Low sulfated heparan sulfate mimetic differentially affects repair in immune-mediated and toxin-induced experimental models of demyelination

Lindsay, S. L. , McCanney, G. A., Zhan, J., Scheld, M., Sherrard Smith, R., Goodyear, C. S. , Yates, E. A., Kipp, M., Turnbull, J. E. and Barnett, S. C. (2023) Low sulfated heparan sulfate mimetic differentially affects repair in immune-mediated and toxin-induced experimental models of demyelination. Glia, 71(7), pp. 1683-1698. (doi: 10.1002/glia.24363) (PMID:36945189)

Abstract

There is an urgent need for therapies that target the multicellular pathology of central nervous system (CNS) disease. Modified, nonanticoagulant heparins mimic the heparan sulfate glycan family and are known regulators of multiple cellular processes. In vitro studies have demonstrated that low sulfated modified heparin mimetics (LS-mHeps) drive repair after CNS demyelination. Herein, we test LS-mHep7 (an in vitro lead compound) in experimental autoimmune encephalomyelitis (EAE) and cuprizone-induced demyelination. In EAE, LS-mHep7 treatment resulted in faster recovery and rapidly reduced inflammation which was accompanied by restoration of animal weight. LS-mHep7 treatment had no effect on remyelination or on OLIG2 positive oligodendrocyte numbers within the corpus callosum in the cuprizone model. Further in vitro investigation confirmed that LS-mHep7 likely mediates its pro-repair effect in the EAE model by sequestering inflammatory cytokines, such as CCL5 which are upregulated during immune-mediated inflammatory attacks. These data support the future clinical translation of this next generation modified heparin as a treatment for CNS diseases with active immune system involvement.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Sherrard Smith, rebecca and McCanney, George and Barnett, Professor Susan and Lindsay, Dr Susan and Goodyear, Professor Carl
• Authors: Lindsay, S. L., McCanney, G. A., Zhan, J., Scheld, M., Sherrard Smith, R., Goodyear, C. S., Yates, E. A., Kipp, M., Turnbull, J. E., and Barnett, S. C.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Research Centre: College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Immunobiology
• Journal Name: Glia
• Publisher: Wiley
• ISSN: 0894-1491
• ISSN (Online): 1098-1136
• Published Online: 21 March 2023
• Copyright Holders: Copyright © 2023 The Authors
• First Published: First published in Glia 71(7): 1683-1698
• Publisher Policy: Reproduced under a Creative Commons License

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
309989		Heparin mimetics: Novel non-anticoagulant compounds to promote CNS repair	Susan Barnett	Medical Research Council (MRC)	MR/V00381X/1	III - Immunology
171863		Development of glycomolecules as novel therapeutics for the treatment of multiple sclerosis	Hugh Willison	Medical Research Scotland (MEDRESSC)	PhD-769-2014	III - Immunology