LINGO-1 antagonist promotes spinal cord remyelination and axonal integrity in MOG-induced experimental autoimmune encephalomyelitis

Abstract

Demyelinating diseases, such as multiple sclerosis, are characterized by the loss of the myelin sheath around neurons, owing to inflammation and gliosis in the central nervous system (CNS). Current treatments therefore target anti-inflammatory mechanisms to impede or slow disease progression. The identification of a means to enhance axon myelination would present new therapeutic approaches to inhibit and possibly reverse disease progression. Previously, LRR and Ig domain-containing, Nogo receptor-interacting protein (LINGO-1) has been identified as an in vitro and in vivo negative regulator of oligodendrocyte differentiation and myelination. Here we show that loss of LINGO-1 function by Lingo1 gene knockout or by treatment with an antibody antagonist of LINGO-1 function leads to functional recovery from experimental autoimmune encephalomyelitis. This is reflected biologically by improved axonal integrity, as confirmed by magnetic resonance diffusion tensor imaging, and by newly formed myelin sheaths, as determined by electron microscopy. Antagonism of LINGO-1 or its pathway is therefore a promising approach for the treatment of demyelinating diseases of the CNS.

Cell Therapy for Multiple Sclerosis

“…Among several neurotrophic factors tested, the ciliary neurotrophic factor family was found to promote oligodendrocyte differentiation and remyelination [107]. More recently, pharmacologic induction of OPC differentiation by inhibition of RhoA-Rho-kinase II (ROCK-II), and/or protein kinase C signaling [108], or by anti-Leucine-rich repeats and Ig domain-containing, neurite outgrowth inhibitor (Nogo) receptor-interacting protein-1 (LINGO1) antibodies [109,110] accelerated remyelination. Statins and inhibitors of receptor tyrosine phosphatases are other pharmacologic agents that induce rodent [111] and human [112] oligodendrocyte differentiation.…”

Myelin Regeneration in Multiple Sclerosis: Targeting Endogenous Stem Cells

“…Treatment of cultured OPCs with small interference RNAs (siRNAs) generated against LINGO-1, dominant negative LINGO-1, or soluble LINGO (LINGOFc) resulted in increased morphological differentiation of oligodendrocytes as characterized by the abundance of terminal membrane sheets. Mice deficient in LINGO-1 or treated with an antibody antagonist against LINGO-1 exhibited increased remyelination and functional recovery from EAE, a model of immune-mediated demyelination [53]. Moreover, the LINGO-1 antagonist is able to promote CNS remyelination by directly stimulating OPC differentiation in nonimmune, toxin-induced models of demyelination in rats [54].…”

Predictors of response to opicinumab in acute optic neuritis

“…Opicinumab (anti‐LINGO‐1, BIIB033) is a human monoclonal antibody against leucine‐rich repeat and immunoglobulin‐like domain‐containing protein 1 (LINGO‐1; an oligodendrocyte differentiation and myelination suppressor) that was genetically engineered to reduce immunoglobulin effector function. In preclinical models, opicinumab has no apparent effects on the immune system; remyelination/neuroprotection effects in the central nervous system (CNS) as well as acceptable tolerability were observed 7, 8, 9, 10. Therefore, opicinumab is being further tested in Phase II proof‐of‐biology/concept studies.…”