Antisense oligonucleotide targeting macrophage migration inhibitory factor ameliorates experimental autoimmune encephalomyelitis

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Antisense oligonucleotide targeting macrophage migration inhibitory factor ameliorates experimental autoimmune encephalomyelitis

Benyuan Zhang1, 2, Sang-Hyeon Ju3, Minsung Park3, Min Hee Lee4, Hyun Jung Hong3, Jung Tae Kim3, Dong Yun Lee3, Jaehun Kim3, Ju Hee Lee1, 2, 5, Jiebo Zhu2, Jun Young Heo2, Yunju Jo6, Dongryeol Ryu6, Jinkuk Kim3, Hyon-Seung Yi1, 2, 5,**, Minho Shong3, 4, 7*

1Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, Daejeon 35015, Republic of Korea
2Department of Medical Science, Chungnam National University School of Medicine, Daejeon 35015, Republic of Korea
3Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea
4THOR Therapeutics, Inc., Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea
5Department of Internal Medicine, Chungnam National University Hospital, Daejeon 35015, Republic of Korea
6Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea
7Lead contact

SUMMARY
Multiple sclerosis (MS) is a chronic, debilitating disease of the central nervous system (CNS), characterized by demyelination and axonal damage. This research investigates the role of macrophage migration inhibitory factor (MIF) in MS pathogenesis, focusing on the development and therapeutic potential of antisense oligonucleotides (ASOs) targeting MIF. Transcriptomic analysis of MS patients highlighted increased expression of MIF and its receptor CD74 in CNS lesions. In response, MIF-specific ASOs were designed and shown to effectively reduce MIF levels in vitro and in vivo. The study utilized the experimental autoimmune encephalomyelitis (EAE) mouse model, where intracerebroventricular administration of these ASOs led to significant reductions in demyelination and immune cell infiltration, while also improving motor functions. These findings suggest that targeting MIF with ASOs could be a viable treatment strategy for reducing both inflammation and neurodegeneration in MS.

Keywords: Macrophage migration inhibitory factor, antisense oligonucleotide, experimental autoimmune encephalomyelitis, multiple sclerosis, CNS inflammation