Abstract

Mechanisms of myelin regeneration

Major progress have been achieved in multiple sclerosis treatment, through the development of immunotherapies reducing central nervous system inflammation and related relapse rate. Prevention of handicap progression, which mostly correlates to irreversible neuronal/axonal damage and loss, is however still an unmet need, notably during the progressive phase of the disease. In this context, promoting remyelination, which results in prevention of neurodegeneration, represents a promising therapeutic strategy to slow or suppress disability progression. Recent years have been fruitful in our understanding of the cellular and molecular mechanisms of the remyelination process, taking advantage of a wide variety of demyelination/remyelination models. One pre-requisite for successful remyelination is the presence of axons (at least without irreversible damage). The other is a sufficient number of remyelinating cells. Aside from oligodendrocyte precursors cells, progenitor cells from the sub-ventricular zone but also mature oligodendrocytes might participate in remyelination, although this is still a matter of debate. Different steps, consisting of cell division, activation, recruitment to the demyelinated area, oligodendroglial maturation and myelin wrapping are needed for remyelination, the relative importance of each step depending on the lesion type. Key molecular pathways have been identified: PDGF and FGF induce cell division, several guidance cues influence OPC recruitment towards the lesion, Semaphorin 3F being attractant, in contrast to the repellent effect of Semaphorin 3A and Netrin 1. Several cues and pathways favoring or inhibiting the oligodendroglial maturation process have been identified. Among the inhibitors of maturation are the Notch signaling pathway , Lingo-1, the Wnt pathway, muscarinic receptor signaling, H3 receptor signaling hyaluronan, chondroitin sulfate proteoglycan, and fibrinogen. The mechano-responsive ion channel PIEZO1 has been identified as an inhibitor of maturation, involved in age- related loss of function of OPC. In contrast, activation of the retinoid X receptor gamma favors oligodendroglial maturation, as well as thyroid hormone and Vitamin D. Furthermore, complementary lines of evidence have highlighted the key role of neuronal electrical activity in myelination onset. From this very active research field, and with the caveat that these mechanisms of remyelination might differ between experimental models and multiple sclerosis, several therapeutic targets have emerged, paving the way to translation.

Abstract

Advances in anti-inflammatory activity have opened the way for similar brakthroughs to be made in the fields of neuroprotection and remyelination.

This talk will examine these areas from the standpoint of trial design, particularly from the unmet needs of progressive disease.

A review of the characteristics of major outcome measures which are and/or maybe of value to measure these elements in terms of current understanding of the pathology.

A variety of outcome mesures and trial design elements will be discussed. For example MRI, OCT and Neurofilaments. They will be placed in context of current and recent clinical trials.

Human trials in neuroprotection and recently remyelination have started to report and a number of lessons are being learnt. Whilst many are at the early/mid-phase there are encouraging signs as the trial process continues to be refined.