, Peter A. CalabresiHans Schoemaker, Bernhard K. Mueller

Research output: Contribution to journalArticle

Abstract

Repulsive guidance molecule A (RGMa) is a potent inhibitor of neuronal regeneration and a regulator of cell death, and it plays a role in multiple sclerosis (MS). In autopsy material from progressive MS patients, RGMa was found in active and chronic lesions, as well as in normal-appearing gray and white matter, and was expressed by cellular meningeal infiltrates. Levels of soluble RGMa in the cerebrospinal fluid were decreased in progressive MS patients successfully treated with intrathecal corticosteroid triamcinolone acetonide (TCA), showing functional improvements. Invitro, RGMa monoclonal antibodies (mAbs) reversed RGMa-mediated neurite outgrowth inhibition and chemorepulsion. In animal models of CNS damage and MS, RGMa antibody stimulated regeneration and remyelination of damaged nerve fibers, accelerated functional recovery, and protected the retinal nerve fiber layer as measured by clinically relevant optic coherence tomography. These data suggest that targeting RGMa is a promising strategy to improve functional recovery in MS patients. •Decreased RGMa levels in MS patients correlate with functional improvements•Anti-RGMa treatment in an optic nerve crush model protects retinae•Anti-RGMa enhances regeneration after optic nerve crush and spinal cord inflammation•Animal models of multiple sclerosis show functional improvements after treatment. RGMa is a potent inhibitor of nerve growth and is expressed in several brain diseases, including Alzheimer's disease and multiple sclerosis (MS). Demicheva etal. use an anti-RGMa-specific antibody in animal models of MS and show neural regeneration in the optic nerve after injury and in the spine after inflammation, accompanied by functional improvements.

Original languageEnglish (US)
Pages (from-to)1887-1898
Number of pages12
JournalCell Reports
Volume10
Issue number11
DOIs
StatePublished - Mar 24 2015

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Demicheva, E., Cui, Y. F., Bardwell, P., Barghorn, S., Kron, M., Meyer, A. H., Schmidt, M., Gerlach, B., Leddy, M., Barlow, E., O'Connor, E., Choi, C. H., Huang, L., Veldman, G. M., Rus, H., Shabanzadeh, A. P., Tassew, N. G., Monnier, P. P., Müller, T., ... Mueller, B. K. (2015). Targeting repulsive guidance molecule A to promote regeneration and neuroprotection in multiple sclerosis. Cell Reports, 10(11), 1887-1898. https://doi.org/10.1016/j.celrep.2015.02.048