Optogenetics for retinal disease

For decades, I had to deliver the difficult message to patients with inherited retinal diseases (IRDs) that there was no treatment available for them. The cruel reality was that their condition would continue to cause irreversible vision loss.¹ In 2017, voretigene neparvovec-rzyl (Luxturna; Spark Therapeutics) was the first in human gene therapy to receive US approval for Leber congenital amaurosis (LCA) due to biallelic RPE65 mutation. This ushered in a new era of gene therapy across medicine. LCA is one of hundreds of genetically characterized IRDs. The population with LCA is limited; about 1000 to 2000 individuals in the US are affected.² Although I still communicate to patients with other IRDs that no treatment is available for their conditions, I now can say one may be on the horizon. Optogenetics offers a promising mutation-agnostic approach to gene therapy, helping us deliver hope to more patients.

IRDs: Leading cause of blindness

Degenerative retinal disease progressively damages the photoreceptors responsible for capturing light and transmitting visual signals to the brain. Generally—and because of associated and progressive vision loss—IRDs are considered a degenerative disease.

Studies show that IRDs account for about 20% to 25% of the world’s blindness in the working-age population.^3,4 The most common IRD is retinitis pigmentosa (RP).⁵ RP is generally characterized by retinal pigmentary changes and a gradual loss of night and peripheral vision. Black peripheral retinal “bone spicules” are a classic clinical feature, but pigmentary changes may be subtle to absent. Patients often progress to complete blindness.⁶ Stargardt disease—often caused by ABCA4 mutation—is another type of IRD clinically characterized by yellow flecks in the macula and retinal midperiphery, progressing to macular “beaten bronze” atrophic changes, leading to central vision loss,⁷ and severely impacting daily tasks like reading and recognizing faces.⁸

Despite the prevalence and impact of RP and Stargardt disease, treatment options remain limited. This is especially true for individuals with advanced vision loss.

What is optogenetics?

Optogenetics uses gene therapy strategies to introduce light-sensitive transmembrane proteins called opsins into the retina. Unlike gene replacement therapies targeting specific genetic mutations, optogenetics is both mutation- and disease-agnostic. Optogenetic strategies use remaining retinal cells (eg, bipolar and ganglion cells) to regain light sensitivity and restore a degree of functional vision,⁹ opening new possibilities for individuals with severe vision loss and potentially transforming the management of conditions such as RP and Stargardt disease.

Table 1

The field of optogenetics is evolving. Current therapies in development include, in order of most advanced clinical status to preclinical therapies, MCO-010 (Nanoscope Therapeutics), RST-001 (RetroSense/Allergan), GS030 (GenSight Biologics), BS01 (Bionic Sight), and RTx-015 (Ray Therapeutics). These therapies differ with respect to their cellular targets, kinetics, and spectral and light sensitivity (Table 1).

The most advanced optogenetic in development is MCO-010. Multicharacteristic opsin (MCO) is a transgene for a high-performing opsin that sensitizes bipolar cells to light.^10-12 It is sensitive across the visible light spectrum, has rapid kinetics for tracking movement, and responds to ambient light levels. It is delivered by a proprietary adeno-associated virus (AAV2) in a single office-based intravitreal injection and, unlike some other treatments in development, does not require a light-intensifying device to mimic photoreceptor function (Figure 1). In a phase 1/2a clinical study, intravitreal treatment with MCO-010 has demonstrated restoration of vision in patients with advanced RP.¹³

Figure 1

In RESTORE (NCT04945772), a randomized, multicenter, sham-controlled phase 2 clinical trial of 27 patients with severe vision loss from advanced RP, no better than logMAR +1.9 (20/1600 Snellen equivalent, counting fingers), MCO-010 demonstrated a clinically meaningful improvement in vision. Patients received either a single intravitreal injection (IVT) of a high- or low-dose MCO-010 or sham IVT. At the 52-week primary end point, approximately 40% of patients who received MCO-010 experienced a mean change in best-corrected visual acuity (BCVA) improvement from baseline of at least +0.3 logMAR, equivalent to 3 lines of Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity improvement, which was statistically significant in both the high- and low-dose MCO-010 groups compared with the sham (Figure 2).

Figure 2

Vision gains were durable, with sustained results at the 76-week key secondary end point. Vision improvement relative to baseline continued to be observed through 2.5 years, including about a 5× greater BCVA area under the curve at the end of 126 weeks in both groups treated with MCO-010 vs those treated with sham. The difference was statistically significant. MCO-010 was well tolerated, and there were no serious or severe adverse events, including severe inflammation, vasculitis, and hypotony. Although inflammation was seen in some patients, it was effectively treated with topical steroids. Based on these results, Nanoscope is preparing a biologics licensing application for marketing approval through the FDA. Additionally, a phase 4 RP postapproval study will begin later in 2025.

What makes MCO-010 particularly exciting is its visible light sensitivity and fast on-and-off kinetics. Unlike other optogenetic therapies that require external laser-stimulation goggles or a light amplification device, MCO-010 works with ambient light. This significantly enhances the therapy’s practicality for patients in their everyday lives.

Expanding the reach of optogenetics

Although the focus has been on RP, the use of MCO-010 for Stargardt disease is also under investigation. Early clinical data in this population show promising improvements in visual acuity and functional vision. In the open-label, phase 2 STARLIGHT study (NCT05417126) enrolling 6 individuals with severe vision loss (visual acuity no better than 20/800) from advanced Stargardt disease, MCO-010 continued to show a positive safety profile with improvements in visual function across multiple parameters such as visual acuity, visual field, and patient-reported outcome measures. The findings in STARLIGHT support continued development. A randomized, controlled phase 3 registrational study will begin dosing this year. MCO-020 (Nanoscope Therapeutics) is under an investigational new drug (IND)–ready phase for geographic atrophy (GA).

Companies like Ray Therapeutics and GenSight Biologics are also advancing optogenetic programs that target retinal ganglion cells. A phase 1 study (NCT06460844) of RTx-015 (Ray Therapeutics) for RP is under way to evaluate the safety and preliminary efficacy of a single uniocular intravitreal injection. Up to 3 dose cohorts are planned. RTx-021 (Ray Therapeutics) is under an IND-enabling study phase for GA and Stargardt disease. BS01 (Bionic Sight) and GS030 (GenSight Biologics) combine optogenetic therapy with goggles enabling laser stimulation of the transduced ganglion cells. GenSight has initiated a dose-escalation study to evaluate the safety and tolerability of GS030 in patients with RP and plans to investigate the potential for GS030 to treat GA thereafter.

Each optogenetics approach has unique advantages. As the field progresses, we will better understand how best to tailor these therapies for different retinal conditions.

Paradigm shift and potential for a brighter future

Optogenetics represents a potential paradigm shift for retina specialists. Historically, our role was limited to monitoring disease progression and offering low-vision support for patients with IRDs. An approved optogenetic therapy may deliver an opportunity to restore some functional vision in some patients with significant vision loss.

From a clinical perspective—and if an optogenetic strategy is approved—we will need to study and understand who the most suitable candidates for optogenetic therapy will be and who will most likely benefit. Additionally, managing patient expectations and providing comprehensive counseling on potential outcomes will be essential.

Integrating potential optogenetic treatments into clinical practice will require ongoing education and collaboration within the ophthalmology community. Retina specialists will be key in posttreatment care, monitoring patients for efficacy and safety and collaborating with low-vision specialists to maximize functional outcomes.

The prospect of offering mutation-agnostic vision restoration to a population that has long been without options is exciting. For the countless patients with RP, Stargardt disease, and other IRDs without current available treatment, we may be able to provide hope and brighter days based on randomized controlled clinical trial evidence.

References

1. Retinal degeneration. Chapter: Stem cell therapy and retinal regeneration. Science Direct. Accessed March 18, 2025. https://www.sciencedirect.com/topics/neuroscience/retinal-degeneration

2. Hu ML, Edwards TL, O’Hare F, et al. Gene therapy for inherited retinal diseases: progress and possibilities. Clin Exp Optom. 2021;104(4):444-454. doi:10.1080/08164622.2021.1880863

3. Crewe JM, Morlet N, Morgan WH, et al. Mortality and hospital morbidity of working-age blind. Br J Ophthalmol. 2013;97(12):1579-1585. doi:10.1136/bjophthalmol-2013-303993

4. Liew G, Michaelides M, Bunce C. 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. 2014;4(2):e004015. doi:10.1136/bmjopen-2013-004015

5. Inherited retinal dystrophies including retinitis pigmentosa. Royal National Institute of Blind People. Reviewed October 12, 2022. Accessed March 18, 2025. https://www.rnib.org.uk/your-eyes/eye-conditions-az/retinitis-pigmentosa

6. Diagnosis, clinical trials and treatments for inherited retinal diseases. Mayo Clinic. October 14, 2023. Accessed March 18, 2025. https://www.mayoclinic.org/medical-professionals/ophthalmology/news/diagnosis-clinical-trials-and-treatments-for-inherited-retinal-diseases/mac-20556115

7. Stargardt disease. National Eye Institute. Updated December 4, 2024. Accessed March 18, 2025. https://www.nei.nih.gov/learn-about-eye-health/eye-conditions-and-diseases/stargardt-disease

8. Stargardt disease. Royal National Institute of Blind People. Updated February 1, 2024. Accessed March 18, 2025. https://www.rnib.org.uk/your-eyes/eye-conditions-az/stargardt-disease

9. Wood EH, Kreymerman A, Kowal T, et al. Cellular and subcellular optogenetic approaches towards neuroprotection and vision restoration. Prog Retin Eye Res. 2023;96:101153. doi:10.1016/j.preteyeres.2022.101153

10. Wright W, Gajjeraman S, Batabyal S, et al. Restoring vision in mice with retinal degeneration using multicharacteristic opsin. Neurophotonics. 2017;4(4):041505. doi:10.1117/1.NPh.4.4.041505

11. Batabyal S, Gajjeraman S, Pradhan S, Bhattacharya S, Wright W, Mohanty S. Sensitization of ON-bipolar cells with ambient light activatable multi-characteristic opsin rescues vision in mice. Gene Ther. 2021;28(3-4):162-176. doi:10.1038/s41434-020-00200-2

12. Batabyal S, Kim S, Carlson M, et al. Multi-characteristic opsin therapy to functionalize retina, attenuate retinal degeneration, and restore vision in mouse models of retinitis pigmentosa. Transl Vis Sci Technol. 2024;13(10):25. doi:10.1167/tvst.13.10.25

13. Mohanty SK, Mahapatra S, Batabyal S,et al. A synthetic opsin restores vision in patients with severe retinal degeneration. Mol Ther. 2025;33(5):2279-2290. doi:10.1016/j.ymthe.2025.03.031

Allen C. Ho, MD, FACS, FASRS, is director of retina research, Mid Atlantic Retina, Wills Eye Hospital, and professor of ophthalmology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia. Ho is a consultant and/or receives grant funding from Adverum Biotechnologies, Apellis Pharmaceuticals, AsclepiX Therapeutics, Astellas Pharma, Clearside Biomedical, Genentech/Roche, Gyroscope Therapeutics, Kodiak Sciences, Lineage, Nanoscope Therapeutics, and Regenxbio.

E: acho@midatlanticretina.com