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

McMurran, Christopher E; Mukherjee, Trisha; Brown, J William L; Michell, Andrew W.; Chard, Declan; Franklin, R. J. M.; Coles, Alasdair; Cunniffe, Nick

doi:10.1002/acn3.51595

Cited by 11 publications

(12 citation statements)

References 16 publications

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“…One possible explanation for the decrease in OL repopulation in chronic MS patients is aging [ 97 , 98 ]. Interestingly, a recent phase 2a study showed that bexarotene, a retinoic acid receptor RXR-gamma agonist with CNS pro-remyelinating effects demonstrated in preclinical studies [ 99 ], improved VEP latency in patients with chronic optic neuropathy aged up to early 40s but not older [ 100 ]. Similarly, remyelination is also less efficient in aged animals after lysolecithin- or cuprizone-mediated demyelination [ 96 , 101 ].…”

Section: Roles Of Oligodendrocyte Lineage Cells In Remyelinationmentioning

confidence: 99%

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Mechanisms of Demyelination and Remyelination Strategies for Multiple Sclerosis

Zhao

Jacob

2023

IJMS

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All currently licensed medications for multiple sclerosis (MS) target the immune system. Albeit promising preclinical results demonstrated disease amelioration and remyelination enhancement via modulating oligodendrocyte lineage cells, most drug candidates showed only modest or no effects in human clinical trials. This might be due to the fact that remyelination is a sophistically orchestrated process that calls for the interplay between oligodendrocyte lineage cells, neurons, central nervous system (CNS) resident innate immune cells, and peripheral immune infiltrates and that this process may somewhat differ in humans and rodent models used in research. To ensure successful remyelination, the recruitment and activation/repression of each cell type should be regulated in a highly organized spatio–temporal manner. As a result, drug candidates targeting one single pathway or a single cell population have difficulty restoring the optimal microenvironment at lesion sites for remyelination. Therefore, when exploring new drug candidates for MS, it is instrumental to consider not only the effects on all CNS cell populations but also the optimal time of administration during disease progression. In this review, we describe the dysregulated mechanisms in each relevant cell type and the disruption of their coordination as causes of remyelination failure, providing an overview of the complex cell interplay in CNS lesion sites.

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Section: Roles Of Oligodendrocyte Lineage Cells In Remyelinationmentioning

confidence: 99%

“…As mentioned, bexarotene activates RXR-gamma and thereby stimulates OPC differentiation. Interestingly, its effect on VEP improvement was only significant in patients under 43 years old, which indicates an age-related decline in remyelination capacity [ 99 , 100 ].…”

Section: Treatment Perspectives For Remyelinationmentioning

confidence: 99%

Mechanisms of Demyelination and Remyelination Strategies for Multiple Sclerosis

Zhao

Jacob

2023

IJMS

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“…91 Results from a phase 2a clinical trial in which bexarotene was administered to relapsing-remitting MS patients have shown promise in the ability to enhance remyelination in the human CNS, although the efficacy decreases with age. 138,139 Unfortunately, side effects from this medication preclude it from being taken further in the drug development process.…”

Section: Therapeutic Strategies To Target Glial Cell Aging To Enhance...mentioning

confidence: 99%

“…Furthermore, aging mouse microglia as well as monocytes from MS patients show defects in the RXR alpha pathway, and treatment with an RXR agonist, bexarotene, enhanced myelin debris phagocytosis 91 . Results from a phase 2a clinical trial in which bexarotene was administered to relapsing‐remitting MS patients have shown promise in the ability to enhance remyelination in the human CNS, although the efficacy decreases with age 138,139 . Unfortunately, side effects from this medication preclude it from being taken further in the drug development process.…”

Section: Therapeutic Strategies To Target Glial Cell Aging To Enhance...mentioning

confidence: 99%

Glial aging and its impact on central nervous system myelin regeneration

Rawji¹,

Neumann²,

Franklin³

2022

Annals of the New York Academy of Sciences

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Aging is a major risk factor for several neurodegenerative diseases and is associated with cognitive decline. In addition to affecting neuronal function, the aging process significantly affects the functional phenotype of the glial cell compartment, comprising oligodendrocyte lineage cells, astrocytes, and microglia. These changes result in a more inflammatory microenvironment, resulting in a condition that is favorable for neuron and synapse loss. In addition to facilitating neurodegeneration, the aging glial cell population has negative implications for central nervous system remyelination, a regenerative process that is of particular importance to the chronic demyelinating disease multiple sclerosis. This review will discuss the changes that occur with aging in the three main glial populations and provide an overview of the studies documenting the impact these changes have on remyelination.

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“…In humans, response to putatively remyelinating drugs decreases with age ( McMurran et al, 2022 ), and yet we must acknowledge that most clinical trials exclude patients over the age of 55. Future studies assessing remyelination should be conducted in cohorts of a broader age range.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Multiple Sclerosis and Aging: The Dynamics of Demyelination and Remyelination

Correale¹,

Ysrraelit²

2022

ASN Neuro

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Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) leading to demyelination and neurodegeneration. Life expectancy and age of onset in MS patients have been rising over the last decades, and previous studies have shown that age affects disease progression. Therefore, age appears as one of the most important factors in accumulating disability in MS patients. Indeed, the degeneration of oligodendrocytes (OGDs) and OGD precursors (OPCs) increases with age, in association with increased inflammatory activity of astrocytes and microglia. Similarly, age-related neuronal changes such as mitochondrial alterations, an increase in oxidative stress, and disrupted paranodal junctions can impact myelin integrity. Conversely, once myelination is complete, the long-term integrity of axons depends on OGD supply of energy. These alterations determine pathological myelin changes consisting of myelin outfolding, splitting, and accumulation of multilamellar fragments. Overall, these data demonstrate that old mature OGDs lose their ability to produce and maintain healthy myelin over time, to induce de novo myelination, and to remodel pre-existing myelinated axons that contribute to neural plasticity in the CNS. Furthermore, as observed in other tissues, aging induces a general decline in regenerative processes and, not surprisingly, progressively hinders remyelination in MS. In this context, this review will provide an overview of the current knowledge of age-related changes occurring in cells of the oligodendroglial lineage and how they impact myelin synthesis, axonal degeneration, and remyelination efficiency.

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

Cited by 11 publications

References 16 publications

Mechanisms of Demyelination and Remyelination Strategies for Multiple Sclerosis

Mechanisms of Demyelination and Remyelination Strategies for Multiple Sclerosis

Glial aging and its impact on central nervous system myelin regeneration

Multiple Sclerosis and Aging: The Dynamics of Demyelination and Remyelination

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