Introduction
The role of myelin
Biology of remyelination
Mechanisms of remyelination
Remyelination has been studied in several animal models: |
Experimental autoimmune encephalomyelitis (EAE): this model of autoimmune inflammation, driven by injection of a myelin peptide alongside an adjuvant, sees inflammation and remyelination occurring concurrently. However, when used experimentally to explore potential medicines, it is often hard to distinguish an effect of attenuation of inflammation from promotion of remyelination. Hence non-inflammatory models have been developed, as below |
Gliotoxin injections: lysolecithin and ethidium bromide (EB) are toxic to oligodendrocytes, yet spare axons. Experimentally, they can be injected into the CNS of animals to induce demyelination. Their particular benefit has been that the kinetics of demyelination and remyelination can be closely studied [162]. The limitation is that the lesions do not necessarily model the complexity of those in multiple sclerosis, which contain a myriad of remyelination inhibitors and inflammatory cells |
Oral cuprizone administration: dietary ingestion of the copper chelator cuprizone results in demyelination of white matter tracts, particularly in the corpus callosum [163]. It models remyelination, ongoing in the face of continued demyelination. However, the normally small diameter axons seen in the corpus callosum makes distinguishing a remyelinated from an unaffected axon challenging, and interpretation correspondingly difficult |
The best model for progressive MS is debated and variations of these employed (reviewed in [164]). Our view is, for reasons that will become apparent, that experiments should be performed in aged animals when studying the underlying mechanisms of remyelination failure in progressive MS |
Reasons for remyelination failure
Identification of agents capable of remyelination
Remyelination clinical trials
Treatment (trial name, NCT ID) | Information | Primary outcome | Status/result (references) |
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Liothyronine (MST3K, NCT02760056) | A phase I, randomised, double-blind, placebo-controlled, dose-finding trial of liothyronine sodium (L-T3) given for 1 week to people with any type of MS | Maximum tolerated dose of L-T3 as measured by hyperthyroid symptom scale | Completed. Results awaited |
Interferon β1a/rebif (NCT01085318) | A phase IV, open label study of Rebif 44 mcg three times weekly in people with RRMS compared to healthy controls | Change in volume of normal-appearing brain tissue (NABT) showing increasing MTR at 24 weeks | Completed. Failed to meet primary end point, though NABT volume with increasing MTR was greater in patients at 12 weeks compared to healthy controls [165] |
Natalizumab/tysabri (NCT00937677) | A phase IV, open label, observational, single-blinded study of people with relapsing and relapsing progressive MS. 77 treated with natalizumab, 26 treated with intramuscular interferon, 22 healthy controls | Change in volume of NABT with increasing MTR at 2 years | Volume of NABT undergoing increases in MTR higher in natalizumab-treated group compared to interferon and healthy controls [166] |
CNM-Au8 Nanocrystalline gold (NCT03536559) | A phase II, randomised, double-blind, placebo-controlled, parallel group study in 150 people with MS and evidence of chronic optic neuropathy | Multifocal visual evoked potential latency at 24 weeks | Recruiting |
Bexarotene (CCMR One) | A phase II, randomised, double-blind, placebo-controlled trial of 50 people with RRMS treated with dimethyl fumarate | Change in mean lesional MTR in chronic lesions with an MTR below the within-patient median | Completed. Results awaited |
Alemtuzumab (NCT01395316) | A phase IV cohort study, in group of 8 patients with MS treated with two cycles of alemtuzumab | Diffusion and MWF changes on MRI | Completed. Results awaited |
Adrenocorticotrophin, ACTH (NCT02446886) | A phase IV, randomised, open-label study of ACTH gel on remyelination in patients with RRMS or SPMS and new contrast-enhancing lesions | Change in MWF within new Gd-enhancing lesions over the course of 12 months | Recruiting |
GSK239512 (NCT01772199) | A phase II, randomised, placebo-controlled, single-blind study in 131 people with RRMS on interferon or glatiramer acetate | Mean change in Gd-enhancing lesion MTR from before enhancement to stable recovery | Completed. Small positive effect observed in treated group [114] |
Biotin/MD1003 (MS-SPI, NCT02220933) | A phase III, randomised, placebo-controlled, double-blind trial of high-dose biotin in 154 people with SPMS or PPMS | Disability reversal with EDSS decrease of > 1 or > 20% decrease in T25FW | Completed. 12.6% of treated patients achieved primary end point versus none of the untreated patients [120] |
Biotin/MD1003 (MS-SPII, NCT02936037) | A phase III, randomised, placebo-controlled, double-blind trial of high-dose biotin in 642 people with SPMS or PPMS | As above | Ongoing |
Biotin/MD1003 (MS-ON, NCT02220244) | A phase III, randomised, placebo-controlled, double-blind trial of high-dose biotin in 93 people with SPMS or PPMS | Change in visual acuity over 6 months | Completed. No significant changes in visual acuity [121] |
Olesoxime (MSREPAIR, NCT01808885) | A phase Ib, randomised, placebo-controlled, double-blind trial of olesoxime compared to placebo in people with RRMS | Safety criteria, though MTR included in exploratory outcome measures | Completed |
Clemastine (ReBUILD, NCT02040298) | A phase II, randomised, placebo-controlled, double-blind, crossover trial in 50 people with RRMS and chronic stable optic neuropathy | Change in P100 latency of the full-field VEP | Completed. Significant latency reduction of 1.7 ms in the crossover model and 3.2 ms in delayed treatment analysis [101] |
Clemastine (ReCOVER, NCT02521311) | A phase II, randomised, double-blind, placebo-controlled trial in 90 people diagnosed with acute demyelinating optic neuritis | Change in P100 latency of the full-field VEP and change in low contrast visual acuity | Recruiting |
Quetiapine (NCT02087631) | A phase I/II open label, dose-ranging study of quetiapine in people with RRMS and PMS | Dose-limiting toxicity, no specific remyelination outcomes | Recruiting |
Opicinumab (RENEW, NCT01721161) | A phase II, randomised, placebo-controlled, double-blind, study of opicinumab in subjects with a first episode of acute optic neuritis | Change in VEP P100 latency in affected eye, referenced to the unaffected eye, over 24 weeks of treatment | Completed. Significant improvement in latency, but only on per protocol analysis [109] |
Opicinumab (SYNERGY, NCT01864148) | A phase II, randomised, placebo-controlled, double-blind trial of opicinumab (at 3, 10, 30, or 100 mg/kg) in 418 subjects with RRMS treated with interferon β1a | Change in performance at EDSS, T25FW, 9HPT and 3 s-PASAT | Completed. Did not meet primary end point, but increased percentage of improvement responders at 10 and 30 mg/kg doses [110] |
Opicinumab (AFFINITY, NCT03222973) | A phase II randomised, double-blind, placebo-controlled study of opicinumab versus placebo in 263 people with RRMS | Overall response score composed of EDSS, T25FW and 9HPT from each hand | Ongoing |
rHIgM22 (NCT02398461) | A phase I randomised, double-blind, placebo-controlled study of rHIgM22 compared to placebo in 27 people with RRMS following a relapse | Safety and tolerability end points | Completed [167] |
Domperidone (NCT02493049) | A phase II randomised, open-label, single-blind study of domperidone 10 mg three times daily in people with RRMS and new Gd-enhancing lesions | Texture analysis, DTI and MTR in enhancing lesions over 32 weeks | Ongoing |