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Development of new therapies for promoting myelin repair in multiple sclerosis

Graham McLeod

University of Manitoba


Resubmission Introduction: Multiple Sclerosis (MS) is a progressive autoimmune disease of the central nervous system (CNS) characterized by destruction of myelin sheaths, death of oligodendrocytes, and eventual permanent degeneration of axons. The healthy CNS maintains myelin by endogenously renewing oligodendrocytes from resident precursor cells, but in MS, this capacity diminishes. Our group has made the original observation that depletion of Factor X (an endogenous growth factor which we have been advised not to identify due to patenting potential) in demyelinating lesions seems to be an underlying cause of the limited remyelination. We sought to investigate the impact of Factor X therapy in a clinically relevant mouse model of MS, experimental autoimmune encephalomyelitis (EAE). Methods: EAE was induced in adult female C57BL/6 mice. Mice were randomly assigned to receive daily systemic injections of either Factor X or vehicle for 4 weeks. An age-matched naïve non-EAE group was also included as a baseline normal control. At 4 weeks following treatment, semi-thin spinal cord cross sections were prepared. Myelin thickness was assessed by analyzing the g-ratios, which is the ratio of inner to outer diameter of myelin sheath for a circular axon in cross-section. (g-ratio has an inverse relationship with myelin thickness.) Axon density was assessed by counting the number of axons in images from the lesion and perilesional area. Results of g-ratio and axon count were compared by student t-test and one-way ANOVA respectively, followed by post hoc pairwise comparison of groups, with results of P <0.05 considered significant. Results: Analysis of non-EAE control tissue revealed a g-ratio of 0.674. Demyelination in EAE group increased the g-ratio to 0.699 ± 0.006. Factor X treatment decreased the g-ratio to 0.664 ± 0.009, indicating increased myelin thickness (data represent mean ± SEM, *P = 0.018, student t test, N = 4/group). EAE significantly decreased axonal density (198 ± 12 per 104 μm2) compared to non-EAE control tissue (382 ± 4 axons per 104 μm2). Factor X treatment significantly increased axon preservation in EAE lesions (277 ± 11 axons per 104 μm2) compared to vehicle treated EAE mice (data represent mean ± SEM, *P < 0.003, one-way ANOVA, N = 4/group). Conclusion: We demonstrate that bioavailability of Factor X in EAE lesions promotes remyelination and axonal integrity. Our findings suggest the potential of Factor X as a regenerative therap

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