Ремонтные механизмы центральной нервной системы: от вырастания аксона до воспроизводства.

Introduction

The central nervous system (CNS), has limited natural capacity for self-repair, which is an important aspect to consider for the treatment of various diseases or trauma of the brain and spinal cord. However, advances in neuroscience have introduced encouraging approaches to stimulate CNS repair, targeting both the root causes of neurodegeneration and innovative methods to restore lost functions.

CNS repair has gained significant attention in recent years, especially in the context of neurological diseases such as multiple sclerosis (MS), stroke, Parkinson's disease and traumatic brain injury (TBI). The complex interplay between neurodegeneration, inflammation, and repair mechanisms which is present in most neurological diseases, presents both challenges and opportunities for therapeutic interventions. This article explores the current landscape of CNS repair, highlighting the mechanism of remyelination and provides a critical evaluation of ongoing and completed ( Table 1 ) clinical studies. The progressive loss of myelin in MS leads to axonal damage, neurodegeneration, and clinical disability, making remyelination—a process in which oligodendrocyte progenitor cells (OPCs) repair or replace damaged myelin—an essential therapeutic target [ 1 , 2 ]. However, while the CNS possesses some capacity for remyelination, this process becomes less efficient with age or in progressive forms of MS.

Table 1 Overview of discussed topics. Table 1 Main Topic Subtopics Remyelination OPC differentiation and rejuvenation, metformin, caloric restriction, antioxidants, monoclonal antibodies, gene editing Axon sprouting Adhesion molecules, glia cell and extra cellular matrix, axon sprouting, MAI block, electrical stimulation Boosting cellular energy Ketones, glycolysis, mitochondria Stem cell therapy NSC, MSC, iPSC, exosomes Anti-aging and senescence Senolytics, rapamycin Brain machine interface and exoskeleton Neuroplasticity OPC= Oligodendrocyte progenitor cell, MAI ​= ​Myelin associated inhibitor, NSC ​= ​neural stem cell, MSC ​= ​Mesenchymal stem cell, iPSC= Induced pluripotent stem cell.

Overview of discussed topics.

OPC= Oligodendrocyte progenitor cell, MAI ​= ​Myelin associated inhibitor, NSC ​= ​neural stem cell, MSC ​= ​Mesenchymal stem cell, iPSC= Induced pluripotent stem cell.

This review also highlights advancements and knowledge in axonal sprouting, the process by which damaged neurons form new branches to reconnect with target tissues, holds great promise as a mechanism for repair [ 3 ]. However, this process is hindered by inhibitory signals from myelin and the surrounding glial cells, making the modulation of these pathways a critical area of research. In addition to promoting axon sprouting, boosting cellular energy levels [ 4 , 5 ] and improving mitochondrial function are essential strategies to support the high metabolic demands of injured neurons, facilitate repair, and prevent cell death.

Stem cell therapy also represents a major breakthrough in CNS repair, with promising potential to regenerate lost neurons and glial cells and mitigate the damage caused by neurodegeneration [ [6] , [7] , [8] ]. Similarly, targeting cellular aging and senescence processes [ [6] , [7] , [8] ] offers a novel approach to counteract the progressive nature of CNS diseases, potentially rejuvenating tissue and fostering regeneration.

Alongside cellular and molecular strategies, technological advances such as brain-machine interfaces [ 9 ] and exoskeletons [ 10 , 11 ] are providing innovative ways to restore motor function and promote neuroplasticity.

Overall, CNS repair involves a range of biological responses, which are often constrained by both intrinsic and extrinsic factors and involve complex cellular and molecular mechanisms [ Fig. 1 ]. The repair mechanisms are constrained by inhibitory factors in the CNS, including glial scarring, myelin-associated inhibitors, and chronic neuroinflammation. While neuroplasticity, glial cell responses, neurotrophic factors, stem cells, and neurogenesis provide a foundation for repair, significant challenges remain.

Figure demonstrating different CNS repair strategies, including remyelination, axone sprouting, boosting cell energy, stem cell repair, brain machine interface, aging, senescence and exercises.

Remyelination

Myelin is crucial for efficient neural communication throughout the nervous system. In the CNS, oligodendrocytes create myelin along an axon separated by nodes of Ranvier, which contain sodium channels that facilitate fast saltatory conduction. Demyelination slows conduction across axons and also predisposes nerve cells to neurodegeneration based on altered metabolic demand, trophic support, and loss of axonal integrity [ 1 , 2 ].

There are many CNS disease processes that result in demyelination, spanning genetic disorders, infections, trauma, and toxins. This also occurs in primary CNS demyelinating diseases, including MS, neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein (MOG)-associated disease (MOGAD), and acute disseminated encephalomyelitis (ADEM). As demyelination can cause significant clinical disability and is an adaptable process different in individual lesions and patients, remyelination is a prime therapeutic target.

Remyelination of denuded axons happens to varying degrees in the CNS. This can depend on location, as brain neurons are surrounded by higher density of OPCs and more efficient remyelination [ 12 ], as well as age, as remyelination becomes less efficient over time due to exhaustion of OPCs and failure to promote proper differentiation [ 13 ]. As it relates to MS, relapsing versus progressive subtypes allow for different remyelination potential, which may help explain why some patients have better recovery of neurological deficits [ 14 , 15 ]. Interestingly, all subtypes of MS have been shown to undergo remyelination with wide heterogeneity at an inter-individual level [ 14 , 15 ].

Oligodendrocyte progenitor cells (OPCs) are multipotent stem cells that are recruited to areas of CNS damage, differentiate into mature oligodendrocytes, and deposit new myelin sheaths to restore saltatory conduction. On the other hand, OPCs have also been shown to cross-present antigen on MHC class I molecules and activate CD8 + T cells, possibly indicating a triggering role in the inflammatory cascade of MS attacks [ 16 , 17 ]. This dual role highlights the need for a deeper understanding of the signaling pathways and molecular factors that govern OPC fate decisions. For example, growth factors, cytokines, and transcriptional regulators can either promote the differentiation of OPCs into oligodendrocytes [ 18 , 19 ] or induce them to turn into different cell types such as astrocytes or microglia [ 19 ]. Cell differentiation is an important step, since MS demyelinated plaques contain low numbers of OPCs and post-mortem brain samples from patients with progressive MS show fewer OPCs [ 20 ]. In addition, insufficient migration and recruitment of OPCs into demyelinated MS lesions is another cause of failed remyelination [ 21 ].

Research has long suggested that only newly differentiated oligodendrocytes contribute to remyelination, including evidence that the number of oligodendrocytes in areas of remyelination was greater than that of normal-appearing white matter [ 22 ]. Newer in vivo research identified both newly matured and pre-existing oligodendrocytes participating in remyelination [ [23] , [24] , [25] ]. However, pre-existing cells were less efficient, with one study demonstrating only a gain of 8 ​% of original myelin length [ 25 ].

New regenerative therapies have been explored over the last decade. One potential target is promoting OPC differentiation, and transmembrane protein LINGO-1 is a negative regulator of oligodendrocyte differentiation [ 26 ]. Anti-LINGO-1 promotes remyelination in animal models of MS [ 27 ]), however the anti-LINGO-1 monoclonal antibody opicinumab did not show significant differences in clinical outcomes in human subjects with MS over several studies in the 2010s [ 27 , 28 ]. Clemastine fumarate is a muscarinic receptor antagonist that can enhance oligodendrocyte differentiation and myelin wrapping [ 29 ] (see Table 1 ) and reduce oxidative stress. In a phase 3 clinical trial, it showed improved P100 latency as a measure of optic nerve function and remyelination, but was complicated by drowsiness as a first-generation antihistamine [ 29 ]. However a recent trial was stopped, given the possible accumulation of disability in patients with MS [ 30 ]. Another molecule of interest was retinoid X receptor (RXR), which is upregulated during the regenerative phase of remyelination and thought to promote OPC differentiation and myelin repair. In rats, administration of RXR agonist 9-cis-retinoic acid after demyelination caused an increase in remyelinated axons [ 31 ]. Bexarotene, a chemotherapeutic that binds RXR on oligodendrocytes, was studied in a human trial that did not replicate these clinical results but did cause significant adverse effects in all study participants [ 32 ]. Importantly, therapies aimed at OPC differentiation are not applicable to all types of lesions or patient groups. There is variability between chronic active and chronic inactive lesion types, and responses can also differ from one patient to another [ 33 ].

Another repair approach is rejuvenating aged OPCs and OCs. Metformin, used to treat diabetes, has shown promise as an adjunctive therapy in MS and CNS disease due to mechanisms that reverse age-related changes, increase OPC recruitment, and improve OPC response to differentiation factors [ 34 ]. A prospective cohort study in Argentina showed that adding metformin to standard-of-care disease-modifying therapy improved MS clinical outcomes as well as reduced pro-inflammatory mononuclear cells [ 35 ]. This study also examined pioglitazone, another diabetes treatment, adjunctive to standard-of-care, which showed similar benefit [ 35 ]. The proposed mechanism of action of pioglitazone toward remyelination is by decreasing pro-inflammatory immune cells and potentially enhancing phagocytosis of myelin debris [ 36 ]. In addition, there are several concluded and active randomized clinical trials studying combinations of metformin, lipoic acid and pioglitazone alone or in combination to test for clinical stabilization or improvement in patients with MS [ [37] , [38] , [39] , [40] ] that hold promise. One of these trials, the OCTOPUS trial, was launched in 2023 and involves patients with progressive MS. It randomizes 125 participants to receive either metformin, the antioxidant alpha lipoic acid, which is discussed below, or a placebo [ 41 ].

Similarly, caloric restriction (CR) and fasting have been extensively studied for its effects on longevity and age-related diseases. In animal models, CR has been shown to enhance neurogenesis, improve synaptic plasticity, and reduce markers of inflammation within the brain [ [42] , [43] , [44] ]. These effects are thought to occur through mechanisms such as the activation of autophagy, a cellular process that clears damaged proteins and organelles, and the modulation of metabolic pathways like AMP-activated protein kinase (AMPK) and sirtuins, which regulate stress resistance and cellular repair [ [45] , [46] , [47] , [48] ]. In addition to CR, physical exercise has been recognized as a potent modulator of brain health. Regular physical activity has been shown to stimulate the release of neurotrophic factors such as BDNF, which promote neuronal survival, growth, and plasticity [ 49 ]. Exercise also reduces systemic inflammation and supports cognitive function by enhancing mitochondrial function, improving blood flow to the brain, and boosting neurogenesis in regions like the hippocampus.

Antioxidants may play a role in improving remyelination [ 50 , 51 ]. Fumarate medications have been studied in clinical and preclinical models for their immunomodulatory and antioxidative properties. Fumarate itself is an intermediate in the citric acid cycle to produce ATP [ 52 , 53 ]. There are several fumarate medications that are FDA-approved to treat MS, including dimethyl fumarate, diroximel fumarate, monomethyl fumarate. While they have not been proven to promote remyelination in humans, there is evidence in animal models of MS by stabilizing the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) which can induce an antioxidant response ultimately restricting cell death [ 54 ]. Clemastine fumarate, as discussed earlier, has also been studied [ 29 ]. Quetiapine fumarate's antioxidative properties were of interest following in vitro studies demonstrating promotion of OPC differentiation, however phase 1 clinical trial results were not published [ 55 ]. The red blood cell-stimulating hormone erythropoietin also has antioxidant properties and showed in a small phase 1 study to improve motor function in patients with MS, but showed no clinical benefit in a phase 2 study [ 56 ].

Alpha-lipoic acid (ALA) is another antioxidant that has shown promise in remyelination by increasing the population of mature oligodendrocytes and stimulating NG2+ glia that help provide structure for regenerating axons [ 57 ]. However, its role in reducing oxidative stress may also be relevant here, as reactive oxygen species contribute to MS lesion development and progression [ 55 ]. A phase 3 study of lipoic acid in patients with secondary progressive MS showed slightly but significantly decreased percent change in brain volume [ 58 ].

Human monoclonal IgM antibody 22 (rHIgM22) is a promising compound shown in rats to bind white matter in the CNS and ultimately prevent oligodendrocyte apoptosis. A phase 1 study of peripherally injected rHIgM22 showed a dose-dependent increase in CSF levels of rHIgM22, which raises interest for future studies [ 59 ].

Gene editing has also been applied to CNS remyelination efforts. In one study on rodent models, CRISPR/Cas9 technology was used to edit human embryonic stem cell-derived OPCs (hOPCs) to delete the neuropilin-1 (NRP1) receptor, which binds protein SEMA3A, a chemorepulsive factor for OPCs, to improve OPC recruitment and remyelination. The edited hOPCs did show enhanced migration and remyelination compared to controls, regardless of host age [ 20 ]. Another technique used transplanted macrophages with upregulated SEMA3F, an OPC attractant, derived from genetically modified hematopoietic stem cells (HSC) to stimulate OPC migration. While there were no measured changes in inflammation or OPC survival, there was enhanced OPC recruitment that accelerated onset of remyelination [ 60 ]. This research shows potential for this technology to overcome intrinsic cell and extrinsic challenges of remyelination.

Another promising approach for promoting remyelination in MS is the transplantation of OPCs. In their 2022 study, Borda and colleagues discuss the potential of OPC transplantation to bypass the limited regenerative capacity of endogenous OPCs and facilitate remyelination and ideally restore axonal function [ 61 ]. However, several challenges remain, including ensuring the survival and integration of transplanted OPCs, promoting their differentiation into oligodendrocytes rather than other cell types, and overcoming immune rejection. The study highlighted strategies to improve outcomes, such as modifying the host microenvironment to reduce inflammation and enhance OPC survival.

Also important to mention are different mechanisms that are supportive for remyelination, including the use of antibodies, vitamins or investigational drugs. For example, TREM2 agonistic antibodies are being explored for their potential to enhance microglial activation and myelin clearance, a process critical for removing debris and promoting remyelination after myelin damage [ 62 ]. In addition, Vitamin B3 (nicotinamide), through its interaction with the receptor CD36, has been shown to modulate immune responses and support oligodendrocyte precursor cell (OPC) survival and differentiation, further facilitating myelin repair [ 63 ]. Several factors regulate OPC differentiation, with Activin-1 playing a role in promoting OPC maturation into oligodendrocytes [ 64 ].

Tregs, or regulatory T cells, are well known for their immune-modulating properties, but recent research has uncovered a more direct role in tissue repair through the secretion of CCN3. This protein has been implicated in promoting the differentiation of OPCs into mature oligodendrocytes. In the context of MS, enhancing CCN3 signaling could potentially help accelerate the repair of myelin, slowing or even halting the progression of neurodegeneration [ 65 ].

On the other hand, targeting the liver X receptor (LXR) nuclear receptor provides another compelling approach to enhancing myelin regeneration. LXRs play a crucial role in lipid metabolism, and lipids are fundamental components of myelin. Activation of LXRs has been shown to increase the expression of genes involved in cholesterol and lipid metabolism, which are necessary for the synthesis and repair of myelin [ 66 ].

PIPE-307 is an investigational drug being tested in Phase 1b/2a clinical trials. It works by blocking the M1 muscarinic acetylcholine receptor (M1R) on oligodendrocytes, the brain cells responsible for producing myelin. By inhibiting this receptor, PIPE-307 aims to enhance myelin production, potentially promoting the repair of damaged myelin sheaths, as it has been evaluated in a mouse model and initial research has looked into human tissue [ 67 , 68 ]. Together, these pathways represent promising avenues for therapeutic strategies aimed at enhancing myelin repair and limiting disease progression in MS.

In summary, promoting remyelination in MS is a complex but critical therapeutic goal aimed at restoring lost myelin and improving neural function. The diverse mechanisms driving myelin repair, including the modulation of OPCs, myelin clearance, and immune modulation, offer a range of potential strategies. Despite promising preclinical findings, challenges such as optimizing OPC differentiation, overcoming immune rejection, and ensuring long-term safety remain. Myelin imaging has emerged as a potential tool for assessing the extent of myelin damage and potential repair in vivo in MS. Techniques such as magnetization transfer imaging (MTI) [ 69 ], myelin water fraction (MWF) [ 70 , 71 ], and diffusion tensor imaging (DTI) [ [72] , [73] , [74] ] allow for the visualization of myelin integrity and can detect changes in both the demyelinating and remyelinating processes. These imaging modalities provide valuable insights into the dynamics of myelin pathology in MS, enabling researchers to monitor the effectiveness of remyelination therapies in clinical trials. As research continues, these diverse strategies may provide new hope for patients with MS, offering the possibility of repairing myelin, reducing disease progression, and improving clinical outcomes.

Axon sprouting and blocking inhibitory signals

Axonal damage occurs throughout the nervous system in response to traumatic injury and neurodegenerative disease. Even demyelinating diseases like MS lead to neurodegeneration through demyelination and other pathways, either following the demyelinating events or occurring concomitantly. Axon sprouting is one mechanism to promote axonal regeneration, by which damaged axons generate branches and extend neurites toward the area of damage to reconnect with target tissues, reestablish neural circuits, and bypass damaged regions [ 3 ].

In the CNS, axon sprouting and regeneration is supported by a combination of intrinsic and extrinsic factors. Neurotrophic factors like brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), ciliary neurotrophic factor (CNTF), and glial cell-derived neurotrophic factor (GDNF) promote axonal repair by binding receptors and inducing intracellular signaling [ 75 ]. These secreted proteins promote survival and differentiation of glial cells and may be upregulated in disease states including spinal cord injury and stroke [ 76 ]).

Adhesion molecules also stimulate axonal growth, including the embryonic form of neural cell adhesion molecule (NCAM) and L1. Growth-associated proteins including GAP-43 and CRMP-2 are upregulated after injury and are involved in axon sprouting by stabilizing microtubules and supporting axonal growth [ 77 ]. Despite these mechanisms, sprouting in the CNS is often limited and does not reach the lesion site.

Glial cells and the extracellular matrix provide several pathways to promote axon sprouting. CNS microglia aid in debris clearance, which facilitates repair mechanisms, however oligodendrocytes and reactive astrocytes may slow this clearance. Prolonged activation of microglia is also associated with chronic inflammation that can exacerbate injury and hinder recovery. Microglial polarization toward either a pro-inflammatory or reparative phenotype is a critical factor in determining whether recovery of further damage occurs. Astrocytes contribute to axonal regeneration and axon sprouting in the mammalian CNS [ 78 ] through the production of neurotrophic factors, remodeling of the extracellular matrix, clearance of myelin debris, and provision of bioenergetic support for axon growth [ 79 ]. However, astrocytes at the border of injuries may suppress axon growth and sprouting by contributing to multicellular scar tissue [ 80 ]. These glial scars can be protective by isolating damaged unaffected tissue and providing infrastructure along which axons can grow. However, scarring can also impede regeneration by secreting chondroitin sulfate proteoglycans (CSPGs), a myelin-associated inhibitor (MAI). MAIs are proteins including Nogo-A, myelin associated glycoprotein (MAG), and oligodendrocyte myelin glycoprotein (OMGP) produced by oligodendrocytes and myelin [ 81 ]that restrict axonal growth and limit plasticity [ 82 ]. Additionally, transmembrane proteins LINGO-1 and AMIGO3 inhibit OPC differentiation and axonal outgrowth [ 83 , 84 ].

Optimizing axon sprouting is a potential therapeutic approach in several CNS disease processes, including spinal cord injury, stroke, amyotrophic lateral sclerosis (ALS), and MS. One major strategy has been to investigate existing pharmacological agents. Nonsteroidal anti-inflammatory drugs (NSAIDs) including ibuprofen and indomethacin have been shown to overcome axon growth inhibition in mouse and rat models by inhibiting the RhoA and Rho kinase (ROCK) pathways [ 85 , 86 ], but this has not been proven in human models. Recognizing small molecules' and peptides’ ability to penetrate the blood brain barrier (BBB), epothilones have also been studied. These BBB-permeable microtubule stabilizing drugs are currently used to treat cancer, and they have been shown in animal models to reduce fibrotic scarring, deposition of CSPGs, and axon dieback, to induce axonal growth to improve motor function after mild spinal cord injury and stroke [ 87 , 88 ]. Peroxisome proliferator-activated receptor (PPAR) agonists are commonly used to treat diabetes and have also been used in translational models of CNS trauma and disease [ 89 ].

Drug studies have also investigated blocking MAIs to improve regrowth and repair. Nogo-A can be effectively administered intrathecally and intranasally but not through peripheral administration [ 90 , 91 ]. Joly et al. [ 92 ] have overcome this by combining monoclonal antibody 11C7 monoclonal antibody and the single-chain variable fragment (scFv) of 8D3, a rat antibody that mediates BBB transcytosis, with successful stimulation of neuronal growth mechanisms in mouse CNS. Additional animal models have explored Nogo-A blockade via gene deletion or vaccination, showing increased pro-regenerative cytokine and cellular expression [ [93] , [94] , [95] ], improved clinical recovery [ 93 , 96 ], and slowed disease progression [ 93 , 97 ]. LINGO-1 has been targeted as a component of the NgR1-Nogo-A receptor complex but without positive studies in human clinical trials via monoclonal antibody opicinumab [ 98 ]. The compound NVG-291 is a peptide that can relieve inhibitory effects of CSPGs in animal models of MS [ 99 ], and it is being studied in Phase 1b/2a trials in spinal cord injury.

Masitinib, a tyrosine kinase inhibitor, has been studied in MS and other CNS diseases due to its neuroprotective effects, including inhibiting microglia, macrophage, and mast cell activity. A phase 3 study of 300 patients with progressive MS showed decreased worsening on the Expanded Disability Status Scale (EDSS) [ 100 ]. A confirmatory phase 3 trial is ongoing.

In addition to medications, there has been an investigation into stem cell therapy to promote axon repair through varied mechanisms, including the production of neurotrophic factors including CDNF, NGF, BDNF, GDNF, NT3. Studies have also tested the effects of stem cell-derived extracellular vesicles rather than the cells themselves, with one group concluding there is no significant difference between the two interventions on nerve regeneration [ 101 ].

There has also been research into electrical stimulation to enhance axon sprouting and remodeling. This has been used for decades in PNS disease models and more recently to investigate CNS plasticity in rodent models and in humans with spinal cord injury [ 102 ].

Multiple sclerosis is a prime disease target for strategies to induce axon sprouting [ 103 ]. In acute MS attacks, spinal serotonergic neuronal sprouting may be associated with improvement of neurological symptoms. Conversely, in progressive MS, axonal degenerative changes with reduced nerve terminals lose their sprouting capability [ 104 ]. In EAE models, axon remodeling including regenerative sprouting is associated with cellular recovery [ 105 ].

In conclusion, axonal damage is a common feature in many CNS diseases, including MS, where demyelination and neurodegeneration disrupt neural circuits and impair function. In MS, where axonal damage contributes significantly to disability, these regenerative strategies could be transformative, helping to repair neural circuits, slow disease progression, and improve clinical outcomes. As research advances, the combination of pharmacological, stem cell-based, and neurostimulation approaches may offer new therapeutic avenues to restore axonal function and promote long-term recovery in MS and other neurodegenerative diseases.

Boosting cellular energy

Neurons have high energy demands to maintain resting membrane potentials, propagate action potentials, recycle synaptic vesicles, and transport nutrients, organelles, and proteins along an axon. Under normal conditions, neurons largely rely on oxidative phosphorylation in the mitochondria for ATP production. Glucose is the main energy source in the CNS, although lactate [ 106 , 5 ] and occasionally acetate may also be used [ 107 ]. Ketones may be used under specific conditions, including fasting [ 106 ]. Glycolysis may also be used as a supplemental energy source, particularly anaerobic glycolysis in response to neuronal injury and ischemia. Due to the general reliance on glucose, glucose transporters are extremely important to maintain homeostasis in the CNS [ 107 ]. Monocarboxylate transporters (MCTs) that carry lactate are also important for metabolic shuttling between glia and neurons, which particularly supports myelination by oligodendrocytes [ 5 , 108 ].

Damaged neurons require even more energy to maintain function within the CNS. Immediately following neuronal injury, cell membrane ion gradients become disrupted, which challenges varied processes of homeostasis including axonal transport and signal conduction [ 4 ]. Repair of membranes themselves involves vesicle trafficking and synthesis of both lipids and proteins. Both autophagy and mitophagy of mitochondria are increased in response to injury and require additional energy resources [ 109 ]. Axon sprouting and synaptic remodeling also require increased energy, as discussed above.

In cases of neurodegeneration, energy is used to cause glial cells to become reactive. Microglia are activated to promote phagocytosis of debris and release of additional cytokines. Astrocytes are activated to buffer excitotoxicity, repair the BBB, and support neuronal survival. As more energy is consumed, there is competition for resources that can delay other vital repair mechanisms, like axonal transport and myelin repair. When the energy required to maintain cell function exceeds the supply, neurons may undergo apoptosis and trigger other cell death pathways [ 107 ].

Axonal mitochondrial signaling can respond to injury by activating damaged mitochondria for replacement, thereby maintaining local energy supply to support axonal survival [ 110 ]. Emerging therapies like CNM-Au8, a suspension of catalytic gold nanocrystals, aim to boost mitochondrial efficiency, helping neurons generate the energy required for recovery. This approach shows promise, particularly in energy-deficient CNS conditions, like progressive MS or ALS [ 111 , 112 ].

In conclusion, maintaining neuronal energy homeostasis is crucial for supporting repair mechanisms following injury or neurodegeneration, and emerging therapies targeting mitochondrial efficiency, such as CNM-Au8, offer a promising strategy to address energy deficits and promote recovery in CNS disorders.

Stem cell therapy

Stem cell therapy presents a possible approach to CNS repair by replacing or regenerating damaged cells. Stem cells have the unique ability to differentiate into various cell types, making them a promising resource for repairing damaged tissues in the CNS with its limited regenerative capacity.

Among the most studied neural stem cells (NSC) for CNS repair are mesenchymal stem cells (MSCs) and induced pluripotent stem cells (iPSCs). MSCs, which can be isolated from various tissues such as bone marrow, adipose tissue, and umbilical cord blood, are known for their ability to differentiate into a variety of cell types, including neurons, glial cells, and oligodendrocytes [ [6] , [7] , [8] ]. These cells can help regenerate damaged neural tissue and provide supportive factors that promote healing and neuroprotection. Furthermore, MSCs have demonstrated anti-inflammatory and immunomodulatory properties, which could potentially mitigate the immune response often triggered by CNS injury such as TBI [ 113 ] or neurodegenerative diseases [ 114 ].

On the other hand, iPSCs are derived from adult somatic cells that are reprogrammed back into a pluripotent state, enabling them to differentiate into virtually any cell type, including neurons and glial cells. iPSCs offer a personalized approach to therapy since they can be generated from a patient's own cells, significantly reducing the risk of immune rejection. Researchers are exploring the potential of iPSCs to generate large numbers of neurons and glial cells for transplantation into damaged regions of the CNS, aiming to restore function lost due to injury or degenerative diseases like Parkinson's disease, Alzheimer's disease, and MS [ 115 , 116 ].

In animal models, the transplantation of NSCs has shown potential for replacing lost neurons and glial cells and promoting functional recovery [ 117 , 118 ]. However, there are challenges related to stem cell survival, integration into existing neural circuits, and there is potential for tumor formation.

In addition to direct stem cell transplantation, exosomes, which are tiny vesicles secreted by stem cells, are being investigated for their potential in CNS repair such as in stroke and TBI [ [119] , [120] , [121] ]. Exosomes are rich in bioactive molecules, such as proteins, lipids, and RNA, and can be used to deliver therapeutic agents across the BBB, a significant challenge in CNS treatment. Exosomes can facilitate the targeted delivery of growth factors, anti-inflammatory molecules, and gene-editing tools, all of which could promote neuronal repair and tissue regeneration without the need for invasive procedures. This method has the added benefit of being minimally invasive, offering a safer and more accessible alternative to direct cell transplantation [ 122 , 123 ].

The combination of stem cell-based therapies and exosome technology represents a promising frontier in CNS repair. Researchers are focusing on refining these techniques to improve cell survival, integration, and functionality in the damaged CNS environment. Although challenges such as immune rejection, tumor formation, and ethical considerations remain, these advanced therapies have the potential to revolutionize the treatment of CNS injuries and disorders, potentially offering long-term solutions for patients suffering from a variety of neurological conditions. Stem cell therapy using MSCs, iPSCs, and exosomes offers a multifaceted strategy for CNS repair. These approaches focus on replacing lost or damaged cells and also on creating a supportive environment that fosters long-term regeneration and functional recovery. The continued research into stem cell-based therapies holds great promise for the development of effective treatments for some of the most challenging and debilitating neurological diseases.

Anti-aging and senescence targeting

Aging is a major risk factor for a range of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and age-related cognitive decline. One of the most important processes contributing to neurodegeneration is cellular senescence [ 124 , 125 ]. Senescent cells, which are typically in a state of irreversible growth arrest, accumulate in tissues with age and play a pivotal role in age-related pathology. These cells exhibit a phenotype known as the senescence-associated secretory phenotype (SASP), in which they secrete a variety of pro-inflammatory cytokines, chemokines, growth factors, and proteases [ 126 ]. The SASP induces chronic low-grade inflammation in the surrounding tissue, also known as “inflammaging,” which can lead to the dysfunction of neighboring cells and contribute to the progressive damage of the CNS [ 127 ]. Furthermore, these senescent cells do not repair themselves, leading to tissue dysfunction and impairments in neuronal regeneration.

Given the detrimental impact of senescent cells on CNS health, senolytic therapies have emerged as a promising approach for mitigating neurodegeneration. Senolytic agents are designed to selectively target and eliminate senescent cells, thereby reducing the inflammatory burden and restoring a more youthful tissue environment. These therapies may not only clear damaged cells but also foster the regeneration of neurons and glial cells, which are essential for CNS repair and homeostasis [ 128 ]. Several compounds have been identified as potential senolytic agents, including small molecules such as dasatinib, quercetin, and fisetin, which have shown efficacy in preclinical models by clearing senescent cells and reducing neuroinflammation [ [129] , [130] , [131] ]. By removing these dysfunctional cells, senolytic treatments create a more favorable environment for neural repair, neuronal survival, and tissue regeneration [ 129 , 132 ]. Furthermore, early clinical trials involving senolytic therapies have demonstrated promising results, particularly in improving cognitive function and reducing the burden of neurodegenerative diseases associated with aging [ 130 , 133 ].

Another key intervention is the use of rapamycin, a mechanistic target of rapamycin (mTOR) inhibitor that has demonstrated promising effects in promoting longevity and reducing the cellular aging process [ 134 ]. Rapamycin may delay age-related cognitive decline, improve synaptic function, and enhance neurogenesis in animal models. It exerts its effects by inhibiting mTOR signaling, a central regulator of cell growth and metabolism, thereby promoting autophagy and reducing cellular stress [ 135 ]. Studies have suggested that rapamycin may protect against neurodegeneration by preventing the accumulation of damaged proteins and dysfunctional mitochondria, two hallmarks of aging that contribute to neuroinflammation and neuronal death [ 136 , 137 ].

Anti-aging and senescence-targeting therapies, including senolytics, offer promising approaches to mitigate age-related neurodegeneration by targeting the accumulation of senescent cells and reducing chronic inflammation, thus promoting a more regenerative CNS environment and enhancing neuronal survival and function.

Brain machine interface and exoskeletons

The potential for exoskeletons and brain-machine interfaces to promote CNS repair in MS patients lies primarily in their ability to facilitate neuroplasticity and enhance the brain's capacity for self-repair [ 9 ]. Exoskeletons, by providing external support for movement, encourage repetitive motor activity and weight-bearing exercises, which are crucial for stimulating neural activity and promoting plastic changes in both the CNS. In MS regular exercise could help reinforce motor pathways, potentially leading to remyelination or compensatory rewiring of the affected neurons [ 138 ]. Furthermore, physical activity through exoskeletons can improve circulation and reduce spasticity, both of which can support overall brain and spinal cord health [ [139] , [140] , [141] ].

Brain machine interfaces by directly linking the brain to external devices, bypass damaged or degenerated neural pathways, enabling patients to regain voluntary control over movements such as in patient with locked-in syndrome [ 10 , 11 ]. This direct brain control of assistive technologies may not only aid in motor function but also promote neuroplasticity by reinforcing and establishing new neural connections, which has been seen in the rehabilitation process of patients with stroke [ 142 ]. In MS brain machine interfaces offer a way to bypass areas of damage in the brain or spinal cord, allowing the brain to reroute motor commands to alternative neural circuits that are less affected by the disease [ 143 , 144 ]. Additionally, as patients engage with BMIs, the brain's motor cortex is stimulated, which may help maintain or even enhance the integrity of remaining neural pathways, fostering a form of adaptive recovery [ 143 ].

In summary, exoskeletons and brain-machine interfaces hold promising potential for promoting CNS repair in MS by facilitating neuroplasticity, supporting motor function, and enhancing brain self-repair through repetitive movement, improved circulation, and bypassing damaged neural pathways to establish new neural connections.

The ability to repair and regenerate the CNS following injury, inflammation or neurodegeneration remains a significant challenge, but recent advances in therapeutic approaches offer promising avenues for improving outcomes. Frequently the focus is on remyelination strategies when repair mechanisms are discuss in MS. However other methods, such as promoting axonal sprouting, targeting senescence, and leveraging stem cell therapies have shown potential in supporting CNS repair and mitigating the effects of neurodegenerative diseases like MS, Alzheimer's, and Parkinson's disease. Additionally, harnessing emerging technologies such as exoskeletons and brain-machine interfaces offers novel ways to enhance neuroplasticity and functional recovery, while optimizing neuronal energy metabolism through mitochondrial support can help overcome the metabolic challenges associated with neurodegeneration. Although these approaches are still in various stages of development, ongoing research and clinical trials continue to refine these therapies, offering hope for more effective, targeted treatments. It will be crucial to assess the safety of these measures and to have a set ob objective tools to measure the efficacy of these various interventions and procedures. Ultimately, a multifaceted strategy combining cell-based therapies, neuroprotective agents, and innovative assistive technologies may provide a comprehensive solution to promoting CNS repair and improving the quality of life for individuals with neurological disorders, such as MS ( Table 2 ).

Table 2 Completed clinical trials targeting CNS remyelination in patients with multiple sclerosis. Table 2 Intervention Sponsor Study type Disease type Mechanistic target Clinical outcome Adverse and serious adverse events Clemastine fumarate [ 29 ] UCSF and the Rachleff Family, 2017 Phase 2 RCT, n ​= ​50 RRMS Remyelination via OPC differentiation, reducing inflammation, preserving myelin sheath integrity Reduced VEP latency compared to placebo; decreased serum neurofilament light chain levels compared to placebo AE: Drowsiness, fatigue; no SAE Opicinumab, BIIB033, anti-LINGO-1 [ 27 ] Biogen, 2017 Phase 2, n ​= ​82 Optic neuritis Inhibit LINGO-1 protein to improve remyelination and axon regeneration No significant difference compared to placebo AE: Hypersensitivity [n ​= ​2]; SAE: Asymptomatic transaminitis [n ​= ​1] Lipoic acid [ 58 ] VA Office of Research And Development, 2017 Phase 2, n ​= ​51 SPMS Oxidative damage repair, increased population of mature oligodendrocytes, inhibited macrophage/microglial activation Decreased annualized percent change in brain volume vs placebo over two years AE: GI upset; SAE: Renal failure [n ​= ​1], glomerulo-nephritis [n ​= ​1] Erythropoietin [ 56 ] Phase 2, n ​= ​50 PPMS or SPMS Clearance of myelin debris, proliferation of OPC No change in clinical outcomes (gait distance, hand dexterity, and cognition) or MRI outcomes compared to placebo SAE: Polycythemia requiring venesection Opicinumab ​+ ​interferon beta-1a [ 28 ] Biogen, 2019 Phase 2, n ​= ​419 Inhibit LINGO-1 protein to improve remyelination and axon regeneration No improvement in disability or slowed progression compared to placebo AE: Influenza-like illness (n ​= ​140 [43 ​%] vs n ​= ​37 [40 ​%] with placebo), MS relapses (n ​= ​117 [36 ​%] vs n ​= ​30 [32 ​%]), and headache (n ​= ​51 [16 ​%] vs n ​= ​23 [25 ​%]). SAE: Suicidal ideation and intentional overdose 1 ​%, bipolar disorder in 1 ​%, hypersensitivity 4 ​% Opicinumab ​+ ​other DMT [ 28 ] Biogen, 2019 Phase 2, n ​= ​174 Inhibit LINGO-1 protein to improve remyelination and axon regeneration No significant difference compared to placebo Not published MD1003 (high-dose biotin) [ 145 ] MedDay Pharmaceuticals, 2020 Phase 3, n ​= ​642 PPMS or SPMS Support myelin repair through fatty acid synthesis and enhancing energy production in neurons No significant difference in EDSS or T25W improvement vs placebo No statistically significant differences in AE and SAE between treatment groups. Did not observe that study drug increased risk MS relapse Bexarotene [ 32 ] Multiple Sclerosis Society of the UK, 2021 Phase 2, n ​= ​52 RRMS Retinoid X receptor-gamma agonist that promotes OPC differentiation and myelin repair No significant difference in MRI outcomes compared to placebo, but improved VEP latency in subjects <43 years old; many adverse events (central hypothyroidism, hypertriglyceridemia, rash, neutropenia) AE: All receiving drug had AE, ie central hypothyroidism [n ​= ​26, 0 placebo], hypertriglyceridemia [n ​= ​24, 0 placebo], rash [n ​= ​13, 1 placebo] and neutropenia [n ​= ​10, 0 placebo]; SAE: Cholecystitis [n ​= ​1] placebo-treated subject Human monoclonal IgM antibody 22 (rHIgM22) [ 59 ] Acorda Therapeutics Inc, 2022 Phase 1, n ​= ​27 Inhibits apoptosis, increases expression of myelin-related gene products Well tolerated AE: Headaches and mild infusion-type reactions (pruritus, arthralgia, flushing) CNM-Au8 [ 112 ] Clene Nanomedicine, 2023 Phase 2, n ​= ​11 Gold nanocrystals that improve metabolism in CNS cells, supporting neuroprotection and remyelination Increased mean NAD+/NADH ratio in the brain in a subanalysis AE: Sinusitis [n ​= ​3], nasopharyngitis [n ​= ​3], and paresthesia [n ​= ​2]. No SAE Simvastatin [ 146 ] University College London, 2025 Phase 3, n ​= ​964 SPMS Reduce inflammation, protect nerves, inhibit expression of MHCI/II and T cell receptors No significant difference vs placebo Rhabdomyolysis [n ​= ​1] Table showing completed remyelination trials in patients with multiple sclerosis (MS) Abbreviations: n ​= ​number, RRMS ​= ​relapsing remitting MS, SPMS ​= ​secondary progressive MS, PPMS ​= ​primary progressive MS, CNS ​= ​central nervous system, CEP ​= ​visual evoked potentials, T25W ​= ​timed 25 foot walk, EDSS ​= ​expanded disability status scale, OPC ​= ​oligodendrocyte precursor cell, AE ​= ​adverse event, SAE, serious adverse event.

Completed clinical trials targeting CNS remyelination in patients with multiple sclerosis.

Table showing completed remyelination trials in patients with multiple sclerosis (MS) Abbreviations: n ​= ​number, RRMS ​= ​relapsing remitting MS, SPMS ​= ​secondary progressive MS, PPMS ​= ​primary progressive MS, CNS ​= ​central nervous system, CEP ​= ​visual evoked potentials, T25W ​= ​timed 25 foot walk, EDSS ​= ​expanded disability status scale, OPC ​= ​oligodendrocyte precursor cell, AE ​= ​adverse event, SAE, serious adverse event.

Author contributions

LG contributed to designing, writing, and editing the manuscript, also made the table.

BG contributed to designing and editing the manuscript.

UWK contributed to designing, writing, and editing the manuscript, also made the figure.

Disclosures relevant to the review

BG: None.

LG: None.

UWK: None.

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ulrike W Kaunzner reports a relationship with Genentech that includes: funding grants. Ulrike W Kaunzner reports a relationship with Med Learn that includes: speaking and lecture fees. Ulrike W Kaunzner reports a relationship with EMD Serono Inc that includes: consulting or advisory. Ulrike W Kaunzner reports a relationship with Alexion Pharmaceuticals Inc that includes: speaking and lecture fees. Ulrike W Kaunzner reports a relationship with Novartis that includes: consulting or advisory. NA If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Footnotes

This article is part of a special issue on Multiple Sclerosis published in Neurotherapeutics

Contributor Information

Lauren Gluck, Email: lgluck@montefiore.org.

Brittany Gerstein, Email: wbl9005@nyp.org.

Ulrike W. Kaunzner, Email: uwk9002@med.cornell.edu.

References