Practice Points
- Optogenetics technology focuses on manipulating cell behavior by combining 2 important elements: genetics and light.
- Optogenetics plays a role in investigating multiple sclerosis (MS) etiology by providing insights into the cellular mechanisms that may underlie cognitive impairment in MS.
- Possible future applications of optogenetics in MS therapy include the induction of oligodendrocyte proliferation, myelin synthesis, enhancing the repair of demyelinating processes, and modulating the severity of MS symptoms.
Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS). The characteristic hallmark of this disease is damage and loss of myelin secondary to inflammation.1 In the late stages of MS, the loss of myelin impairs the protection of neurons and the conduction of electrical impulses, leading to neurodegeneration.2 At the time of diagnosis, most people with MS are diagnosed with a relapsing-remitting form.3,4
Perivenular inflammatory lesions, one of the many variables that contribute to MS development, are caused by autoreactive T cells, mainly CD4-positive and B cells. These cells are responsible for neuronal demyelination and the induction of oligodendrocyte apoptosis, followed by impairment in myelin synthesis,5-7 the production of demyelinating plaques, and axonal damage.2,8 Although oligodendrocytes are the primary remyelinating cells in the CNS, evidence suggests that Schwann cells (SC) may also contribute to remyelination under certain conditions in the spinal cord, brain stem, and cerebrum.9
A comparative study evaluated the efficacy of optogenetic stimulation between glia, such as SCs, and motor neurons, in which the stimulation for SCs resulted in higher rates of myelination in the peripheral nervous system (PNS) than the stimulation of neurons.10 These findings may alter future uses of optogenetics by shifting the focus to SCs as a treatment for MS.
Optogenetics technology focuses on manipulating cell behavior by combining 2 important elements: genetics and light.9 To make certain neurons more susceptible to inhibition or excitation, 3 elements are required: (1) light-activated proteins, (2) light, and (3) a delivery mode. First, the light-activated proteins, called microbial opsins, are delivered to neurons and can inhibit or activate them. The opsins can be delivered to cells by viral carriers such as lentivirus or adeno-associated virus, along with the opsin gene or nonvirally.11 An optic fiber is used to shine a light on opsins (Figure 1),as it can reach deeper brain structures; a light-emitting diode is the most effective method.12
Optogenetics has been used in several medical fields. In ophthalmology, it is used for visual restoration by altering surviving retinal neurons with a light-sensitive optogenetic gene.13 It also plays an important role in cardiology, including arrhythmia treatment, where it helps restore pacing and recover the conduction system to achieve cardiac resynchronization with precise and low-energy optical control. Photosensitive proteins, which usually act as ion channels, pumps, or receptors, are delivered to target cells, where they respond to light pulses of specific wavelengths, evoke transient transmembrane ion currents, and induce signal transmission.14 Optogenetics might also play a vital role in cancer research and treatment with the development of gene-editing technologies in combination with light-sensitive systems15 and in neuropsychiatry by helping researchers understand the mechanisms and neuronal circuits of depression and pain.16,17
Because the main pathology in MS is the demyelination of neurons, optogenetics can induce oligodendrocyte proliferation and myelin synthesis.18 Current literature discusses how optogenetics can modulate the severity of MS symptoms in the long term, even without continuous exposure to photostimulation, which could be very convenient for the patient and quite innovative for our health care systems.11 Optogenetics provides high spatial resolution without encroachment of brain structures, which could provide safe and effective treatment of MS and other neurodegenerative diseases in the future. This review will discuss potential optogenetics applications in neuroscience and MS, possible combinations with other treatments for MS, the challenges to implementation, and future research directions.
Methods
We searched the PubMed, Scopus, and Web of Science databases for studies published from 2022 to 2024. The search strategy used keywords and search terms including multiple sclerosis, MS, optogenetics, myelination, and Schwann cells. We also included experimental optogenetics trials on experimental autoimmune encephalomyelitis and neurons.
Results
The Table presents a summary of selected studies.
Investigating the Etiology of Multiple Sclerosis
Heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) plays a critical role in RNA processing and cellular stress responses. Findings from recent studies have highlighted its mutations, particularly P275S and F281L, as significant contributors to neurodegenerative processes in MS. These mutations lead to cytoplasmic mislocalization of hnRNP A1, which alters the kinetics of its cluster formation and enhances stress granule formation. Optogenetic systems have demonstrated that blue light stimulation can accelerate this stress granule formation. This mislocalization and the resultant cellular stress responses may exacerbate neurodegeneration and underlie cognitive impairment in people with MS, suggesting a need for novel therapeutic strategies targeting these mechanisms.19,20
Targeted Therapeutics
IFN-β was the first disease-modifying therapy to treat MS, decreasing relapse rates and delaying the onset of disability.21 Many immune and nonimmune cell types secrete the interferon family of cytokines. The type I family of interferons includes the IFN-βs that are used to treat MS,22 but the mechanism of action remains unclear. Once IFN-β binds to specific cell surface receptors, there is an increased expression of anti-inflammatory cytokines (eg, IL-4, IL-5, IL-10, IL-13, and transforming growth factor β) and downregulation of expression of pro-inflammatory cytokines (eg, IL-17, IFN-γ), which help stabilize the CNS21,23 and decrease the demyelination process.
A downside of IFN-β therapy is injection frequency, which affects adherence.24 A recent trial utilized optogenetics to develop a bioelectronic cell-based wireless implant to deliver IFN-β in a controlled, less invasive manner to improve adherence.25 The device uses immortalized human mesenchymal stem cells, known for their immunomodulatory properties,26 that researchers have genetically modified to express a bacteriophytochrome diguanylate cyclase (DGCL). This enzyme is crucial for the optogenetic control of protein secretion. New opsins have been developed with enhanced specificity and sensitivity to respond to specific light wavelengths, allowing for targeted modulation of specific cells, reducing the effects on normal cells.27 The DGCL is activated by near-infrared light, which triggers the production of cyclic di–guanosine monophosphate. This signaling molecule plays a role in activating the stimulator of interferon genes (STING) pathway. The device uses rhodopsins, G protein–coupled receptors, that can activate endogenous signaling pathways upon light stimulation.28 Once activated, the STING pathway leads to the phosphorylation of interferon regulatory factor 3, which then translocates to the nucleus. There, it drives the expression of the gene encoding IFN-β, resulting in the secretion of this therapeutic protein into the surrounding tissue. Because the device is wireless, it allows remote activation without the need for invasive procedures, enabling precise control over the timing and amount of IFN-β released based on external light stimuli. The wireless method is superior to the traditional method, which requires invasive fiber optic implants for light delivery and carries risks for infection and tissue damage.
After synthesizing the device, researchers implemented the optogenetic cell device in an experimental autoimmune encephalomyelitis mouse model and found that Optoferon cell devices significantly prevented acute demyelination and had clear benefits for treating neuroinflammation.25
From Demyelination to Repair
Another characteristic of MS is the loss of myelination, leading to damage of the myelin sheaths, impairing impulse conduction, and causing axon degeneration. Remyelination could delay disease progression, as it could restore conduction properties to axons, thereby restoring neurological function29 and decreasing the patient’s Expanded Disability Status Scale score. Remyelination is a complicated process that is not fully understood, and effective clinical therapies remain limited. Findings from recent optogenetic studies have shown promising results in remyelination, warranting further exploration.
Role of Oligodendrocytes
Oligodendrocytes are the main cells responsible for remyelination in the CNS. Although neuronal activity normally stimulates oligodendrocyte production and myelination30 it is unclear whether activating demyelinated axons could restore function in a harmful environment. To investigate, a researcher used optogenetic-based electric stimuli on the demyelinated corpus callosums of mice.18 The stimulation protocol was 30-second light pulse trains at 20 Hz repeated every 4.5 minutes, which allowed targeted stimulation of demyelinated axons without affecting the overall circuit function.
The data demonstrated that repeated electric stimuli enhanced neuronal activity and promoted enhanced oligodendrocyte precursor cell differentiation into mature oligodendrocytes, essential to myelin regeneration. Ultrastructural improvements and increased functional recovery in the affected axons suggest a new therapeutic implication in conditions such as MS (Figure 2).
Role of SCs in the PNS
SCs are the main glial cells in the PNS and can initiate a regenerative response after peripheral nerve injury.31 They undergo various changes, such as changes in the expression of genes related to nerve repair, to promote the repair process.32 SC remyelination was recently discovered in cerebral and spinal cord lesions during autopsies of people with MS.33
By exposing glial cells to optogenetics, it was discovered that the amount of calcium ions in the stimulated cells is significant in the regulation of the neural network and synapses.34 This was optimized in monoculture settings.35 Optogenetic stimulation significantly increased the proliferation of SCs, as evidenced by higher counts of bromodeoxyuridine-positive SCs over time.
Differentiation of SCs was also possible by promoting the expression of key myelin-related proteins such as EGR2 and myelin basic protein. SCs not only proliferated and differentiated but also contributed to the formation of a compact myelin sheath when cocultured with motor neurons. This was because optogenetic stimulation increased calcium movement from inositol trisphosphate–sensitive stores and calcium inward movement through T-type voltage-gated calcium channels. This calcium signaling is crucial for both the proliferation and differentiation processes of SCs.
Optogenetic stimulation has emerged as an effective stimulator for axon growth compared with other stimuli, such as electric and chemical stimulation, as these methods lack its specificity.36 Researchers used it in an SC model to study its effect on motor neurons, promoting axonal regeneration and remyelination.37 Motor neurons were transfected with a light-sensitive channelrhodopsin gene, enabling them to respond to light stimulation. When subjected to repeated light pulses (20 Hz for 1 hour), optogenetic stimulation significantly increased the number of SCs expressing myelin basic protein, indicating enhanced initiation of myelination. Ultrastructural analysis revealed that the optogenetically stimulated motor neurons had a thicker, more compact myelin sheath around their axons, with thickness approaching in vivo estimates.
G-Ratio Considerations
Optogenetic stimulation of SCs significantly influences the g-ratio of myelinated axons, a critical parameter for assessing myelin sheath quality and nerve conduction efficiency. The g-ratio is the ratio of the axon’s inner diameter to the myelinated fiber’s total outer diameter. Researchers indicate that when SCs are optogenetically stimulated, the g-ratio of myelinated axons approaches the theoretical optimal value for effective nerve conduction.10 These advantages highlight the potential of targeting glial cells in therapeutic strategies; however, the full therapeutic potential of these findings and the refinement of optogenetic techniques for clinical applications in demyelinating diseases such as MS must be explored further.
Cognitive Function
Cognitive impairment is a common and debilitating symptom in MS, affecting quality of life. Optogenetics offers a potential avenue for enhancing cognitive function by selectively activating neural circuits involved in learning and memory. By targeting specific brain regions, optogenetic stimulation could help restore normal cognitive processes disrupted by neurodegenerative changes associated with MS.
Research has shown that optogenetic activation can promote neuroplasticity,20 which is crucial for recovery and adaptation in neural circuits. One study’s results indicate that stimulating the prefrontal cortex can enhance working memory performance in animal models, suggesting that similar approaches could be beneficial for people with MS with cognitive deficits.20
Understanding the molecular mechanisms behind hnRNP A1 mutations and their impact on cognitive function in people with MS may pave the way for innovative therapeutic strategies. By combining optogenetics with targeted therapies aimed at correcting hnRNP A1 dysfunction, researchers could develop interventions that mitigate neurodegeneration and enhance cognitive resilience in people with MS.19
Conclusions
This narrative review covered the potential role of optogenetics in treating MS, specifically as it targets remyelination by inducing oligodendrocytes and SC proliferation. In addition, by combining optogenetics with targeted therapies aimed at correcting hnRNP A1 dysfunction, researchers could develop interventions that mitigate neurodegeneration, enhance cognition and resilience, and enhance memory and learning in people with MS.
Optogenetics can stimulate oligodendrocyte and SC proliferation to repair the demyelination of axons in animal models with MS. Optogenetics could also possibly improve drug delivery, such as for IFN-β, where the combination of 2 treatment modalities could promote adherence by reducing injection frequency. Optogenetics might also play a role in repairing cognitive decline, including in memory and learning, which are often impaired in people with MS. Optogenetics could also be used to study specific mutations of MS, including hnRNP A1, as well as to treat such mutations.
Although optogenetics presents significant opportunities, it also faces technical and ethical challenges. MS is a complex disease with many patterns, so it will be difficult to develop a technology to treat all types with the same efficacy. The need for genetic modification to introduce opsins raises ethical questions, especially about potential applications in humans. As well as the potential of inducing an immune response to microbial opsins, there is also the risk of whether introducing these genes will lead to genetic modification over time. Belgrad et al38 discussed how patterned neural activities can alter the transcription of genes and induce epigenetic changes. One of the complications of such changes is tumor formation.39 Another challenge surrounding optogenetics applications is the risk of CNS infection and tissue damage due to using optogenetics tools on the brain.11 Moreover, the complexity of neural circuits necessitates developing more sophisticated targeting and control methods to ensure intervention specificity and efficacy.37 It is crucial to conduct more research and clinical trials on the efficacy of optogenetics to treat MS and work on minimizing potential adverse effects.
