- How does optogenetics work?
- Is it available to patients now?
- Is it safe?
- Related experimental treatments
The human retina contains photoreceptor cells which detect light coming into the eye and converting it into electrical signals. These signals are transmitted along other specialised cells in the retina, the optic nerve and eventually reaching the brain to generate a visual image (what we see). The reason that our photoreceptors but not the other cells in the retina are able to detect light is because of a light sensitive protein called opsin.
In the advanced stages of many inherited retinal diseases, photoreceptors are usually damaged but other cells involved in transmitting the generated electrical signal tend to remain intact. These cells are collectively called inner retinal cells. Optogenetics is a new approach that aims to restore some level of vision by conferring light-detection ability to the inner retinal cells.
The key to this approach is having the surviving inner retinal cells produce light-sensitive opsin. Gene therapy principles are utilised to achieve this. Firstly, a gene containing instructions to make the opsin protein is “packaged” into a harmless virus, usually the adeno-associated virus (AAV). The virus containing this gene is then injected into the retina using a common outpatient technique called intravitreal injections. As a result, the inner retinal cells are able to detect light and generate some level of vision.
Optogenetics mainly aims to restore some sight to patients with advanced or end-stage retinal degenerations where most of the photoreceptor cells are damaged. The safety and potential visual benefits of optogenetics in humans are currently being investigated in three phase 1/2 clinical trials (NCT 02556736, NCT 03326336, NCT 04278131) for patients with end-stage retinitis pigmentosa. If shown to be safe and effective, optogenetics may be potentially applied to other inherited retinal conditions where the photoreceptors undergo extensive damage.
Safety data is unavailable yet as all the listed optogenetics trials are still ongoing. However, the safety profile of the AAV vector is well established based on previous retinal gene therapy trials, the most notable being Luxturna which was approved for the treatment of another inherited retinal condition called Leber congenital amaurosis (LCA) caused by mutations in the RPE65 gene. Furthermore, intravitreal injection is a safe and common procedure performed by many eye doctors worldwide for the treatment of age-related macular degeneration (AMD).
1) Unknown long-term side effects and therapeutic effect
Although AAV mediated gene therapy seems to be safe whilst sustaining its treatment effect in the short term, its long term outlook is unknown with the longest follow-up being only 4 years.[2-4] Hence, long-term follow-up studies of other gene therapy trials will be of interest here.
2) The ideal opsin protein has not been identified yet
Sources of opsin protein used in optogenetics can be broadly divided into two categories:
- Those obtained from micro-organisms (examples include channelrhodopsin and halorhoropsin)
- Those obtained from mammals (examples include rhodopsin and melanopsin)
Each of these opsins has their own characteristics but in general, opsins from micro-organisms tend operate in light levels below our normal vision but are able to generate electrical signals rapidly, closely mimicking human photoreceptors. On the other hand, mammalian opsins operate in light levels closer to our normal vision but generate electrical signals at a slower rate. Opsins that are currently being tested in the aforementioned clinical trials are either channelrhodopsin or halorhodopsin.
In addition to the inherent properties of each opsin, the type of inner retinal cells being targeted for optogenetics also affects the quality of the vision generated. Electrical signals originating from cells situated closer to the photoreceptors such as the bipolar cells tend to generate better visual quality but may be more challenging technically to target. Cells further away from the photoreceptors such as the ganglion cells can be easily and safely targeted with intravitreal injections but the visual quality may not be as good.
- Russell S, Bennett J, Wellman JA, et al. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet. 2017;390(10097):849-860
- Ramlogan-Steel CA, Murali A, Andrzejewski S, Dhungel B, Steel JC, Layton CJ. Gene therapy and the adeno-associated virus in the treatment of genetic and acquired ophthalmic diseases in humans: Trials, future directions and safety considerations. Clin Exp Ophthalmol. 2019;47(4):521-536
- Healio Ocular Surgery News. Improvements maintained at 4 years after Luxturna administration. https://www.healio.com/ophthalmology/pediatrics-strabismus/news/online/%7B12b99224-aa31-46e3-b05e-f91affea1a0e%7D/improvements-maintained-at-4-years-after-luxturna-administration. Published 2019. Accessed 18 December 2019
- GenSight Biologics. GenSight Biologics reports positive 96-week data from REVERSE Phase III clinical trial of GS010 for the treatment of Leber Hereditary Optic Neuropathy (LHON). https://www.gensight-biologics.com/2019/05/15/gensight-biologics-reports-positive-96-week-data-from-reverse-phase-iii-clinical-trial-of-gs010-for-the-treatment-of-leber-hereditary-optic-neuropathy-lhon/?cn-reloaded=1. Published 2019. Accessed 18 December 2019
- Simunovic MP, Shen W, Lin JY, Protti DA, Lisowski L, Gillies MC. Optogenetic approaches to vision restoration. Exp Eye Res. 2019;178:15-26
- Chaffiol A, Duebel J. Mini-Review: Cell Type-Specific Optogenetic Vision Restoration Approaches. Adv Exp Med Biol. 2018;1074:69-73