Abstract
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system that is characterized by motor deficits, fatigue, pain, cognitive impairment, and sensory and visual dysfunction. Secondary progressive multiple sclerosis (SPMS) is a progressive form of MS that develops from relapsing-remitting MS. Repulsive guidance molecule-a (RGMa) has diverse functions, including axon growth inhibition and immune regulation. Here, we show inhibiting RGMa had therapeutic effects in mouse models of SPMS. We induced experimental autoimmune encephalomyelitis in nonobese diabetic mice (NOD-EAE mice) and treated them with humanized anti-RGMa monoclonal antibody. This treatment significantly suppressed secondary progression of disease and inflammation, demyelination and axonal degeneration. In addition, treatment with anti-RGMa antibody promoted the growth of corticospinal tracts and motor recovery in targeted EAE mice with inflammatory lesions in the spinal cord. Collectively, these results show that a humanized anti-RGMa antibody has therapeutic effects in mouse models of SPMS.
Highlights
Multiple sclerosis (MS) is an autoimmune disease characterized by inflammation, demyelination, and axonal degeneration in the central nervous system (CNS)[1,2]
The expression of Repulsive guidance molecule-a (RGMa) appears to be increased in the spinal cord of NODEAE mice at the secondary progressive phase (50 days post-immunization) when compared with control mice, but did not change compared with the acute phase (14 days post-immunization) (Fig. 1b, c), suggesting involvement of RGMa in the secondary disease progression in nonobese diabetic (NOD)-EAE mice
The antibody promoted neuroregeneration by repairing the neural network. It had no effect on the onset of secondary progression and only partially suppressed progression in our model, suggesting complexities in the mechanisms of secondary progressive MS (SPMS) that are not fully dependent on RGMa
Summary
Multiple sclerosis (MS) is an autoimmune disease characterized by inflammation, demyelination, and axonal degeneration in the central nervous system (CNS)[1,2]. 85% of MS patients exhibit relapsing-remitting MS (RRMS), a biphasic course with alternating episodes of neurological disability and recovery. Within 10 years, 50% of RRMS patients develop secondary progressive MS (SPMS), which is characterized by progressive neurological decline[3]. Ocrelizumab has therapeutic effects for primary progression of MS, which is characterized by progressive neurological deficit without relapsingremitting[4,5]. Mitoxantron is approved for SPMS treatment with significant toxicity[7]. These treatments are not able to halt disease progression of SPMS without toxicity, or recover the neurological deficits. While immunosuppressive treatments have therapeutic effects on RRMS, many of them are not effective in patients with SPMS8. Progressed neurodegeneration resulted in the atrophy of brain and spinal cord of SPMS patients[12], suggesting that neurodegeneration is a key to treat disease progression of SPMS
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