Failed remyelination of the nonhuman primate optic nerve leads to axon degeneration, retinal damages, and visual dysfunction

Sarrazin, Nadège; Chavret-Reculon, Estelle; Bachelin, Corinne; Felfli, Mehdi; Arab, Rafik; Gilardeau, Sophie; Brazhnikova, Elena; Dubus, Élisabeth; Yaha-Cherif, Lydia; Lorenceau, Jean; Picaud, Serge; Rosolen, Serge G.; Moissonnier, P.; Pouget, Pierre; Evercooren, Anne Baron-Van

doi:10.1073/pnas.2115973119

Cited by 11 publications

(23 citation statements)

References 60 publications

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“…Indeed, numerous investigations of brain tissue from pwMS showed accelerated pathology in chronically demyelinated axons through mitochondrial dysfunction, enhancement of oxidative injury, energy failure and altered calcium homoeostasis 21. Moreover, more recent studies, both in non-human primate models and pwMS, demonstrated an association between chronic VEP delays and longitudinal retinal neuronal loss 22 23. Altogether, all those findings affirm the relevance of monitoring, preventing and treating myelin injury for neuroaxonal health in pwMS.…”

Section: Discussionmentioning

confidence: 77%

Plasma neurofilament light chain levels suggest neuroaxonal stability following therapeutic remyelination in people with multiple sclerosis

Abdelhak

Cordano

Boscardin

et al. 2022

J Neurol Neurosurg Psychiatry

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BackgroundChronic demyelination is a major contributor to axonal vulnerability in multiple sclerosis (MS). Therefore, remyelination could provide a potent neuroprotective strategy. The ReBUILD trial was the first study showing evidence for successful remyelination following treatment with clemastine in people with MS (pwMS) with no evidence of disease activity or progression (NEDAP). Whether remyelination was associated with neuroprotection remains unexplored.MethodsPlasma neurofilament light chain (NfL) levels were measured from ReBUILD trial’s participants. Mixed linear effect models were fit for individual patients, epoch and longitudinal measurements to compare NfL concentrations between samples collected during the active and placebo treatment period.ResultsNfL concentrations were 9.6% lower in samples collected during the active treatment with clemastine (n=53, geometric mean=6.33 pg/mL) compared to samples collected during treatment with placebo (n=73, 7.00 pg/mL) (B=−0.035 [−0.068 to −0.001], p=0.041). Applying age- and body mass index-standardised NfL Z-scores and percentiles revealed similar results (0.04 vs 0.35, and 27.5 vs 33.3, p=0.023 and 0.042, respectively). Higher NfL concentrations were associated with more delayed P100 latencies (B=1.33 [0.26 to 2.41], p=0.015). In addition, improvement of P100 latencies between visits was associated with a trend for lower NfL values (B=0.003 [−0.0004 to 0.007], p=0.081). Based on a Cohen’s d of 0.248, a future 1:1 parallel-arm placebo-controlled study using a remyelinating agent with comparable effect as clemastine would need 202 subjects per group to achieve 80% power.ConclusionsIn pwMS, treatment with the remyelinating agent clemastine was associated with a reduction of blood NfL, suggesting that neuroprotection is achievable and measurable with therapeutic remyelination.Trial registration numberNCT02040298.

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Section: Discussionmentioning

confidence: 77%

Plasma neurofilament light chain levels suggest neuroaxonal stability following therapeutic remyelination in people with multiple sclerosis

Abdelhak

Cordano

Boscardin

et al. 2022

J Neurol Neurosurg Psychiatry

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“…The failure of OPC recruitment in the rabbit recapitulates that observed in the majority of MS lesions and thereby provides a suitable test bed for therapeutic approaches to improve the migration and proliferation of OPCs. Indeed, rabbit OPC recruitment resembles that following lysolecithin-induced demyelination of the non-human primate optic nerve, in that densities of OPC and OL do not return to normal white matter levels at 6 months and demyelination is present a 9 months (Sarrazin et al, 2022). In contrast to the macaque, the rabbit is substantially more cost-effective and accessible to most neuroscience laboratories.…”

Section: Discussionmentioning

confidence: 99%

“…While the dynamics of OPC recruitment in humans is difficult to ascertain from postmortem tissue, MS lesions rarely display OPC densities that exceed that of NAWM (Lucchinetti et al, 1999, Kuhlmann et al, 2008, Boyd et al, 2013, Moll et al, 2013, Tepavcevic et al, 2014). Demyelination of the optic nerve in non-human primates similarly lacks the abundant recruitment of OPCs that is observed in murine models, with densities of OPCs and OLs not recovering until 9 months after injection of lysolecithin (Sarrazin et al, 2022). Fascinatingly, even at 9 months when OLs and OPC densities have recovered, few axons show evidence of remyelination (Sarrazin et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

“…Demyelination of the optic nerve in non-human primates similarly lacks the abundant recruitment of OPCs that is observed in murine models, with densities of OPCs and OLs not recovering until 9 months after injection of lysolecithin (Sarrazin et al, 2022). Fascinatingly, even at 9 months when OLs and OPC densities have recovered, few axons show evidence of remyelination (Sarrazin et al, 2022). Together these data suggest that OPC recruitment in the rabbit model more closely resembles that observed in MS and non-human primates.…”

Section: Discussionmentioning

confidence: 99%

“…This might also account for the low density of OLs and relatively high density of OPCs found in the lesion core of large rabbit lesions. Likewise, lysolecithin-induced lesions of non-human primate optic nerve induced widespread axonal loss similar to the central region of axonal loss in the rabbit and display similarly low densities of OLs (Sarrazin et al, 2022). However, axonal loss is unlikely to explain the reduced density of OLs observed in edge of large rabbit lesions or across small volume lesions where axonal loss is not as apparent.…”

Section: Discussionmentioning

confidence: 99%

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Chronic demyelination of rabbit lesions is attributable to failed oligodendrocyte progenitor cell repopulation

Cooper

Polanco

Saraswat

et al. 2022

Preprint

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Remyelination-inducing therapies have the potential to restore neurologic function and prevent progression in multiple sclerosis (MS). However, preclinical therapies capable of driving oligodendrocyte differentiation and enhancing remyelination in murine models have not yet yielded meaningful clinical improvement. These setbacks suggest that small animal models may be inadequate for the development and identification of promising regenerative therapies. Unlike MS, rodent models of demyelination undergo highly efficient remyelination, have typically very small volumes and exhibit abundant oligodendrocyte recruitment rapidly following demyelination. We hypothesized that oligodendrocyte progenitor cell (OPC) recruitment becomes rate-limiting as lesion volume increases leading to a failure of oligodendrocyte differentiation and endogenous remyelination. In this study, we utilized lysolecithin injection into the large white matter tracts of the rabbit to create demyelinated lesions that have cross-sectional areas 20-fold larger than those previously reported in mice, and volumes 8-fold larger. Unlike rodent lesions which show robust supernumerary OPC recruitment (representing a 3-10 fold increase in Olig2+ cell density), recruitment in the rabbit never exceeds normal levels. Importantly, the density of mature CC1+ oligodendrocytes failed to return to NAWM levels by 56 dpl and the percentage of differentiated oligodendrocytes drastically lagged behind that of rodent lesions. These results suggest that as lesion volume increases the requirement for increased OPC proliferation and migration becomes limiting. As oligodendrocyte differentiation from human OPCs is dependent on the local density of progenitors, the reduced density of progenitors in large lesions may contribute to failed differentiation and remyelination. Together, we show that large volume demyelination in the white matter of the rabbit recapitulates several key features of human MS lesions, and represents an important preclinical model for the assessment of remyelination therapies in human demyelinating disease.

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Chronic demyelination of rabbit lesions is attributable to failed oligodendrocyte progenitor cell repopulation

Cooper

Polanco

Saraswat

et al. 2022

Glia

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The failure of remyelination in the human CNS contributes to axonal injury and disease progression in multiple sclerosis (MS). In contrast to regions of chronic demyelination in the human brain, remyelination in murine models is preceded by abundant oligodendrocyte progenitor cell (OPC) repopulation, such that OPC density within regions of demyelination far exceeds that of normal white matter (NWM). As such, we hypothesized that efficient OPC repopulation was a prerequisite of successful remyelination, and that increased lesion volume may contribute to the failure of OPC repopulation in human brain. In this study, we characterized the pattern of OPC activation and proliferation following induction of lysolecithin-induced chronic demyelination in adult rabbits. The density of OPCs never exceeded that of NWM and oligodendrocyte density did not recover even at 6 months post-injection. Rabbit OPC recruitment in large lesions was further characterized by chronic Sox2 expression in OPCs located in the lesion core and upregulation of quiescence-associated Prrx1 mRNA at the lesion border. Surprisingly, when small rabbit lesions of equivalent size to mouse were induced, they too exhibited reduced OPC repopulation. However, small lesions were distinct from large lesions as they displayed an almost complete lack of OPC proliferation following demyelination. These differences in the response to demyelination suggest that both volume dependent and species-specific mechanisms are critical in the regulation of OPC proliferation and lesion repopulation and suggest that alternate models will be necessary to fully understand the mechanisms that contribute to failed remyelination in MS.

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Failed remyelination of the nonhuman primate optic nerve leads to axon degeneration, retinal damages, and visual dysfunction

Cited by 11 publications

References 60 publications

Plasma neurofilament light chain levels suggest neuroaxonal stability following therapeutic remyelination in people with multiple sclerosis

Plasma neurofilament light chain levels suggest neuroaxonal stability following therapeutic remyelination in people with multiple sclerosis

Chronic demyelination of rabbit lesions is attributable to failed oligodendrocyte progenitor cell repopulation

Chronic demyelination of rabbit lesions is attributable to failed oligodendrocyte progenitor cell repopulation

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