Inherited retinal diseases (IRDs) can affect up to 1 in 3000 individuals and is believed to be one of the predominant causes of blindness in developed countries [1]. Recent advancements in biomedical engineering and gene therapy have created novel therapeutic solutions for patients with IRD. In the EU, there are four approved electronic retinal implants; in the US, there is one (the Argus II device) [2,3]. In 2017, the first Phase 3 clinical trial of a gene therapy for genetic disease concluded gene-replacement therapy modifying the RPE65 gene is a useful tool in correcting RPE65-mediated IRD [4]. However, there are significant limitations to these techniques. Electronic retinal implants provide only a limited field of vision and do not achieve the same resolution as the healthy retina; gene-modification approaches are only useful for patients with specific genotypes [2,3,5]. Optogenetics is a newer alternative in vision restoration approaches that shows promise because of its potential for superior spatial and temporal resolution [5]. This technique involves introducing a gene which encodes a light-sensitive protein to convert secondary neurons into photoreceptors [5].  

These light-sensitive proteins are called opsins; optogenetics techniques for vision restoration typically employ either microbial (type 1) or animal (type 2) opsins. Common microbial opsins are channelrhodopsins, halorhodopsins, and archeorhodopsins [6]. While halorhodopsins are sensitive to yellow light and archeorhodopsins are sensitive to green light, both lead to hyperpolarization. On the other hand, channelrhodopsins are sensitive to blue light and lead to depolarization, making them more useful in optogenetic treatments for blindness [3,7]. Animal opsins are encoded by the rhodopsin gene family; however, different species encode native opsins that respond to varying levels of light. For example, opsins from geckos and zebrafish maximally absorb blue light, while the cichlid opsin responds best to green light [8].  

Adenovirus-associated viral (AAV) vectors are preferred in optogenetics gene modification therapy for vision restoration because of their lack of pathogenicity; these genetic tools are engineered to encode type 1 and type 2 opsins, and induce the expression of the selected opsin once delivered to the retina. The methods for delivering these AAV vectors are intravitreal (IVT) or sub-retinal (SR) injection [3]. Intravitreal injections are some of the most common ocular procedures and are relatively safe, leading many retinal clinicians to feel comfortable with the technique [9]. However, virions delivered using this technique are more diluted in primates than rodents because of the larger volume of the vitreous; transduction efficiency using IVT injection also seems to be limited to the inner retinal cells [9,10]. Unlike IVT, SR injections are performed under general anesthesia and associated with a higher risk of complications (such as increased risk of cataract development and subconjunctival hemorrhage) [9]. In addition, delivery into the sub-retinal space requires the brief detachment of the retina, which is generally believed to have a detrimental effect on future retinal function [3]. Nonetheless, a preclinical study successfully delivered opsins through SR injection in a mouse model of retinal degeneration, leading to behavioral restoration of light avoidance and long-term improvements in a visually guided task [10].  

One of the first preclinical studies to produce structural and functional results in this field was completed in 2006. The researchers injected an AAV vector carrying channelrhodopsin using SR injection and found light-induced expression of these opsins in inner retinal neurons could restore some amount of functional ability after photoreceptor degeneration [11]. The authors demonstrated light-stimulated activation of channelrhodopsin receptors directly produces membrane depolarizations that mimic inner retinal cell activity, making this technique a feasible tool for restoring light sensitivity after retinal degeneration [11].  

A phase I/II clinical trial assessing the feasibility of GS030, an innovative combination of an AAV vector encoding channelrhodopsin and a biomimetic device stimulating the engineered retinal cells, is currently the first reported clinical adaption of the AAV findings in mice [12]. Further studies are needed to accurately gauge the benefits of optogenetics in vision restoration.  

References 

1. Liew, G., Michaelides, M., & Bunce, C. (2014). A Comparison of the Causes of Blindness Certifications in England and Wales in Working age Adults (16–64 years), 1999–2000 with 2009–2010. BMJ Open, 4(2), e004015. https://doi.org/10.1136/bmjopen-2013-004015 

2. Edwards, T. L., Cottriall, C. L., Xue, K., Simunovic, M. P., Ramsden, J. D., Zrenner, E., & MacLaren, R. E. (2018). Assessment of the Electronic Retinal Implant Alpha AMS in Restoring Vision to Blind Patients with End-stage Retinitis Pigmentosa. Ophthalmology, 125(3), 432–443. https://doi.org/10.1016/j.ophtha.2017.09.019  

3. Simunovic, M. P., Shen, W., Lin, J. Y., Protti, D. A., Lisowski, L., & Gillies, M. C. (2019). Optogenetic Approaches to Vision Restoration. Experimental Eye Research, 178, 15–26. https://doi.org/10.1016/j.exer.2018.09.003  

4. Russell, S., Bennett, J., Wellman, J. A., Chung, D. C., Yu, Z.-F., Tillman, A., Wittes, J., Pappas, J., Elci, O., McCague, S., Cross, D., Marshall, K. A., Walshire, J., Kehoe, T. L., Reichert, H., Davis, M., Raffini, L., George, L. A., Hudson, F. P., … Maguire, A. M. (2017). Efficacy and Safety of Voretigene Neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated Inherited Retinal Dystrophy: A Randomized, Controlled, Open-label, Phase 3 trial. The Lancet, 390(10097), 849–860. https://doi.org/10.1016/S0140-6736(17)31868-8  

5. Yue, L., Weiland, J. D., Roska, B., & Humayun, M. S. (2016). Retinal Stimulation Strategies to Restore Vision: Fundamentals and Systems. Progress in Retinal and Eye Research, 53, 21–47. https://doi.org/10.1016/j.preteyeres.2016.05.002  

6. Duebel, J., Marazova, K., & Sahel, J.-A. (2015). Optogenetics. Current Opinion in Ophthalmology, 26(3), 226–232. https://doi.org/10.1097/ICU.0000000000000140   

7. Lin, J. Y. (2011). A User’s Guide to Channelrhodopsin Variants: Features, Limitations and Future Developments. Experimental Physiology, 96(1), 19–25. https://doi.org/10.1113/expphysiol.2009.051961  

8. Yokoyama, S., & Tada, T. (2010). Evolutionary Dynamics of Rhodopsin Type 2 Opsins in Vertebrates. Molecular Biology and Evolution, 27(1), 133–141. https://doi.org/10.1093/molbev/msp217  

9. Ochakovski, G. A., Bartz-Schmidt, K. U., & Fischer, M. D. (2017). Retinal gene therapy: Surgical vector Delivery in the Translation to Clinical trials. Frontiers in Neuroscience, 11. https://www.frontiersin.org/article/10.3389/fnins.2017.00174  

10. De Silva, S. R., Barnard, A. R., Hughes, S., Tam, S. K. E., Martin, C., Singh, M. S., Barnea-Cramer, A. O., McClements, M. E., During, M. J., Peirson, S. N., Hankins, M. W., & MacLaren, R. E. (2017). Long-term Restoration of Visual Function in End-stage Retinal Degeneration using Subretinal Human Melanopsin Gene Therapy. Proceedings of the National Academy of Sciences, 114(42), 11211–11216. https://doi.org/10.1073/pnas.1701589114  

11. Bi, A., Cui, J., Ma, Y.-P., Olshevskaya, E., Pu, M., Dizhoor, A. M., & Pan, Z.-H. (2006). Ectopic expression of a Microbial-type Rhodopsin Restores Visual Responses in Mice with Photoreceptor Degeneration. Neuron, 50(1), 23–33. https://doi.org/10.1016/j.neuron.2006.02.026  

12. GenSight Biologics. (2021). A phase 1/2a,Open-label, Non-randomized, Dose-escalation Study to Evaluate the Safety and Rolerability of GS030 in Subjects with Retinitis Pigmentosa (Clinical Trial Registration No. NCT03326336). clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/NCT03326336