Table of Contents
Overview
Definition and Mechanism
Optogenetics is a technique that utilizes light to precisely control genetically modified cells, particularly neurons, which express light-sensitive ion channels and pumps. This method enables the manipulation of neuronal activity with high temporal resolution, allowing researchers to explore causal links between neural activities and behaviors in neuroscience.[4.1] By integrating optical and genetic techniques, optogenetics provides both temporal and spatial resolution in modulating cellular processes, either activating or silencing excitable cells or neuronal circuits.[5.1] The systems typically involve light-sensitive proteins, known as opsins, derived from organisms like bacteria and algae, which combine light response and cellular function within a single protein domain.[5.1] This overview underscores the state of the art in optogenetics, highlighting its potential applications and the challenges in this rapidly evolving field.[3.1]Applications in Neuroscience
Optogenetics has revolutionized neuroscience by allowing precise control of neuronal activity using light, enabling researchers to manipulate specific neurons, such as those in the subthalamic nucleus (STN). This capability aids in understanding the mechanisms of deep brain stimulation (DBS) and optimizing therapeutic stimulation parameters.[6.1] While the genetic modification of somatic cells for therapeutic purposes is generally considered ethical, provided that safety, informed consent, and equity of access are prioritized, optogenetics introduces new ethical concerns. These include the implications of genetic modifications and potential unintended effects on personality and autonomy in patients undergoing brain interventions.[6.1][7.1] The selection of appropriate opsins—light-sensitive proteins—is crucial for effective optogenetic applications. Factors such as light sensitivity, tissue penetration, and phototoxicity influence this choice.[12.1] An ideal optogenetic therapy requires a safe gene delivery vehicle, targeted delivery to the tissue of interest, and opsins that are non-immunogenic and responsive to light in the red to near-infrared spectrum.[10.1] The development of various opsins has expanded the research toolkit, allowing for tailored approaches to studying neural circuits.[11.1] Optogenetics offers significant advantages over traditional electrophysiological methods by enabling temporally precise modulation of neuronal activity with cell-type specificity.[16.1] This precision facilitates the investigation of neural circuit dynamics and their role in behavior, providing insights previously difficult to obtain.[13.1] Integrating optogenetics with electrophysiology and imaging techniques enhances the ability to dissect complex neural interactions and understand brain diseases.[14.1] Additionally, optogenetics enables the study of enteric neurons, presenting new strategies for addressing disorders of the enteric nervous system that are challenging to target with conventional methods.[17.1]History
Development Timeline
The development of optogenetics can be traced back to significant milestones that have shaped its evolution as a powerful tool in neuroscience. The foundational work in this field is largely credited to Karl Deisseroth from Stanford University and Ed Boyden from MIT, who, along with their colleagues, published a pivotal paper in 2005 in Nature Neuroscience. This publication is often regarded as the inception point of optogenetics, as it introduced the concept of using light to control neuronal activity through genetically encoded proteins, specifically channelrhodopsin-2 (ChR2).[41.1] Prior to this breakthrough, the groundwork for optogenetics was laid through earlier studies that explored the use of light-sensitive proteins for controlling biochemical pathways. Notably, in 2002, researchers demonstrated the use of plant phytochrome to regulate gene transcription in yeast via light-induced interactions. This study highlighted the potential for directed light delivery to target specific cells, a concept that would later be integral to the development of optogenetics in neural tissues.[42.1] Following the introduction of ChR2, additional opsins were identified and engineered to enhance the capabilities of optogenetic tools. One such example is halorhodopsin (NpHR), a light-sensitive chloride pump that allows for significant hyperpolarization of neurons upon activation. Early experiments utilizing NpHR faced challenges regarding efficacy, but they nonetheless contributed to the understanding of optogenetic manipulation of neuronal activity.[68.1] The application of optogenetics has expanded significantly since its inception, enabling researchers to simultaneously stimulate and record various neuronal activities, such as intracellular calcium levels and electrical signals, in freely moving animals. For instance, studies have shown that intermittent optogenetic stimulation of the phrenic motor neuron pool can restore normal electromyography activity in models of spinal injury, while other research has indicated that optogenetic stimulation of neural stem cells can promote recovery and enhance neural plasticity following a stroke.[69.1] As the optogenetic toolbox continues to grow, the potential for its application in treating neurological disorders and advancing our understanding of neural circuits remains vast, marking a revolutionary shift in neuroscience research.[40.1]Recent Advancements
Technological Innovations
Recent advancements in optogenetics have been significantly driven by innovations in optical delivery systems and the development of novel light-activated tools. Introduced in 2006, optogenetics combines genetic engineering with optical technology to control biological functions in cells, tissues, and organisms modified to express photosensitive proteins.[78.1] This technology includes core components like targetable control tools that respond to light, enabling precise manipulation of cellular activities.[79.1] The scope of optogenetics has expanded beyond its original applications in neuroscience, with innovations in optical actuators and light-delivery techniques facilitating control of signaling pathways in non-neuronal cells. This expansion supports applications in phototherapy and immunotherapy.[87.1] For example, less-invasive light delivery methods aim to improve research reliability and enhance animal welfare by minimizing tissue damage associated with traditional invasive optical fibers.[88.1] The versatility of optogenetics is further enhanced by genetically encoded vertebrate opsins, such as G protein-coupled receptors, which allow for the management of intracellular signaling and gene regulation.[87.1] This has led to applications in various medical conditions, including vision restoration in retinitis pigmentosa, immune response modulation in cancer therapy, and blood glucose management in diabetes through controllable drug release.[86.1] Moreover, advanced optical delivery systems, such as the PhyA-based far-red light-mediated micro-optical switch system (REDMAP), have demonstrated significant potential in achieving long-term glycemic control through light modulation.[85.1] These advancements underscore the growing importance of optogenetics as a powerful tool in biomedical research, enabling high spatiotemporal precision in studying biological processes and treating diseases.[86.1]Clinical Applications
Recent advancements in optogenetics have led to significant clinical applications, particularly in treating various medical conditions. A notable application is vision restoration, where optogenetic therapy has shown promise in addressing retinitis pigmentosa (RP) and Stargardt disease. A groundbreaking study reported the first-ever case of partial vision recovery in a blind patient following optogenetic therapy, marking a significant step towards clinical use of this technology in neurodegenerative diseases.[108.1] Current clinical trials primarily focus on retinal diseases due to the feasibility of delivering light through the eyes. GenSight Biologics has reported promising efficacy results in the NCT03326336 trial, demonstrating partial visual restoration in participants.[112.1] Additionally, the OCU400 therapy has shown a good safety profile and notable efficacy, with measurable improvements in visual function tests, particularly in low-light navigation.[113.1] Beyond vision restoration, optogenetics is being explored for its potential in cancer immunotherapy and diabetes management. Recent advances in optogenetic tools have enabled precise modulation of immune responses, which could enhance the efficacy of cancer treatments.[97.1] Furthermore, optogenetics has been utilized for controllable drug release in diabetes management, showcasing its versatility in addressing various medical conditions.[97.1] However, transitioning from laboratory research to clinical practice presents challenges. Developing implantable medical devices capable of delivering sufficient optical stimulation without damaging brain tissue is crucial for the successful application of optogenetics in human patients.[109.1] Moreover, strategies to protect optogenetic constructs from immune responses must be considered to ensure their effectiveness in clinical settings.[100.1] As research progresses, the future of optogenetics in clinical applications appears promising, with ongoing trials and studies aimed at overcoming existing limitations and expanding its therapeutic potential.[99.1]In this section:
Ethical Considerations
Ethical Issues in Clinical Trials
The ethical considerations surrounding optogenetics in clinical trials are complex, particularly regarding the welfare of research participants. A key aspect of these ethical frameworks is the debate over whether Phase 1 trials should include efficacy endpoints alongside safety endpoints. This inclusion is crucial to ensure that trials are conducted fairly and respectfully, balancing scientific progress with participant welfare.[129.1] The application of optogenetics also raises ethical and legal issues, especially concerning animal experiments and its potential human implications. The investigation of optogenetic methods on cerebral organoids introduces questions of social acceptance and the moral implications of the research methods employed.[132.1] Ethical guidelines for clinical trials must address standard issues such as safety, risk-benefit calculations, informed consent, and the protection of vulnerable subjects. These considerations are essential to weigh the benefits of optogenetic interventions against potential risks to participants.[131.1] Furthermore, trials involving optogenetics, particularly in the context of deep brain stimulation (DBS), require a thorough examination of the implications of genetic modifications on personal autonomy and responsibility.[133.1] To ensure the ethical application of optogenetics in clinical settings, it is imperative to engage in broad and open discourse among all stakeholders. This dialogue should aim to clarify the ethical and legal questions arising from the use of this technology, ensuring that its medical potential is realized while maintaining ethical integrity.[132.1]Regulatory Challenges
Neuronal optogenetics presents a range of ethical and legal challenges that researchers and clinicians must navigate, particularly concerning animal experiments and human applications. These challenges are compounded by the complexities of the methods employed and the potential implications for social acceptance of the technology. As the field advances, especially with the exploration of cerebral organoids, there is a growing recognition among scientists, legal scholars, and ethicists of the need to address these open ethical and legal questions through comprehensive discourse involving all stakeholders.[150.1] Regulatory frameworks governing optogenetics are crucial for ensuring the ethical conduct of research and clinical practice. In the United States, the Food and Drug Administration (FDA) oversees regulations that protect human subjects and guide clinical trials, including requirements for informed consent and safety protocols.[153.1] These regulations are designed to address ethical concerns related to patient monitoring and the equitable access to emerging therapies.[152.1] The FDA's guidelines encompass various aspects of clinical research, including Good Clinical Practice (GCP) standards, which are essential for maintaining the integrity of clinical trials involving optogenetic techniques.[153.1] Moreover, the implementation of optogenetics in clinical settings necessitates the development of implantable medical devices capable of delivering precise optical stimulation without causing harm to brain tissue. This requirement adds another layer of complexity to the regulatory landscape, as the first human trials are anticipated to occur within the next decade.[152.1] The integration of gene therapy with optogenetic devices in clinical studies is expected to yield significant data on safety and efficacy, further informing the regulatory environment surrounding these innovative therapies.[152.1]In this section:
Tools And Techniques
Light-Sensitive Proteins
Light-sensitive proteins, particularly microbial opsins, are pivotal in optogenetics, offering precise modulation of neuronal activity. These proteins are genetically encoded and can be introduced into neurons using methods such as viral vectors and transgenic techniques, allowing for targeted manipulation of specific neuronal types.[155.1] Unlike the broader gene delivery mechanisms discussed elsewhere, this section focuses on the unique properties and applications of opsins themselves. Microbial opsins are distinguished by their ability to respond to light, enabling researchers to activate or inhibit neuronal functions with exceptional precision.[170.1] The choice of opsin is critical and depends on factors like light sensitivity and tissue compatibility. Single-component opsins, despite their limited processing capabilities compared to multicomponent systems, offer advantages in compactness and speed, making them ideal for rapid neuronal manipulation.[171.1] Advancements in molecular engineering and comparative genomics have significantly enhanced the understanding and application of these opsins in optogenetic research.[171.1] The selection of the appropriate opsin is crucial for aligning with experimental goals, ensuring the effectiveness of optogenetic techniques in exploring neural circuits and behaviors.[170.1]Gene Delivery Mechanisms
The integration of optogenetics with CRISPR technology has led to the development of innovative gene delivery mechanisms that enable precise spatiotemporal control of genome editing. One notable advancement is the engineering of photoactivatable Cas9, which allows for the control of genome sequences in a highly dynamic manner through light activation. This method combines the capabilities of CRISPR-Cas9 with optogenetics, facilitating the generation of guide RNA vectors and enabling light-mediated genome editing experiments.[179.1] The juxtaposition of CRISPR and optogenetics provides unprecedented potential for biology and biomedicine, as it allows for spatiotemporally confined genome perturbations in living cells and organisms. Current optogenetic CRISPR systems primarily utilize light-induced dimerization of split-Cas9 fragments, which can be activated or deactivated by light, thus offering a sophisticated approach to gene editing.[181.1] This capability is further enhanced by the use of photoinducible dimerization domains, which enable the switching of CRISPR-Cas9 activity on and off in response to light, thereby providing researchers with a powerful tool for manipulating gene expression with high precision.[182.1]Future Directions
Potential for Cognitive Enhancement
Recent advancements in optogenetics have significantly enhanced our understanding of cognitive functions and behaviors in animal models, paving the way for potential therapeutic applications in humans. This technology allows for genetically defined, light-based control of neural circuits, enabling researchers to manipulate neural activity and observe the resulting cognitive effects with high precision.[203.1] Such capabilities have been instrumental in elucidating the complex roles of specific brain regions, such as the infralimbic cortex, in regulating habitual behaviors, which may involve rapid neuroplasticity during optogenetic interventions.[200.1] Moreover, the exploration of striatal circuitry through optogenetic techniques is crucial for developing new treatments for disorders characterized by impaired motor and cognitive functions, such as Parkinson's disease.[202.1] By understanding how neuronal and behavioral functions can be influenced and potentially rescued through optogenetic manipulation, researchers can inform future brain-stimulation strategies aimed at addressing motor and cognitive abnormalities.[204.1] The versatility of optogenetics extends beyond neuroscience, as it has been applied to various biomedical fields, including phototherapy and immunotherapy, demonstrating its potential to modulate biological functions with high spatial and temporal resolution.[198.1] As optogenetic tools continue to evolve, their applications in cognitive enhancement and therapeutic interventions are likely to expand, offering new avenues for treating neuropsychiatric diseases and enhancing cognitive capabilities in humans.Interdisciplinary Research Opportunities
Recent advancements in optogenetics have opened up numerous interdisciplinary research opportunities, particularly in the therapeutic applications of this innovative technology. Optogenetics has shown promise in various medical fields, including vision restoration, diabetes management, cancer therapy, and bioelectric medicine, highlighting its potential to transcend its origins in neuroscience and contribute to broader biological research.[206.1] The ability to precisely control biological functions with high spatial and temporal resolution has established optogenetics as a powerful tool for disease treatment, enabling applications such as light-activated ion channels for vision restoration in retinitis pigmentosa and controllable drug release for blood glucose management in diabetes.[208.1] However, the integration of optogenetics into clinical practice faces several challenges that necessitate interdisciplinary collaboration. There is an urgent need for the development of specialized hardware and software for clinical training, testing, and rehabilitation in optogenetic therapy, which current ophthalmic equipment cannot adequately support.[205.1] Additionally, engineering challenges related to cell or tissue delivery capabilities must be addressed to facilitate the prompt introduction of optogenetic therapies into clinical settings.[207.1] The creation of implantable medical devices capable of delivering sufficient optical stimulation without damaging underlying brain tissue is also critical for the successful application of optogenetics in human trials.[209.1] As researchers work towards the first-in-human applications of optogenetics, interdisciplinary efforts will be essential in overcoming these obstacles. Collaborative research that combines expertise from engineering, biology, and clinical medicine will be vital in developing the necessary tools and methodologies to translate optogenetic findings into effective clinical therapies. The anticipated first human trials within the next decade will provide meaningful data on the safety and efficacy of these innovative treatments, paving the way for future advancements in the field.[209.1]In this section:
References
[3] Optogenetics - an overview | ScienceDirect Topics — Optogenetics is a novel technology that combines optical and genetic methods to activate or silence excitable cells or neuronal circuits with temporal and spatial resolution. ... Here, we provide a comprehensive overview of the state of the art in this rapidly growing discipline and attempt to sketch some of its future prospects and challenges
[4] Optogenetics - an overview | ScienceDirect Topics — Optogenetics is a cutting-edge technology that allows for precise manipulation of neuronal activity in specific cell types using light-sensitive proteins called opsins. It enables researchers to explore causal relationships between neural activities and behaviors with high temporal resolution in the field of neuroscience. ... Brief Overview of
[5] Optogenetics - an overview | ScienceDirect Topics — Optogenetics is an approach that combines genetic manipulation and optical stimulation for regulating cellular processes (Deisseroth, 2011). ... Overview of commonly used optogenetic tools. A. Optogenetic systems, where light response and cellular function are combined in a single protein domain, include bacterial and algal type II rhodopsins
[6] 7 Ethical Issues Raised by Recent Developments in Neuroscience: The ... — By allowing specific neurons (e.g., STN neurons) to be manipulated in a known direction (e.g., excited), optogenetics avoids these problems, offering the potential to understand the mechanism of action of eDBS and identifying beneficial stimulation parameters, both of which would improve eDBS therapy (Gradinaru, Mogri, et al., 2009; Kravitz et al., 2010). Genetically modifying somatic cells to treat diseases is generally considered potentially ethical as long as standard issues are addressed (i.e., safety, risk–benefit calculation, protection of vulnerable subjects, informed consent, patient monitoring, and equity of access; National Academies of Sciences, 2017; Cavaliere, 2019; Coller, 2019), including by the public (Condit, 2010; Robillard et al., 2014). In light of this, a novel ethical issue raised by optogenetics involves considering the ethical requirements for clinical trials of oDBS (Gilbert et al., 2014).
[7] Neurotechnology: Current Developments and Ethical Issues — Keywords: neurotechnology and brain-machine interface, ethics, self, personhood, deep brain stimulation However, changes to personality can also be an unintended side effect of brain intervention, as occasionally reported in PD patients receiving DBS. Along similar lines, the concept of a person can provide an ethical benchmark, assuming that we do not want to impair personal capabilities such as autonomy and responsibility by interventions in the brain. Current developments in stimulation technology based on optogenetics raise ethical concerns, not only regarding the acceptability of interventions in the brain and their consequences, but also in view of the necessary genetic modifications of the organism. 10.1093/brain/aww286 [DOI] [PMC free article] [PubMed] [Google Scholar]
[10] Frontiers | Challenges for Therapeutic Applications of Opsin-Based ... — While there are several different classes of optogenetic tools (e.g., LOV domains, phytochromes, photocleavable proteins; Rost et al., 2017; Zhang et al., 2017), genetically encoded opsins (light-activated ion channels or pumps; Zhang et al., 2006; Deisseroth, 2015), are of the most relevance for therapeutic control of the nervous system. At a minimum, to be applied for stimulation of neurons in human patients, an ideal optogenetic therapy would require: (1) a safe and efficient gene delivery vehicle; (2) Targeting of the gene delivery vehicle to the tissue of interest; (3) a delivery vehicle, transgene, and therapeutic protein gene-product, that is non-immunogenic and non-mutagenic; and (4) an optogenetic protein that is highly sensitive to light in the red to near-infrared wavelength range (to keep light doses low, maximize light penetration, and minimize photodamage). Citation: Shen Y, Campbell RE, Côté DC and Paquet M-E (2020) Challenges for Therapeutic Applications of Opsin-Based Optogenetic Tools in Humans.
[11] #LabHacks: Choosing the best opsin for your optogenetics experiments — According to Tye and Deisseroth 2012 1, designing an optogenetics experiment can be broken down into five main parts, the first of which is finding the most suitable opsin for your particular investigation.. Since the establishment of optogenetics as a powerful technique to study neural circuit function, several research groups have worked on expanding the number of available opsins.
[12] 3 Factors Influencing In-Vitro Optogenetics Experiments — The 3 key factors to consider during in-vivo research are opsin sensitivity, tissue penetration, and phototoxicity. By selecting the appropriate opsins and wavelengths of light, researchers are able to investigate cellular responses and signaling pathways in their target tissue while keeping phototoxicity to a minimum.
[13] Multimodal neural probes for combined optogenetics and electrophysiology — Multimodal neural probes, especially those that combine optogenetics with electrophysiology, provide a powerful tool for the dissection of neural circuit functions and understanding of brain diseases. ... A central goal of neuroscience is to understand how animal behaviors are controlled by neural circuit ... Schematic comparison of traditional
[14] Optogenetics - New Potentials for Electrophysiology | Neuroscience and ... — This review addresses the new potentials opened up by the development of optogenetic methods and the advantages of combining these with conventional electrophysiological approaches in experimental studies to resolve a wide range of neurophysiological tasks. This review includes descriptions of the main difficulties and nuances in studies using optogenetic methods and examples of technical
[16] Integration of optogenetics with complementary methodologies in systems ... — Modern optogenetics enables temporally precise, acute or chronic, excitatory or inhibitory modulation of neuronal activity with cell type and anatomical specificity that can be tuned to timing and magnitude of naturally occurring patterns within the same experimental subject. This outcome has been facilitated not only by the development of core features of optogenetics over the past 10 years (microbial-opsin variants, opsin-targeting strategies and light-targeting devices) but also by the recent integration of optogenetics with complementary technologies, spanning electrophysiology, activity imaging and anatomical methods for structural and molecular analysis. Figure 3: Integrating optogenetic control with optical methods: matching naturally occurring activity patterns and linking to brain-wide projection activity. Targeted optogenetic stimulation and recording of neurons in vivo using cell-type-specific expression of channelrhodopsin-2.
[17] Optogenetics and its influence on the clinical neurosciences — Optogenetics, the control of neural activity using light, is a recent development in the field of clinical neuroscience and has brought significant reform to the domain. The possibility created by optogenetics of single-cell manipulation and the identification of specific neuronal pathways allows for a radically clearer grasp of the brain’s functioning. Contrastingly, optogenetic methods allow the activity of single neural cells and the pathways which they constitute to be observed. Furthermore, thanks to optogenetics it is possible to control the activity of enteric neurons, providing a new strategy for treating enteric nervous system (ENS) diseases which are especially difficult to target by traditional methods. In conclusion, optogenetics allowed innovative studies based on cell-type specificity and single-cell electrical and biochemical modulation.
[40] The Development and Application of Optogenetics - Annual Reviews — Genetically encoded, single-component optogenetic tools have made a significant impact on neuroscience, enabling specific modulation of selected cells within complex neural tissues. As the optogenetic toolbox contents grow and diversify, the opportunities for neuroscience continue to grow. In this review, we outline the development of currently available single-component optogenetic tools and
[41] The History of Optogenetics Revised | The Scientist — PIXABAY, GERALT The creation of optogenetics as a popular approach to manipulating neural behavior is largely attributed to Stanford University's Karl Deisseroth and MIT's Ed Boyden.The pair, in collaboration with their colleagues, published a seminal Nature Neuroscience paper (cited more than 2,100 times, according to Google Scholar) in 2005 that is often credited as the beginning of
[42] Optogenetics - Wikipedia — Analogously to how natural light-gated ion channels such as channelrhodopsin-2 allows optical control of ion flux, which is especially useful in neuroscience, natural light-controlled signal transduction proteins also allow optical control of biochemical pathways, including both second-messenger generation and protein-protein interactions, which is especially useful in studying cell and developmental biology. In 2002, the first example of using photoproteins from another organism for controlling a biochemical pathway was demonstrated using the light-induced interaction between plant phytochrome and phytochrome-interacting factor (PIF) to control gene transcription in yeast. By fusing phytochrome to a DNA-binding domain and PIF to a transcriptional activation domain, transcriptional activation of genes recognized by the DNA-binding domain could be induced by light. This study anticipated aspects of the later development of optogenetics in the brain, for example, by suggesting that "Directed light delivery by fiber optics has the potential to target selected cells or tissues, even within larger, more-opaque organisms." The literature has been inconsistent as to whether control of cellular biochemistry with photoproteins should be subsumed within the definition of optogenetics, as optogenetics in common usage refers specifically to the control of neuronal firing with opsins, and as control of neuronal firing with opsins postdates and uses distinct mechanisms from control of cellular biochemistry with photoproteins.
[68] A new technique for controlling the brain: optogenetics and its ... — Since the development of ChR2, other opsins have been identified or engineered and used to control neural activity. Halorhodopsin (NpHR) is a light-sensitive chloride pump (see Figure 1 for a depiction of halorhodopsin) that, when activated, provides significant hyperpolarization of the transduced neuron. 4 Although early work with NpHR demonstrated problems with efficacy and intracellular
[69] Optogenetics and its application in neural degeneration and ... — Coupled with optogenetics technology, it is possible to simultaneously stimulate and record intracellular Ca2+, electrical activity, and/or fluorescent proteins in specific groups of neurons in any brain structure and observe the resulting behaviour in freely moving animals (Gradinaru et al., 2007; Miyamoto and Murayama, 2016). In this study, intermittent optogenetic stimulation of the phrenic motor neuron pool following cervical 2 (C2) spinal hemisection resulted in return to normal hemidiaphragm electromyography (EMG) activity in synchrony with the non-lesioned side (Alilain et al., 2008). Similarly, a different study showed optogenetic stimulation of transplanted neural stem cells containing ChR2 promoted motor function recovery, increased expression of neural plasticity markers, and downregulated transcription of pro-inflammatory genes in a stroke model (Daadi et al., 2016).
[78] Optogenetics: Background, Methodological Advances and Potential ... — The term "optogenetics" was first introduced in 2006 by Deisseroth et al. and it broadly refers to an elegant approach that utilizes genetic engineering and optical technology to control and monitor biological functions of isolated or in situ cells, tissues, organs or organisms, modified to express photosensitive proteins (Deisseroth et al
[79] Optogenetics - PMC — In the broadest sense2, optogenetics encompasses a core technology—targetable control tools that respond to light and deliver effector function—and enabling technologies for (i) delivering light into tissues under investigation, (ii) targeting the control tools to cells of interest and (iii) obtaining compatible readouts and performing analysis, such as targeted imaging or electrical recording of evoked activity. Certain elements have been known to exist in earlier forms and in other contexts, though not conceptualized or developed as a control technology, as far back3 as 1971, with their fundamental transition to the emergence of optogenetics beginning in 2005 (Fig. 1) triggered by the demonstration of single-component control tools in neuroscience: microbial opsin genes that could safely confer to neurons both light-detection capability and defined high-speed effector function in a single readily targetable module4.
[85] Emerging optogenetics technologies in biomedical applications — For instance, Yang et al. have developed a PhyA‐based far‐red light‐mediated micro‐optical switch system (REDMAP), which has demonstrated various applications, including long‐term glycemic control through light modulation. 50. Optogenetics has emerged as a powerful tool for studying biological processes with high spatiotemporal precision.
[86] Optogenetics in medicine: innovations and therapeutic applications — In this review, we highlight recent advances in optogenetic tools and their applications across a range of medical conditions, including vision restoration in retinitis pigmentosa via light-activated ion channels, precise immune response modulation in cancer immunotherapy, and blood glucose management in diabetes through controllable drug release. This ability to precisely traceless control biological functions with high spatial and temporal resolution has established optogenetics as a powerful tool in disease treatment, expanding its applications far beyond its origins in neuroscience into various areas of biological research such as gene expression control , genome editing , and biomedicine, including phototherapy for blindness , metabolic , oncological diseases , and so on.
[87] Recent advances in cellular optogenetics for photomedicine — In recent years, the development of various optical actuators and novel light-delivery techniques has greatly expanded the scope of optogenetics, enabling the control of other signal pathways in non-neuronal cells for different biomedical applications, such as phototherapy and immunotherapy. Optogenetics has evolved into an important research method in life sciences by providing versatile control over genetically encoded vertebrate opsins (e.g., G protein-coupled receptors) to manage intracellular signaling, subcellular localization, and gene regulation . The rapid development of optogenetics in recent years largely benefits from the advances in optogenetic tools and light-delivery platforms, which provide innovative approaches to establish relationships between cellular activity and behavior phenotypes, expanding the utility of optogenetics in disease diagnosis and treatment (Fig. 1).
[88] Recent advances in optogenetics research — Less-invasive ways of using optogenetics. Light delivery in optogenetics often uses invasive optical fibres, which can cause tissue damage and alter behaviour. Developing ways to less-invasively, and even non-invasively, deliver light to specific neurons in the brain, will improve reliability of research as well as animal welfare.
[97] Optogenetics in medicine: innovations and therapeutic applications — In this review, we highlight recent advances in optogenetic tools and their applications across a range of medical conditions, including vision restoration in retinitis pigmentosa via light-activated ion channels, precise immune response modulation in cancer immunotherapy, and blood glucose management in diabetes through controllable drug release. This ability to precisely traceless control biological functions with high spatial and temporal resolution has established optogenetics as a powerful tool in disease treatment, expanding its applications far beyond its origins in neuroscience into various areas of biological research such as gene expression control , genome editing , and biomedicine, including phototherapy for blindness , metabolic , oncological diseases , and so on.
[99] Frontiers | Challenges for Therapeutic Applications of Opsin-Based ... — While there are several different classes of optogenetic tools (e.g., LOV domains, phytochromes, photocleavable proteins; Rost et al., 2017; Zhang et al., 2017), genetically encoded opsins (light-activated ion channels or pumps; Zhang et al., 2006; Deisseroth, 2015), are of the most relevance for therapeutic control of the nervous system. At a minimum, to be applied for stimulation of neurons in human patients, an ideal optogenetic therapy would require: (1) a safe and efficient gene delivery vehicle; (2) Targeting of the gene delivery vehicle to the tissue of interest; (3) a delivery vehicle, transgene, and therapeutic protein gene-product, that is non-immunogenic and non-mutagenic; and (4) an optogenetic protein that is highly sensitive to light in the red to near-infrared wavelength range (to keep light doses low, maximize light penetration, and minimize photodamage). Citation: Shen Y, Campbell RE, Côté DC and Paquet M-E (2020) Challenges for Therapeutic Applications of Opsin-Based Optogenetic Tools in Humans.
[100] Lighting the way: recent developments and applications in molecular ... — When moving optogenetics to other clinical applications, strategies must be considered to (temporally) protect the optogenetic constructs from an immune response. In the biomedical context, optogenetics might evolve as a driver of digital health. ... In the near future, such artificial prediction tools are expected to be used to design new
[108] PDF — a blind patient was treated withoptogenetic therapy. "These are truly groundbreakingfindings that move the promise of optogenetics another step from therapeutic concept to clinical use" commented , Bernard Gilly, Co-Founder and Chief Executive Officer of GenSight.
[109] Taking Optogenetics into the Human Brain: Opportunities and Challenges ... — An implantable medical device is also required that is capable of delivering sufficient optical stimulation to produce a clinical effect without damaging the underlying brain tissue.11 Despite these challenges, several groups are currently working towards the first-in-human application of optogenetics in the human brain, and the first human trials are likely to occur within the next decade. A review of the benefits and risks suggests that the first clinical study for an optogenetic therapy should be of both the gene therapy and the implanted device together, and should be of sufficient duration to provide meaningful data on safety and efficacy.
[112] The clinical potential of optogenetic interrogation of pathogenesis — Current clinical trials of optogenetics mainly focus on treating blindness due to the easy delivery of light through the eyes. We discuss six records of clinical trials, five active and one completed, which target retinal diseases. ... GenSight Biologics reported promising efficacy results in the NCT03326336 trial, which showed partial visual
[113] My Top Five: Promising gene therapies for ocular conditions — Following the promising results from phase 1/2 trials, OCU400 demonstrated a good safety profile and notable efficacy. Specifically, the studies reported a measurable improvement in the visual function tests that assess the ability to navigate under dim lighting, with all participants showing some degree of functional vision enhancement .
[129] Controlling Brain Cells With Light: Ethical Considerations for ... — This study explores the evolving ethical issues surrounding optogenetics' potential harm to participants within trial design, especially focusing on whether Phase 1 trials should incorporate efficacy as well as safety endpoints in ways that are fair and respectful to research trial participants.
[131] 7 Ethical Issues Raised by Recent Developments in Neuroscience: The ... — By allowing specific neurons (e.g., STN neurons) to be manipulated in a known direction (e.g., excited), optogenetics avoids these problems, offering the potential to understand the mechanism of action of eDBS and identifying beneficial stimulation parameters, both of which would improve eDBS therapy (Gradinaru, Mogri, et al., 2009; Kravitz et al., 2010). Genetically modifying somatic cells to treat diseases is generally considered potentially ethical as long as standard issues are addressed (i.e., safety, risk–benefit calculation, protection of vulnerable subjects, informed consent, patient monitoring, and equity of access; National Academies of Sciences, 2017; Cavaliere, 2019; Coller, 2019), including by the public (Condit, 2010; Robillard et al., 2014). In light of this, a novel ethical issue raised by optogenetics involves considering the ethical requirements for clinical trials of oDBS (Gilbert et al., 2014).
[132] PDF — Keywords Neuronal optogenetic · Cerebral organoids · Ethics · Law · Regulation · Translation Introduction Neuronal optogenetics raises (medico-) ethical and legal questions as well as questions of social acceptance due to the investigated objects, the methods of research, and the pos-sible application in humans. To enable the use of the medical 1515 Pflügers Archiv - European Journal of Physiology (2023) 475:1505–1517 1 3 potential of neuronal optogenetics, for which translation into clinical application is a prerequisite, it is necessary to bring the open ethical and legal questions into a broad and open discourse with all involved stakeholders.
[133] Neurotechnology: Current Developments and Ethical Issues — Keywords: neurotechnology and brain-machine interface, ethics, self, personhood, deep brain stimulation However, changes to personality can also be an unintended side effect of brain intervention, as occasionally reported in PD patients receiving DBS. Along similar lines, the concept of a person can provide an ethical benchmark, assuming that we do not want to impair personal capabilities such as autonomy and responsibility by interventions in the brain. Current developments in stimulation technology based on optogenetics raise ethical concerns, not only regarding the acceptability of interventions in the brain and their consequences, but also in view of the necessary genetic modifications of the organism. 10.1093/brain/aww286 [DOI] [PMC free article] [PubMed] [Google Scholar]
[150] PDF — Keywords Neuronal optogenetic · Cerebral organoids · Ethics · Law · Regulation · Translation Introduction Neuronal optogenetics raises (medico-) ethical and legal questions as well as questions of social acceptance due to the investigated objects, the methods of research, and the pos-sible application in humans. To enable the use of the medical 1515 Pflügers Archiv - European Journal of Physiology (2023) 475:1505–1517 1 3 potential of neuronal optogenetics, for which translation into clinical application is a prerequisite, it is necessary to bring the open ethical and legal questions into a broad and open discourse with all involved stakeholders.
[152] Taking Optogenetics into the Human Brain: Opportunities and Challenges ... — An implantable medical device is also required that is capable of delivering sufficient optical stimulation to produce a clinical effect without damaging the underlying brain tissue.11 Despite these challenges, several groups are currently working towards the first-in-human application of optogenetics in the human brain, and the first human trials are likely to occur within the next decade. A review of the benefits and risks suggests that the first clinical study for an optogenetic therapy should be of both the gene therapy and the implanted device together, and should be of sufficient duration to provide meaningful data on safety and efficacy.
[153] Regulations: Good Clinical Practice and Clinical Trials | FDA — U.S. Food and Drug Administration ================================= Search Menu Search FDA Submit search Featured Report a Product Problem Contact FDA FDA Guidance Documents Recalls, Market Withdrawals and Safety Alerts Press Announcements Warning Letters Advisory Committees En Español Products Food Drugs Medical Devices Radiation-Emitting Products Vaccines, Blood, and Biologics Animal and Veterinary Cosmetics Tobacco Products Topics About FDA Combination Products Regulatory Information Safety Emergency Preparedness International Programs News and Events Training and Continuing Education Inspections and Compliance Science and Research Information For Consumers Patients Industry Health Professionals Federal, State and Local Officials In this section: Clinical Trials and Human Subject Protection Clinical Trials and Human Subject Protection BIMO Inspection Metrics HSP/BIMO Initiative Good Clinical Practice (GCP) Inspection Collaboration with International Regulators for Drug Development ICH Guidance Documents Regulations: Good Clinical Practice and Clinical Trials Clinical Trials Guidance Documents Clinical Investigations Compliance & Enforcement FDA's Role: ClinicalTrials.gov Information Good Clinical Practice Educational Materials Report Problems to FDA Reporting Complaints Related to FDA-Regulated Clinical Trials Good Clinical Practice Inquiries Home Science & Research Science and Research Special Topics Clinical Trials and Human Subject Protection Regulations: Good Clinical Practice and Clinical Trials Clinical Trials and Human Subject Protection Regulations: Good Clinical Practice and Clinical Trials Subscribe to Email Updates Share Post Linkedin Email Print FDA Regulations Relating to Good Clinical Practice and Clinical Trials Here are links to FDA regulations governing human subject protection and the conduct of clinical trials. Electronic Records; Electronic Signatures (21 CFR Part 11) Regulatory Hearing Before the Food and Drug Administration (21 CFR Part 16) Protection of Human Subjects (Informed Consent) (21 CFR Part 50) Financial Disclosure by Clinical Investigators (21 CFR Part 54) Institutional Review Boards (21 CFR Part 56) Good Laboratory Practice for Nonclinical Laboratory Studies (21 CFR Part 58) Investigational New Drug Application (21 CFR Part 312) Applications for FDA Approval to Market a New Drug (21 CFR Part 314) Bioavailability and Bioequivalence Requirements (21 CFR Part 320) New Animal Drugs for Investigational Use (21 CFR Part 511) New Animal Drug Applications (21 CFR Part 514) Applications for FDA Approval of a Biologic License (21 CFR Part 601) Investigational Device Exemptions (21 CFR Part 812) Premarket Approval of Medical Devices (21 CFR Part 814) Preambles to GCP Regulations Each time Congress enacts a law affecting products regulated by the Food and Drug Administration, the FDA develops rules to implement the law. The FDA takes various steps to develop these rules, including publishing a variety of documents in the Federal Register announcing the FDA's interest in formulating, amending or repealing a rule, and offering the public the opportunity to comment on the agency's proposal. The documents posted below include the various publications that contributed to the development of final rules related to FDA's regulations on good clinical practice and clinical trials.
[155] Optogenetics Tools | Precision, Control & Neuroscience Breakthroughs — The precision of optogenetics comes from its tools and techniques, which include: Light Sources: LED arrays and lasers that can be precisely controlled in terms of intensity, wavelength, and timing. Genetic Engineering: Methods to introduce light-sensitive proteins into specific types of neurons using viral vectors or transgenic animals.
[170] Optogenetics: 10 years of microbial opsins in neuroscience — Optogenetics is the combination of genetic and optical methods to cause or inhibit well-defined events in specific cells of living tissue and behaving animals 1. This technology, as employed today to study the neural circuit underpinnings of behavior, most commonly involves three core features: (i) microbial opsins, members of an ancient, but uniquely well-suited, gene family adapted from
[171] The Microbial Opsin Family of Optogenetic Tools: Cell — The capture and utilization of light is an exquisitely evolved process. The single-component microbial opsins, although more limited than multicomponent cascades in processing, display unparalleled compactness and speed. Recent advances in understanding microbial opsins have been driven by molecular engineering for optogenetics and by comparative genomics. Here we provide a Primer on these
[179] Optical Control of Genome Editing by Photoactivatable Cas9 — Combining the CRISPR-Cas9 with optogenetics technology, we have engineered photoactivatable Cas9 to precisely control the genome sequence in a spatiotemporal manner. Here we provide a detailed protocol for optogenetic genome editing experiments using photoactivatable Cas9, including that for the generation of guide RNA vectors, light-mediated
[181] Light-induced expression of gRNA allows for ... - Oxford Academic — Since optogenetics is ideally suited for precise spatiotemporal control, optogenetic CRISPR has emerged as a promising method for spatiotemporal gene editing. Most current optogenetic CRISPR systems are based on light-induced dimerization of split-Cas [ 1 ], dimerization of Cas with effectors [ 1-5 ], single-chain modified Cas proteins [ 6
[182] Photoactivatable CRISPR-Cas9 for optogenetic genome editing — The genome editing activity of CRISPR-Cas9 can be switched on and off by light using split Cas9 fragments fused tophotoinducible dimerization domains. We describe an engineered photoactivatable
[198] Optogenetics in medicine: innovations and therapeutic applications — In this review, we highlight recent advances in optogenetic tools and their applications across a range of medical conditions, including vision restoration in retinitis pigmentosa via light-activated ion channels, precise immune response modulation in cancer immunotherapy, and blood glucose management in diabetes through controllable drug release. This ability to precisely traceless control biological functions with high spatial and temporal resolution has established optogenetics as a powerful tool in disease treatment, expanding its applications far beyond its origins in neuroscience into various areas of biological research such as gene expression control , genome editing , and biomedicine, including phototherapy for blindness , metabolic , oncological diseases , and so on.
[200] Recent advances in optogenetics and pharmacogenetics - PMC — Recent advances in optogenetics and pharmacogenetics. Gary Aston-Jones a, * and Karl Deisseroth b ... They find that optogenetic inhibition of infralimbic cortex in rats reveals a surprisingly complex role of this area in regulating habitual behavior, perhaps involving rapid neuroplasticity during or after optogenetic inhibition of IL neurons.
[202] Optogenetic approaches to evaluate striatal function in animal models ... — Yet, it is clear that if we aim to inspire new treatments for PD, there is a great need for further optogenetic exploration of striatal circuitry and function in animal models. Looking forward, optogenetics can be used to pave the way for emerging technologies to adaptively stimulate brain circuitry in diseases of impaired motor and cognitive
[203] Using Optogenetic Dyadic Animal Models to Elucidate the Neural Basis ... — Optogenetics is a revolutionary technology that permits genetically defined, light-based control of neural circuits, ... allowing experimental control of neural activity—and the cognitive functions that these neural circuits subserve—at the flick of a light switch. Animal models have long been used to study basic learning and social
[204] Optogenetic approaches to evaluate striatal function in animal models ... — Elucidating how neuronal and behavioral functions are influenced and potentially rescued by optogenetic manipulation in animal models could prove to be translatable to humans. These insights can be used to guide future brain-stimulation approaches for motor and cognitive abnormalities in Parkinson disease and other neuropsychiatric diseases.
[205] An Engineering Platform for Clinical Application of Optogenetic Therapy ... — In the past several years, optogenetics has advanced into an early clinical stage, and promising results have been reported. At the current stage, there is an urgent need to develop hardware and software for clinical training, testing, and rehabilitation in optogenetic therapy, which is beyond the capability of existing ophthalmic equipment.
[206] Optogenetics in medicine: innovations and therapeutic applications — This review provides an overview of the latest advancements in the therapeutic applications of optogenetics, with a particular focus on vision restoration, diabetes management, cancer therapy, and bioelectric medicine. Additionally, it discusses the challenges and future directions for translating these findings into clinical practice.
[207] Optogenetics and Targeted Gene Therapy for Retinal Diseases ... — Having partially leveraged the challenges limiting their prompt introduction into the clinical practice (i.e., engineering, cell or tissue delivery capabilities), it is crucial to deepen the fields of knowledge applied to optogenetics and targeted gene therapy.
[208] Optogenetics in medicine: innovations and therapeutic applications — In this review, we highlight recent advances in optogenetic tools and their applications across a range of medical conditions, including vision restoration in retinitis pigmentosa via light-activated ion channels, precise immune response modulation in cancer immunotherapy, and blood glucose management in diabetes through controllable drug release. This ability to precisely traceless control biological functions with high spatial and temporal resolution has established optogenetics as a powerful tool in disease treatment, expanding its applications far beyond its origins in neuroscience into various areas of biological research such as gene expression control , genome editing , and biomedicine, including phototherapy for blindness , metabolic , oncological diseases , and so on.
[209] Taking Optogenetics into the Human Brain: Opportunities and Challenges ... — An implantable medical device is also required that is capable of delivering sufficient optical stimulation to produce a clinical effect without damaging the underlying brain tissue.11 Despite these challenges, several groups are currently working towards the first-in-human application of optogenetics in the human brain, and the first human trials are likely to occur within the next decade. A review of the benefits and risks suggests that the first clinical study for an optogenetic therapy should be of both the gene therapy and the implanted device together, and should be of sufficient duration to provide meaningful data on safety and efficacy.