Timothy Flanagan

Background:  Retinitis Pigmentosa (RP) is a common type of Inherited Retinal Disorder (IRD) with a variety of presentations that lead to vision loss, typically with early loss of peripheral and night vision, followed by progressive loss of vision.¹  As a genetic disease, gene therapy approaches have proved effective, particularly targeting the RPE65 mutation, but this approach requires the presence of functional retinal cells and only treats one of the many mutations, over 70+, that can cause RP.¹  Optogenetics, on the other hand, delivers light-sensitive proteins (channelrhodopsins + promoters) via viral particles that are transduced into surviving secondary or tertiary cells in the retina.  These are then expressed when exposed to light, restoring function.¹  There are many potential target cells in the retina, including Retinal Ganglion Cells (RGCs), Bipolar Cells (BCs), and Amacrine Cells (ACs).^1,3,4

Objectives:  In this review, I explored the benefits, mechanisms, and clinical applications of optogenetic therapy for Retinosa Pigmentosa.

Search Methods: An online search in the PubMed Database was conducted from 2017-2025 with the following keywords:  “Optogenetics”, “Retinitis Pigmentosa”, “Retinal Ganglion Cells”, “Bipolar Cells”, and “Amacrine Cells”.

Results:  In one animal study, cytomegalovirus (CMV) and human gamma-synuclein gene (SNCG) and their resulting channelrhodopsin (CatCh) expression and light-mediated response were compared.¹  The promoter found to be the most ideal in both measures was the promoter inside the SNCG.  In macaques with the SNCG promoter, the activation threshold is “just below the radiation safety limits for the human eye.”¹  Adeno-associated virus (AAV) vectors are commonly used in animal studies and human clinical trials.⁷  The “sweet spot” of viral dosage appeared to be between 10⁸ vg and 10⁹, showing optimal transduction efficiency, visual acuity, and light sensitivity. Results showed that a 10⁹ vg viral dose or greater showed an increase in immune response, measured by GFAP and Iba1 immunoreactivity, despite the fact that the retina is an immune privileged tissue.⁷  In an open-label phase 1/2a PIONEER study, a study investigating optogenetic RGC-targeting treatment in patients with non-syndromic RP was conducted.⁶  Using ChrimsonR, a red-shifted channelrhodopsin with a peak sensitivity around 590 nm, was safer for the retina compared to blue-shifted channelrhodopsins.⁶  Weeks after vector injection,^, results of the study showed that the patient was able to perform basic visual and visuomotor tests.⁶  EEG recordings also showed stimulation of the primary visual coretex, showing efficacy.⁶  Other studies have shown potential advantages in the targeting of Bipolar Cells or Amacrine Cells, such as improved visual acuity and restoriation of wild-type vision.^3,4,5  However, practical difficulties, such as vector administration to these cells’ location, hinder this method.^3,4,5

Conclusions:  RGCs are typically seen as the ideal target in optogenetic therapy, but ACs and BCs may have advantages in future therapies.³  Further research into other targets is still needed.  Proper promoters, viral vectors, and channelrhodopsins are all needed for effective optogenetic therapy.^1,3

Works Cited:

1. Chaffiol, A., Caplette, R., Jaillard, C., et. al. (2017). A New Promoter Allows Optogenetic Vision Restoration with Enhanced Sensitivity in Macaque Retina. Molecular therapy : the journal of the American Society of Gene Therapy, 25(11), 2546–2560. https://doi.org/10.1016/j.ymthe.2017.07.011
2. Tanaka, T., Hososhima, S., Yamashita, Y., et. al. (2024). The high-light-sensitivity mechanism and optogenetic properties of the bacteriorhodopsin-like channelrhodopsin GtCCR4. Molecular cell, 84(18), 3530–3544.e6. https://doi.org/10.1016/j.molcel.2024.08.016
3. Rodgers, J., Hughes, S., Ebrahimi, A. et. al. (2025). Enhanced restoration of visual code after targeting ON bipolar cells compared with retinal ganglion cells with optogenetic therapy. Molecular therapy : the journal of the American Society of Gene Therapy, 33(3), 1264–1281. https://doi.org/10.1016/j.ymthe.2025.01.030
4. Khabou, H., Orendorff, E., Trapani, F., et. al. (2023). Optogenetic targeting of AII amacrine cells restores retinal computations performed by the inner retina. Molecular therapy. Methods & clinical development, 31, 101107. https://doi.org/10.1016/j.omtm.2023.09.003
5. Katada, Y., Kunimi, H., Serizawa, N., et. al. (2023). Starburst amacrine cells amplify optogenetic visual restoration through gap junctions. Molecular therapy. Methods & clinical development, 30, 1–13. https://doi.org/10.1016/j.omtm.2023.05.011
6. Sahel, JA., Boulanger-Scemama, E., Pagot, C. et al. Partial recovery of visual function in a blind patient after optogenetic therapy. Nat Med 27, 1223–1229 (2021). https://doi.org/10.1038/s41591-021-01351-4
7. Lu, Q., Wright, A. & Pan, ZH. AAV dose-dependent transduction efficiency in retinal ganglion cells and functional efficacy of optogenetic vision restoration. Gene Ther 31, 572–579 (2024). https://doi.org/10.1038/s41434-024-00485-7