Humanized Anti-RGMa Antibody Treatment Promotes Repair of Blood-Spinal Cord Barrier Under Autoimmune Encephalomyelitis in Mice

The lack of established biomarkers which reflect dynamic neuropathological alterations in multiple sclerosis (MS) makes it difficult to determine the therapeutic response to the tested drugs and to identify the key biological process that mediates the beneficial effect of them. In the present study, we applied high-field MR imaging in locally-induced experimental autoimmune encephalomyelitis (EAE) mice to evaluate dynamic changes following treatment with a humanized anti-repulsive guidance molecule-a (RGMa) antibody, a potential drug for MS. Based on the longitudinal evaluation of various MRI parameters including white matter, axon, and myelin integrity as well as blood-spinal cord barrier (BSCB) disruption, anti-RGMa antibody treatment exhibited a strong and prompt therapeutic effect on the disrupted BSCB, which was paralleled by functional improvement. The antibody's effect on BSCB repair was also suggested via GeneChip analysis. Moreover, immunohistochemical analysis revealed that EAE-induced vascular pathology which is characterized by aberrant thickening of endothelial cells and perivascular type I/IV collagen deposits were attenuated by anti-RGMa antibody treatment, further supporting the idea that the BSCB is one of the key therapeutic targets of anti-RGMa antibody. Importantly, the extent of BSCB disruption detected by MRI could predict late-phase demyelination, and the predictability of myelin integrity based on the extent of acute-phase BSCB disruption was compromised following anti-RGMa antibody treatment. These results strongly support the concept that longitudinal MRI with simultaneous DCE-MRI and DTI analysis can be used as an imaging biomarker and is useful for unbiased prioritization of the key biological process that mediates the therapeutic effect of tested drugs.

Automated summary

The lack of established biomarkers for monitoring the therapeutic response and identifying key biological processes in multiple sclerosis (MS) hinders drug development. In this study, high-field MR imaging was used to evaluate the effects of a potential MS drug, anti-repulsive guidance molecule-a (RGMa) antibody, in EAE mice. The results showed that anti-RGMa antibody treatment improved blood-spinal cord barrier (BSCB) disruption and functional recovery. MRI assessment of BSCB disruption could predict demyelination, but this predictive ability was compromised by the antibody treatment.