Remyelinating therapies in MS Dr: Osama Ragab Tanta University

Introduction

Introduction Multiple sclerosis (MS) is an immune-mediated disorder of the central nervous system that results in destruction of the myelin sheath that surrounds axons.

Introduction Remyelination can restore neuronal function and prevent further neuronal loss and clinical disability. Molecular and cellular mechanisms regulating myelination, resulted in identification of agents that enhance myelination, and therapies used in preclinical and early clinical development.

Introduction There are many important factors must be considered to effectively translate remyelination therapies into clinical reality: Developing validated biomarkers to measure myelin status. Selecting of the most appropriate form of MS to test remyelination therapies. Determining the most effective period to use a therapeutic for remyelination (for example, early after a relapse or during stable disease in relapsing– remitting MS).

Development of myelin

Development of myelin Myelination begins with oligodendrocyte progenitor cells (OPCs) differentiating into oligodendrocytes, followed by their maturation into myelinating oligodendrocytes. Following white matter injury, neighboring OPCs proliferate and migrate towards the site of injury or demyelination. The process of myelination is subject to both positive and negative regulation

Development of myelin

Consequence of demyelination

Consequence of demyelination As oligodendrocytes are metabolically coupled to axons, so after demyelination this loss of support might prime axons to degenerate. The increase in the number of Na+ channels along the length of the axon that occurs upon demyelination elevates the energy demands on the axon, and reverse the Na+/Ca2+ exchanger, resulting in toxic levels of Ca+ in the axon.

Remyelination in MS

Remyelination in MS On the basis of histological assessments in patients with MS, remyelination in humans is highly variable: considerable in some cases, and absent in others. In tissue sections, the hallmark of remyelination in MS is a shadow plaque, because these lesions possess an amount of lipid staining that is intermediate between the normal white matter and a demyelinated plaque.

Remyelination in MS Remyelination in MS must also be considered in the context of ageing. Those with early MS tend to have more remyelination, and the rate of shadow plaque accumulation is highest within the first 10 years of the disease or before approximately 55 years of age, suggesting an age- and disease duration- dependent decline in remyelination. One important mechanism of age-dependent impairment in remyelination is a lower capacity of phagocytes to remove inhibitory myelin debris from the lesions site.

Proposed Mechanisms Remyelination in MS

Proposed Mechanisms Remyelination in MS Modulation of Intrinsic Signalling Pathways Altering the Extracellular Environment

Causes of remyelination failure in MS

Causes of remyeleination failure in MS Number of adult OPCs available for remyelination is depleted over time. Disruptions to the blood–brain barrier, leads to aberrant deposition of extracellular matrix (ECM) components, including fibronectin, hyaluronic acid (HA), and chondroitin sulfate proteoglycans (CSPGs), which can block the differentiation of OPCs and premyelinating oligodendrocytes

Causes of remyileination failure in MS Demyelination can expose OPCs inhibitory cues, including components of damaged myelin such as the proteins MAG (myelin- associated glycoprotein), OMgp (oligodendrocyte myelin glycoprotein), and and LINGO-1 (leucine-rich repeat- and Ig domain-containing Nogo receptor-interacting protein 1) to inhibit oligodendrocyte differentiation and remyelination.

Causes of remyileination failure in MS several non-disease-related factors such as age, sex, diet, and individual genetic background can also impact the efficiency of remyelination. Females remyelinate more efficiently than males, which could be due to the effects of sex hormones on oligodendrocyte proliferation and maturation .

Novel therapies for remyelination in MS

Novel therapies for remyelination in MS Clobetasol, a corticosteroid, act directly on oligodendrocytes and stimulate eukaryotic initiation factor 2. (phase 1).

Novel therapies for remyelination in MS Opicinumab is a fully humanized monoclonal antibody directed against LINGO1, was evaluated in a phase II trial participants received six monthly infusions .

Novel therapies for remyelination in MS Guanabenz is an α2 adrenergic receptor agonist enhances oligodendrocyte survival by prevention of eukaryotic initiation factor 2 dephosphorylation. ( phase 1).

Novel therapies for remyelination in MS Olesoxime, is a cholesterol-oxime compound and mitochondrial pore modulator, accelerates oligodendrocyte maturation and enhanced myelination in vitro and in vivo. (Phase 1)

Novel therapies for remyelination in MS Blockade of ASIC1 through amiloride, a potassium-sparing diuretic that showed neuroprotective and myeloprotective effects in experimental models of MS ( clinical trials)

Novel therapies for remyelination in MS Stem cell-based approach is the complete ablation of the immune system, followed by haematopoietic stem cell transplantation to treat highly aggressive MS. (Phase 2)

Current drugs of MS and remyelination

traditional drugs and remyelination

Novel therapies for remyelination in MS Vitamin D may play a role in myelination by acting on factors that influence the microenvironment which promotes both proliferation and differentiation of neural stem cells into oligodendrocyte progenitor cells and oligodendrocytes.

Novel therapies for remyelination in MS Thyroid hormone can induce more OPCs from neural stem cells (NSCs), and promote the differentiation and myelination of OPCs

Novel therapies for remyelination in MS Tamoxifen, improved oligodendrocyte maturation and accelerated remyelination even in the presence of inhibitory myelin debris.

Novel therapies for remyelination in MS Quetiapine is an atypical antipsychotic is being examined in an open-label phase I/II dose- finding study involving both patients with relapsing–remitting MS.

Novel therapies for remyelination in MS Biotin, is a possible remyelinating therapy or as a treatment for progressive MS, as it is a coenzyme for carboxylases involved in metabolism and fatty acid synthesis2; the latter is helpful for composing the high lipid content of myelin. .

Evaluation of remylination.

Evaluation of remylination. Diffusion Tensor Imaging Radial diffusivity might be more sensitive to myelin damage while axial diffusivity may be more sensitive to axonal injury. Newer techniques such as high angular resolution diffusion imaging, which is capable of resolving crossing fibers and neurite orientation dispersion and density imaging, which is more specific for myelination than standard DTI indices.

Images in 35 years old female RRMS patient; (a) axial view FLAIR MRI shows bilateral peri-ventricular WM lesions (the largest one on left side shows black holes). Suggestive of multifocal white matter disease. (b) ROIs for the evaluation of tracts in MS white matter lesions. (c and d) Fiber tractography; shows educed number of fibers when they traverse white matter lesions and cross-sectional area of the CST (green) on the affected side (FA at fibers measures 0.43 while MD 0.90).

Evaluation of remylination. Magnetization Transfer Imaging Remyelinated lesions have higher MTR than unmyelinated lesions, and lower than NAWM .

Evaluation of remylination. Positron Emission Tomography Positron emission tomography (PET) uses radioisotopes that directly bind to different tissue substrates to enable molecular imaging. 18F-florbetaben derivative has an affinity for CNS myelin and demonstrates differential binding to normal and demyelinated white matter.

Amyloid-PET and MRI image of a patient with RRMS using 18F-florbetaben Amyloid-PET and MRI image of a patient with RRMS using 18F-florbetaben. Note the decreased uptake of the tracer in white matter lesions.

Evaluation of remylination. Myelin Water Fraction Imaging Myelin water fraction (MWF). measured as the ratio of myelin water to the total brain water MWF is lower in MS patients compared to that of controls, correlates with disability, and decreases over time in patients with progressive MS.

T2-weighted image (left), axial and sagittal Z-score map of MWF values (middle) and histogram of MWF values (right) for three PPMS patients. PPMS Patient A had an EDSS of 1.5, Patient B had an EDSS of 5.5 and Patient C had an EDSS of 6.5

Conclusions

Medications for myelin repair could provide benefit throughout the entire course of MS. Many challenges remain, including determining which remyelination medications are the best options. Defining the objective means to asess remyelination, and outcomes that can be expected from remyelination medications. However, with so many options to promote repair responses, the future is bright for remyelination strategies in MS.