Advances in Ophthalmic Optogenetics: Approaches and Applications

Abstract

Recent advances in optogenetics hold promise for vision restoration in degenerative eye diseases. Optogenetics refers to techniques that use light to control the cellular activity of targeted cells. Although optogenetics is a relatively new technology, multiple therapeutic options are already being explored in pre-clinical and phase I/II clinical trials with the aim of developing novel, safe, and effective treatments for major blinding eye diseases, such as glaucoma and retinitis pigmentosa. Optogenetic approaches to visual restoration are primarily aimed at replacing lost or dysfunctional photoreceptors by inserting light-sensitive proteins into downstream retinal neurons that have no intrinsic light sensitivity. Such approaches are attractive because they are agnostic to the genetic causes of retinal degeneration, which raises hopes that all forms of retinal dystrophic and degenerative diseases could become treatable. Optogenetic strategies can also have a far-reaching impact on translational research by serving as important tools to study the pathogenesis of retinal degeneration and to identify clinically relevant therapeutic targets. For example, the CRY-CIBN optogenetic system has been recently applied to animal models of glaucoma, suggesting a potential role of OCRL in the regulation of intraocular pressure in trabecular meshwork. As optogenetic strategies are being intensely investigated, it appears crucial to consider the opportunities and challenges such therapies may offer. Here, we review the more recent promising optogenetic molecules, vectors, and applications of optogenetics for the treatment of retinal degeneration and glaucoma. We also summarize the preliminary results of ongoing clinical trials for visual restoration.

Gene Therapy for Inherited Retinal Diseases: From Laboratory Bench to Patient Bedside and Beyond

“…The hypothesis of optogenetics involves transforming viable retinal cells, specifically ganglion cells, into artificial photoreceptors. These photoreceptors can respond to specific wavelengths of light projected by an optical device worn by the patient and generate electric signals transmitted to the brain, resulting in the perception of a binary image [ 31 , 32 ]. Optogenetics with ChrimsonR differs from Luxturna-based gene therapy.…”

Applications and challenges of rhodopsin-based optogenetics in biomedicine

“…This is the first successful optogenetics case in neurodegenerative disease (Sahel et al, 2021). In addition, four companies have promoted ophthalmic optogenetics in clinical trials: (1) GenSight Biologics, GS030(Paris, France), (2) Allergan, RST-001 (Dublin, Ireland), (3) Bionic Sight, BS01(New York, NY, USA), and (4) Nanoscope Therapeutics, vMCO-010 (Bedford, TX, USA) (Prosseda et al, 2022). Although optogenetics has advanced our ability to effect the recovery of visual acuity, there are marked differences between optogenetic vision and natural vision.…”

Camouflage Nanoparticles Enable in Situ Bioluminescence-Driven Optogenetic Therapy of Retinoblastoma

“…Retinoblastoma (RB) is a rare childhood retinal cancer that can develop sporadically or heritably and is fatal if left untreated . Radiotherapy, chemotherapy, local treatments (such as cryotherapy and laser photocoagulation), and oophorectomy are currently used in clinical practice. − Among these, chemotherapy raises the risk of secondary cancer to retinoblastoma. , Other treatment methods might cause retinal toxicity and severe vision damage, with complications such as optic nerve hemorrhage and necrosis. , A consensus has been achieved that the development of targeted therapeutic strategies capable of eradicating tumors while remaining safe for the retina will significantly improve the quality of life of RB patients. , Recently, optogenetic tools have emerged as a powerful technology to spatiotemporally manipulate protein activity for treating a wide range of diseases, including retinal degenerative diseases, − glaucoma, − and uveal melanoma . Generally, they leverage blue-light illumination to activate photoswitches, which in turn control the activity of cellular proteins. − Typically, these photoswitches are activated by the illumination of blue light from external flashlights, implanting micro-light-emitting diodes (LEDs) into tissues or inserting fiber optics into tissues, followed by the recruitment of the functional domains to the promoter region of interest or the plasma membrane. − ,− However, because blue light is easily scattered and absorbed in tissues, it rarely penetrates deep into mammalian tissues .…”

“…6,7 A consensus has been achieved that the development of targeted therapeutic strategies capable of eradicating tumors while remaining safe for the retina will significantly improve the quality of life of RB patients. 8,9 Recently, optogenetic tools have emerged as a powerful technology to spatiotemporally manipulate protein activity for treating a wide range of diseases, including retinal degenerative diseases, 10−12 glaucoma, 13−15 and uveal melanoma. 16 Generally, they leverage bluelight illumination to activate photoswitches, which in turn control the activity of cellular proteins.…”