Funder: Cambridge NIHR Biomedical CentreFunder: Cambridge NIHR Clinical Research FacilityAbstract: Remyelination efficiency declines with advancing age in animal models, but this has been harder to demonstrate in people with multiple sclerosis. We show that bexarotene, a putatively remyelinating retinoid‐X receptor agonist, shortened the visual evoked potential latency in patients with chronic optic neuropathy aged under 42 years only (with the effect diminishing by 0.45 ms per year of age); and increased the magnetization transfer ratio of deep gray matter lesions in those under 43 years only. Addressing this age‐related decline in human remyelination capacity will be an important step in the development of remyelinating therapies that work across the lifespan

Brown, James W. L.

Chard, Declan T.

Coles, Alasdair J.

Cunniffe, Nick G.

Franklin, Robin J. M.

McMurran, Christopher E.

Michell, Andrew W.

Mukherjee, Trisha

PubMed

Remyelination efficiency declines with advancing age in animal models, but this has been harder to demonstrate in people with multiple sclerosis. We show that bexarotene, a putatively remyelinating retinoid‐X receptor agonist, shortened the visual evoked potential latency in patients with chronic optic neuropathy aged under 42 years only (with the effect diminishing by 0.45 ms per year of age); and increased the magnetization transfer ratio of deep gray matter lesions in those under 43 years only. Addressing this age‐related decline in human remyelination capacity will be an important step in the development of remyelinating therapies that work across the lifespan

Brown, J William L.

PubMed Central

Remyelination in humans due to a retinoid‐X receptor agonist is age‐dependent

Apollo (Cambridge)

Remyelination efficiency declines with advancing age in animal models, but this has been harder to demonstrate in people with multiple sclerosis. We show that bexarotene, a putatively remyelinating retinoid-X receptor agonist, shortened the visual evoked potential latency in patients with chronic optic neuropathy aged under 42 years only (with the effect diminishing by 0.45 ms per year of age); and increased the magnetization transfer ratio of deep gray matter lesions in those under 43 years only. Addressing this age-related decline in human remyelination capacity will be an important step in the development of remyelinating therapies that work across the lifespan

McMurran, Christopher E

Brown, J William L

Michell, Andrew W

Chard, Declan T

Franklin, Robin JM

Coles, Alasdair J

Cunniffe, Nick G

UCL Discovery

BRIEF COMMUNICATIONRemyelination in humans due to a retinoid-X receptoragonist is age-dependentChristopher E. McMurran1 , Trisha Mukherjee1, J William L. Brown1,2,3 , Andrew W. Michell1,Declan T. Chard2,4, Robin J. M. Franklin1,5, Alasdair J. Coles1 & Nick G. Cunniffe11Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK2NMR Research Unit, Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, University College London (UCL) Queen SquareInstitute of Neurology, London, UK3Clinical Outcomes Research Unit (CORe), University of Melbourne, Melbourne, Australia4National Institute for Health Research (NIHR), University College London Hospitals (UCLH) Biomedical Research Centre, UK5Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UKCorrespondenceChristopher E. McMurran, Department ofClinical Neurosciences, University ofCambridge, Cambridge, UK. Tel/Fax: 01223216751; E-mail: cem73@cam.ac.ukFunding InformationThis study was supported by the CambridgeNIHR Biomedical Centre and Clinical ResearchFacility and the UK MS Society.Received: 1 March 2022; Revised: 27 April2022; Accepted: 10 May 2022doi: 10.1002/acn3.51595AbstractRemyelination efficiency declines with advancing age in animal models, but thishas been harder to demonstrate in people with multiple sclerosis. We show thatbexarotene, a putatively remyelinating retinoid-X receptor agonist, shortenedthe visual evoked potential latency in patients with chronic optic neuropathyaged under 42 years only (with the effect diminishing by 0.45 ms per year ofage); and increased the magnetization transfer ratio of deep gray matter lesionsin those under 43 years only. Addressing this age-related decline in humanremyelination capacity will be an important step in the development of remyeli-nating therapies that work across the lifespan.IntroductionTherapeutic enhancement of remyelination is a promis-ing strategy to prevent axonal degeneration and relatedprogressive disability in people with multiple sclerosis(MS). In animal models, remyelination becomes ineffi-cient with advancing age, due to both an intrinsicdecline in oligodendrocyte progenitor cells (OPCs)1 andadverse changes in their environment.2,3 Much preclini-cal research is therefore focused on interventions toreverse hallmarks of aging in OPCs––for example, usingrejuvenating drugs, dietary interventions or gene edit-ing––to mitigate the age-related decline in remyelination(reviewed [4]).With putatively remyelinating drugs reaching clinical tri-als, the effect of patient age on therapeutic remyelination inhumans can now be explored.5 Activation of retinoid-Xreceptor (RXR) signaling can promote remyelination bystimulating OPC differentiation and clearance of myelindebris.6,7 In a two-center, randomized, double-blind,placebo-controlled, phase 2a trial, we recently showed thatbexarotene, an RXR agonist, led to statistically significantimprovements in the latency of the full-field visual evokedpotential (VEP), and of the MTR of gray matter (GM)lesions (deep and cortical) and brainstem lesions.8 Wehypothesized that the response to bexarotene would declinewith age, and so investigated the effect of patient age onmarkers of remyelination in a post hoc analysis of theCCMR One trial (ISRCTN14265371).MethodsThe full protocol and results from the CCMR One trialare published elsewhere.8 Briefly, patients with relapsingremitting MS aged 18 to 50 with Expanded Disability Sta-tus Scale (EDSS) 0.0 to 6.0 were recruited at centers inCambridge and Edinburgh. Participants were randomizedto receive either 300 mg/m2 (up to 750 mg) per day oralbexarotene (n = 26) or equivalent placebo tablets(n = 26). All participants underwent full-field VEP testingand MRI brain at baseline and 6 months. Data were ana-lyzed by intention to treat all those completing baselineª 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in anymedium, provided the original work is properly cited.1and 6-month assessments (n = 49). The age range ofpatients receiving bexarotene was 29 to 49 (mean 40.4)and the placebo group 25 to 49 (mean 38.0).In the current work, for VEP analysis, the effect ofpatient age was estimated using linear mixed models foreyes nested within patients, with patient random intercepts.The change in P100 latency was regressed on an interactionbetween age, treatment group, and baseline value (≤118/>118 ms), as well as three binary minimization factors:EDSS (≤4.0/> 4.0), gender and trial center. Residuals wereexamined for departures from normality and homoscedas-ticity, and satisfied assumptions. For MRI analysis, lesionswere nested within patients, with patient random inter-cepts. Change in whole lesion MTR was regressed on aninteraction between age, treatment group and lesion loca-tion, as well as baseline MTR and the three minimizationfactors. Residuals for the MTR models were non-normal,so confidence intervals were verified using a bootstrapapproach with 500 replicates. Differences between treat-ment and control groups as a function of age were calcu-lated using the Johnson–Neyman technique.ResultsVEPsPrevious work has identified the most robust effects ofpro-remyelinating therapies on VEP among eyes with aprolonged baseline P100 latency (>118 ms).8,9 Analyzingthese eyes from participants of CCMR One (n = 51 eyes),bexarotene shortened the P100 latency maximally inyounger patients (Fig. 1A). With increasing age, the P100improvement among patients on bexarotene diminishedby 0.45 ms/year (95% CI 0.03 to 0.88 ms/year;p = 0.044). Compared to patients on placebo, bexarotenesignificantly improved P100 latency only up to the age of42 years (a = 0.05, Fig. 1B). Ten patients (63%) of thosewith prolonged baseline latency in at least one eye receiv-ing bexarotene were younger than this age. The age-dependence of P100 improvement in the bexarotenegroup was magnified when eyes affected by optic neuritisduring the trial or in the previous 5 years were excluded(reduction by 0.64 ms/year; 95% CI 0.24 to 1.04 ms/year;p = 0.004; n = 42 eyes).To investigate whether this age-dependence may repre-sent an effect of disease duration, we replaced the ageterm in our model with disease duration (years since firstMS symptom onset). Unlike age, disease duration did notsignificantly modify the P100 improvement in the bexaro-tene group (reduction by 0.18 ms/year; 95% CI: 0.26 to0.62 ms/year; p = 0.43). We also considered whetherolder patients might have fewer surviving axons by ana-lyzing baseline VEP amplitude. Age did not significantlyreduce baseline amplitude among those eyes with pro-longed baseline latency (reduction of 0.11 lV/year; 95%CI 0.09 to 0.31 lV/year; p = 0.29), but when all eyeswere included, there was a borderline significant age-dependent reduction in amplitude (by 0.16 lV/year; 95%CI 0.00 to 0.33 lV/year; p = 0.059).MRIBexarotene was previously found to cause a significantincrease (improvement) in MTR signal in deep and corti-cal GM and brainstem lesions.8 In the bexarotene group,we identified an age-related attenuation in MTR increaseamong deep GM lesions (0.34 pu/year; 95% CI 0.64to 0.04 pu/year; p = 0.028, n = 16 lesions from 14 par-ticipants, Fig. 2A and B). Compared to patients on pla-cebo, bexarotene significantly increased deep GM lesionMTR only up to a patient age of 43 years (a = 0.05,Fig. 2C). Four patients (67%) of those receiving bexaro-tene with at least one deep GM lesion were younger thanthis age threshold. MTR increase in cortical GM lesions(0.08 pu/year; 95% CI 0.01 to 0.18 pu/year; p = 0.09;n = 85 lesions from 28 participants) and brainstemlesions (0.01 pu/year; 95% CI 0.10 to 0.07 pu/year;p = 0.73; n = 88 lesions from 36 participants) did notsignificantly depend on age in the bexarotene group. Inthe placebo arm, the magnitude of MTR decrease (wors-ening) increased with age in both brainstem and deepGM lesions (Fig. 2A) though these age effects did notreach statistical significance.Outside radiologically identified lesions, baseline MTRtrended downwards with increasing age, but this was nei-ther significant in normal-appearing white matter(0.02 pu/year; 95% CI 0.07 to 0.03; p = 0.36) nortotal GM (0.02 pu/year; 95% CI 0.06 to 0.02;p = 0.34). There was no age range within which bexaro-tene had a significant treatment effect in these non-lesionareas (a = 0.05).ToxicityBexarotene was poorly tolerated in CCMR One, withcommon side effects including hypertriglyceridemia, cen-tral hypothyroidism, and neutropenia.8 We found thatthe number of adverse events among patients receiving atleast one dose of bexarotene was not significantly affectedby age (0.017 events/year of age; 95% CI: 0.16 to 0.19events/year of age; p = 0.85).DiscussionHere, we demonstrate––for the first time in humans––that the response to a remyelinating drug decreases with2 ª 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.Remyelination RXR Humans Age-Dependent C.E. McMurran et al.age. Bexarotene, an RXR agonist, significantly improvedVEP latency and MTR of deep GM lesions only inpatients up to their early 40s. This is consistent withrodent models where remyelination fails with increasingage,1,3,4 and clinical studies showing age-dependent accu-mulation of disability among people with MS.10–12Indeed, the fifth decade is typically when patients developprogressive disease, regardless of prior disease course,13giving a possible indication of the timescale of age-relatedremyelination failure in humans.Of note, the picture of age-dependence in MRI out-comes was less conclusive than that of the VEP results.While remyelination declined with age in deep GM, nodecline was seen in cortical GM or brainstem lesions. ThisFigure 1. (A) Variation of P100 latency reduction (improvement) with patient age for eyes with a prolonged baseline latency (>118 m). Each datapoint represents an eye, and the model fit with 95% confidence interval is shown. (B) Treatment effect (bexarotene vs. placebo) from (A) as afunction of age. The region to the left of the dashed line shows the age range at which there is a significant treatment effect with type 1 errorrate (a) = 0.05.ª 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. 3C.E. McMurran et al. Remyelination RXR Humans Age-Dependentheterogeneity might point toward genuine regional differ-ences in the resilience of remyelination at older ages. Forexample (while not directly compared to deep GMlesions) pathological literature suggests that cortical GMlesions can actively remyelinate in the brains of patientsinto their 70s.14 However, it should be emphasized thatour study describes relatively few lesions from deep GM,and further work should employ MRI sequences moresensitive to GM lesions to verify these findings.The CCMR One trial, which included patients fromyoung adulthood to middle age (25–50), was neitherdesigned nor powered to assess the effect of age on remyeli-nation. Future studies should therefore examine a broaderage range to assess remyelination across the human lifes-pan. We also found that baseline VEP amplitude tended todecline with age. As remyelination requires intact axons,differential axonal survival should be considered as apotential confounding factor. Despite these limitations,Figure 2. (A) Variation of lesion MTR increase (improvement) with patient age for the three regions with statistically significant increases inMTR.8 The bexarotene group is shown in blue and placebo in red. Each data point represents a lesion, with superimposed horizontal jitter tobetter visualize lesions with the same patient age. The model fit with 95% confidence interval is shown. (B) Volcano plot showing the effect ofage on lesion MTR improvement within the bexarotene group for the locations plotted in (A). Other brain regions are shown in gray forcomparison. (C) Treatment effect (bexarotene vs. placebo) for deep gray matter lesions as a function of age. The region to the left of the dashedline shows the age range at which there is a significant treatment effect with type 1 error rate (a) = 0.05. GM = gray matter,MTR = magnetization transfer ratio.4 ª 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.Remyelination RXR Humans Age-Dependent C.E. McMurran et al.converging neurophysiological and MRI evidence indicatesthat remyelination varies with age in people with MS.Our findings here contrast somewhat with the RENEWtrial, in which the best VEP latency response to opicinu-mab was seen in patients aged 33 and older.5 These dif-ferences may reflect our focus on chronic opticneuropathy rather than acute optic neuritis; indeed, theage-related attenuation in VEP response in our study wasstrengthened when eyes with recent optic neuritis wereexcluded. One similarity between the studies was the poorresponse of older patients receiving placebo, suggestinglittle baseline remyelination in this group.Any approach to promoting remyelination in MS mightbe limited by the intrinsic capacity of the aged CNS torepair. Encouragingly, this capacity can be enhanced inrodent models through interventions that rejuvenate anolder animal’s biological age, such as exposure to a youth-ful systemic environment,3 intermittent fasting1 or drugsincluding niacin15 and metformin.1 With the demographicof people with MS getting older,16 such interventions arelikely to play an important role in emerging strategies topromote remyelination and reduce disability.AcknowledgmentsThis study was supported by the Cambridge NIHRBiomedical Centre and Clinical Research Facility and theUK MS Society. Open Access funding enabled and orga-nized by Projekt DEAL.Author ContributionsCEM, AJC, and NGC conceived and designed the study.JWLB, AWM, AJC, and NGC acquired the data. CEM,JWLB, DTC, RJMF, AJC, and NGC analyzed the data.CEM, TM, JWLB, and NGC drafted a significant portionof the manuscript.Conflict of InterestCEM, TM, AWM, AJC, and NGC report no conflict of inter-est. JWLB reports personal fees from Biogen for real-worldevidence consultation, outside the submitted work. DTC is aconsultant for Biogen and Hoffmann-La Roche. In the last3 years he has received research funding from Hoffmann-LaRoche, the International Progressive MS Alliance, the MSSociety, and the National Institute for Health Research(NIHR) University College London Hospitals (UCLH)Biomedical Research Centre, and speaker’s honorarium fromNovartis. He co-supervises a clinical fellowship at the NationalHospital for Neurology and Neurosurgery, London, which issupported by Merck. RJMF reports consulting fees fromFrequency Therapeutics, Rewind Therapeutics and Biogen.References1. Neumann B, Baror R, Zhao C, et al. Metformin restoresCNS remyelination capacity by rejuvenating aged stemcells. Cell Stem Cell. 2019;25:473-485.e8.2. Segel M, Neumann B, Hill MFE, et al. Niche stiffnessunderlies the ageing of central nervous system progenitorcells. Nature. 2019;573:130-134.3. Ruckh JM, Zhao J-W, Shadrach JL, et al. Rejuvenation ofregeneration in the aging central nervous system. CellStem Cell. 2012;10:96-103.4. Neumann B, Segel M, Chalut KJ, Franklin RJM.Remyelination and ageing: reversing the ravages of time.Mult Scler J. 2019;25:1835-1841.5. Cadavid D, Balcer L, Galetta S, et al. Predictors ofresponse to opicinumab in acute optic neuritis. Ann ClinTransl Neurol. 2018;5:1154-1162.6. Huang JK, Jarjour AA, Oumesmar BN, et al. Retinoid Xreceptor gamma signaling accelerates CNS remyelination.Nat Neurosci. 2011;14:45-53.7. Natrajan MS, De La Fuente AG, Crawford AH, et al.Retinoid X receptor activation reverses age-relateddeficiencies in myelin debris phagocytosis andremyelination. Brain. 2015;138:3581-3597.8. Brown JWL, Cunniffe NG, Prados F, et al. Safety andefficacy of bexarotene in patients with relapsing-remittingmultiple sclerosis (CCMR one): a randomised, double-blind, placebo-controlled, parallel-group, phase 2a study.Lancet Neurol. 2021;20:709-720.9. Green AJ, Gelfand JM, Cree BA, et al. Clemastine fumarateas a remyelinating therapy for multiple sclerosis(ReBUILD): a randomised, controlled, double-blind,crossover trial. Lancet. 2017;390:2481-2489.10. Stankoff B, Mrejen S, Tourbah A, et al. Age at onsetdetermines the occurrence of the progressive phase ofmultiple sclerosis. Neurology. 2007;68:779-781.11. Confavreux C, Vukusic S. Age at disability milestones inmultiple sclerosis. Brain. 2006;129:595-605.12. Conway BL, Zeydan B, Uygunoglu U, et al. Age is acritical determinant in recovery from multiple sclerosisrelapses. Mult Scler J. 2019;25:1754-1763.13. Tutuncu M, Tang J, Zeid NA, et al. Onset of progressivephase is an age-dependent clinical milestone in multiplesclerosis. Mult Scler J. 2013;19:188-198.14. Chang A, Staugaitis SM, Dutta R, et al. Corticalremyelination: a new target for repair therapies in multiplesclerosis. Ann Neurol. 2012;72:918-926.15. Rawji KS, Young AMH, Ghosh T, et al. Niacin-mediatedrejuvenation of macrophage/microglia enhancesremyelination of the aging central nervous system. ActaNeuropathol. 2020;139:893-909.16. Marrie RA, Yu N, Blanchard J, Leung S, Elliott L. The risingprevalence and changing age distribution of multiplesclerosis in Manitoba. Neurology. 2010;74:465-471.ª 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. 5C.E. McMurran et al. Remyelination RXR Humans Age-Dependent

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Remyelination in humans due to a retinoid-X receptor agonist is age-dependent

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Remyelination in humans due to a retinoid‐X receptor agonist is age‐dependent

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