Guest Column | November 7, 2025

When One Gene Isn't Enough: The Case For Gene-Agnostic Vision Rescue

By Laura Erker, Ph.D.

Digital Eye-GettyImages-2184122570

The approval of voretigene neparvovec (Luxturna) marked a turning point in inherited retinal disease, proving that gene therapy can restore vision lost to a single defective gene.1-7 Yet for people with retinitis pigmentosa (RP), the story is far more complex. RP causes progressive vision loss due to the death of photoreceptors, light-sensitive neurons in the retina. RP encompasses more than 120 genes and countless private, ultra-rare, or family-specific, mutations that converge on a shared outcome: progressive vision loss.8-12

The genetic diversity of RP challenges the one-gene-one-therapy model and positions this retinal disease as a proving ground for the next generation of mutation-independent, or gene-agnostic, treatments designed to preserve or restore visual function across genotypes.

The Genetic Landscape Of Retinitis Pigmentosa

RP represents a spectrum of inherited disorders driven by disruptions across nearly every major retinal process, from phototransduction and ciliary transport to outer-segment renewal and RNA splicing.13-16 Some cases are syndromic, with systemic manifestations, such as hearing loss and renal or metabolic dysfunction, while others are confined to the eye.17

This genetic heterogeneity poses a major obstacle for therapy development. Gene-augmentation approaches work well for certain monogenic diseases but cannot feasibly scale across RP’s complex landscape.18 Many causative variants occur only in small subsets of patients, making tailored treatments impractical at the population level.9 Disease course in RP is also shaped by modifier genes, environmental stressors, and differences in cellular resilience. These influences alter how quickly and where degeneration unfolds, meaning that even when a causal mutation is corrected, downstream damage may continue, underscoring why single-gene solutions rarely suffice.19,20

Genomic analyses show extensive overlap between RP and other inherited retinal degenerations, revealing shared molecular pathways that drive cell death. This interconnected biology positions RP not as an exception but as a model for identifying interventions that preserve retinal stability across diverse inherited degenerations.21

Why Gene-Specific Strategies Fall Short

Voretigene neparvovec demonstrated that gene therapy can restore vision in patients with defined mutations,1,6 but most RP-associated genes are too large to fit within standard adeno-associated virus (AAV) vectors.22 Prime editing, a next-generation approach derived from CRISPR gene editing,23-26 has shown early safety in human trials such as Edit-101,27,28 but treatment efficacy remains modest, likely reflecting low editing efficiency in post-mitotic retinal cells. While these results support continued development, such approaches are currently limited to patients with well-characterized single-gene defects. For most individuals with RP — where causative variants remain unidentified or span diverse missense, nonsense, and splice-site mutations across dozens of genes — a single gene-targeted editing strategy remains out of reach.9

Beyond genetics, scalability remains a barrier. Developing a unique vector for each mutation group is unrealistic, as every construct demands separate optimization and regulatory review. Many programs therefore stall before late-phase development, leaving most patients without access to treatment.

Moreover, correcting a gene does not necessarily reverse the secondary processes that cause degeneration. Oxidative stress, inflammation, and glial activation might continue even with restoration of gene function.29 Additionally, genetic repair cannot restore function of cells that have already died.30 These challenges have shifted research toward therapies that protect or reactivate surviving retinal cells, regardless of mutation.

Emerging Gene-Agnostic Approaches

New therapeutic strategies are targeting biological mechanisms common to many RP genotypes, focusing on functional rescue rather than genetic correction.

Neuroprotection and metabolic support. Agents that mitigate oxidative stress,31,32 stabilize mitochondria,33-36 or modulate inflammation37-39 can prolong photoreceptor survival.21,3,40 Molecules such as N-acetylcysteine,41 its more bioavailable derivative N-acetylcysteine amide (NACA), and rod-derived cone-viability factors42 show potential to delay degeneration across diverse mutations. In parallel, stem cell–derived platforms such as those under development by jCyte and Ingel Therapeutics aim to deliver sustained neurotrophic support to the degenerating retina.

RNA-based modulation. Antisense oligonucleotides43-47, RNA editing (most notable is a human study in CEP-290 and Ush2A),48-55,18,56-58,28,59-64 and read-through technologies65-67 can repair or bypass transcriptional errors that recur across genes, expanding reach beyond single variants.68

Optogenetic reactivation. When photoreceptors are gone, light-sensitive proteins can be introduced into surviving inner-retinal neurons to restore photosensitivity.69 Early clinical trials have shown partial visual recovery using this approach.30

Cell-based therapy. Advances in stem cell differentiation enable transplantation of photoreceptor or retinal pigment epithelial cells capable of partial integration with host tissue.70-77 These approaches aim to rebuild complex retinal circuitry rather than repair DNA.78

Combination approaches. The future will likely combine modalities, protecting existing cells while adding light-responsive components.79 AAV gene therapy and nanoparticle vectors are being adapted for modular, multi-target payloads that operate independently of genotype.

Together, these strategies mark a shift from genetic repair to functional restoration, addressing retinal degeneration and stabilizing the retinal environment to slow and, hopefully one day, prevent further vision loss.

Translational Outlook And Future Directions

The move toward gene-agnostic therapy is reshaping discovery, trial design, and translation. A growing number of clinical programs are now translating these concepts into human studies, spanning antisense oligonucleotides (e.g., sepofarsen, ultevursen), optogenetic constructs (e.g., GS030), visual-cycle modulators that limit toxic retinoid accumulation (e.g., tinlarebant), and stem cell therapies. Each approach is entering distinct phases of evaluation with endpoints tailored to structure-function rescue. Collectively, these efforts exemplify how gene-agnostic concepts are shaping translational strategy, linking laboratory insight to real-world clinical implementation. For drug developers, success depends on building scalable platforms that act across genetic subtypes while measuring outcomes through standardized structural and functional biomarkers.

Traditional endpoints, such as best-corrected visual acuity and full-field sensitivity, often miss early or localized gains.80 As therapies act across cell types and disease stages, new biomarkers; structure-based retinal measurements (via optical coherence tomography imaging); individual photoreceptor quantification with adaptive optics; and functional measures, such as full field perimetry or microperimetry and mobility testing, are becoming valuable in this effort.81

Although this review focuses on molecular and translational strategies, the success of any gene-agnostic therapy also will hinge on how improvement is measured. The need for standardized sensitive endpoints capable of detecting early or localized functional gains represents a major area of ongoing work.

Clinically, participant selection is shifting from genotype toward residual cell viability and disease stage, broadening eligibility while preserving mechanistic precision. This evolution aligns with regulatory emphasis on patient-relevant outcomes and long-term safety.82

From a translational perspective, gene-agnostic platforms also enable efficiency. Programs can target multiple retinal diseases using shared delivery systems, biomarkers, and manufacturing frameworks, reducing costs for development and accelerating progress from discovery to clinic.76

Ultimately, the future of RP therapy will be defined not by which gene is corrected but by which visual functions are preserved or restored. Whether achieved through metabolic rescue, optogenetic activation, cell therapy, or combination approaches, progress will depend on developing mutation-independent strategies that maintain retinal integrity and measurable visual function across diverse genotypes.

References

  1. Bainbridge, J. W., Smith, A. J., Barker, S. S., Robbie, S., Henderson, R., Balaggan, K., Viswanathan, A., Holder, G. E., Stockman, A., Tyler, N., Petersen-Jones, S., Bhattacharya, S. S., Thrasher, A. J., Fitzke, F. W., Carter, B. J., Rubin, G. S., Moore, A. T., & Ali, R. R. (2008). Effect of gene therapy on visual function in Leber's congenital amaurosis. N Engl J Med, 358(21), 2231–2239. https://doi.org/10.1056/NEJMoa0802268
  2. Hauswirth, W. W., Aleman, T. S., Kaushal, S., Cideciyan, A. V., Schwartz, S. B., Wang, L., Conlon, T. J., Boye, S. L., Flotte, T. R., Byrne, B. J., & Jacobson, S. G. (2008). Treatment of leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial. Hum Gene Ther, 19(10), 979–990. https://doi.org/10.1089/hum.2008.107
  3. Le Meur, G., Stieger, K., Smith, A. J., Weber, M., Deschamps, J. Y., Nivard, D., Mendes-Madeira, A., Provost, N., Pereon, Y., Cherel, Y., Ali, R. R., Hamel, C., Moullier, P., & Rolling, F. (2007). Restoration of vision in RPE65-deficient Briard dogs using an AAV serotype 4 vector that specifically targets the retinal pigmented epithelium. Gene Ther, 14(4), 292–303. https://doi.org/10.1038/sj.gt.3302861
  4. Lorenz, B., Gyurus, P., Preising, M., Bremser, D., Gu, S., Andrassi, M., Gerth, C., & Gal, A. (2000). Early-onset severe rod-cone dystrophy in young children with RPE65 mutations. Invest Ophthalmol Vis Sci, 41(9), 2735–2742.
  5. Maguire, A. M., Simonelli, F., Pierce, E. A., Pugh, E. N., Jr., Mingozzi, F., Bennicelli, J., Banfi, S., Marshall, K. A., Testa, F., Surace, E. M., Rossi, S., Lyubarsky, A., Arruda, V. R., Konkle, B., Stone, E., Sun, J., Jacobs, J., Dell'Osso, L., Hertle, R.,…Bennett, J. (2008). Safety and efficacy of gene transfer for Leber's congenital amaurosis. N Engl J Med, 358(21), 2240–2248. https://doi.org/10.1056/NEJMoa0802315
  6. 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 randomised, controlled, open-label, phase 3 trial. Lancet, 390(10097), 849–860. https://doi.org/10.1016/S0140-6736(17)31868-8
  7. Veske, A., Nilsson, S. E., Narfstrom, K., & Gal, A. (1999). Retinal dystrophy of Swedish briard/briard-beagle dogs is due to a 4-bp deletion in RPE65. Genomics, 57(1), 57–61. https://doi.org/10.1006/geno.1999.5754
  8. Daiger, S. P., Sullivan, L. S., & Bowne, S. J. (2013). Genes and mutations causing retinitis pigmentosa. Clin Genet, 84(2), 132–141. https://doi.org/10.1111/cge.12203
  9. Ferrari, S., Di Iorio, E., Barbaro, V., Ponzin, D., Sorrentino, F. S., & Parmeggiani, F. (2011). Retinitis pigmentosa: genes and disease mechanisms. Curr Genomics, 12(4), 238–249. https://doi.org/10.2174/138920211795860107
  10. Manley, A., Meshkat, B. I., Jablonski, M. M., & Hollingsworth, T. J. (2023). Cellular and Molecular Mechanisms of Pathogenesis Underlying Inherited Retinal Dystrophies. Biomolecules, 13(2). https://doi.org/10.3390/biom13020271
  11. SP Daiger, B. R., J Greenberg, A Christoffels, W Hide. (1998). RetNet: Data services and software for identifying genes and mutations causing retinal degeneration. Invest. Ophthalmol.Vis. Sci., 39.
  12. Suleman, N. (2025). Current understanding on Retinitis Pigmentosa: a literature review. Front Ophthalmol (Lausanne), 5, 1600283. https://doi.org/10.3389/fopht.2025.1600283
  13. Tanackovic, G., Ransijn, A., Ayuso, C., Harper, S., Berson, E. L., & Rivolta, C. (2011). A missense mutation in PRPF6 causes impairment of pre-mRNA splicing and autosomal-dominant retinitis pigmentosa. Am J Hum Genet, 88(5), 643–649. https://doi.org/10.1016/j.ajhg.2011.04.008
  14. Wilkie, S. E., Vaclavik, V., Wu, H., Bujakowska, K., Chakarova, C. F., Bhattacharya, S. S., Warren, M. J., & Hunt, D. M. (2008). Disease mechanism for retinitis pigmentosa (RP11) caused by missense mutations in the splicing factor gene PRPF31. Mol Vis, 14, 683–690.
  15. Yin, J., Brocher, J., Fischer, U., & Winkler, C. (2011). Mutant Prpf31 causes pre-mRNA splicing defects and rod photoreceptor cell degeneration in a zebrafish model for Retinitis pigmentosa. Mol Neurodegener, 6, 56. https://doi.org/10.1186/1750-1326-6-56
  16. Yuan, L., Kawada, M., Havlioglu, N., Tang, H., & Wu, J. Y. (2005). Mutations in PRPF31 inhibit pre-mRNA splicing of rhodopsin gene and cause apoptosis of retinal cells. J Neurosci, 25(3), 748–757. https://doi.org/10.1523/JNEUROSCI.2399-04.2005
  17. Pierrottet, C. O., Zuntini, M., Digiuni, M., Bazzanella, I., Ferri, P., Paderni, R., Rossetti, L. M., Cecchin, S., Orzalesi, N., & Bertelli, M. (2014). Syndromic and non-syndromic forms of retinitis pigmentosa: a comprehensive Italian clinical and molecular study reveals new mutations. Genet Mol Res, 13(4), 8815–8833. https://doi.org/10.4238/2014.October.27.23
  18. Murati Calderon, R. A., Emanuelli, A., & Izquierdo, N. (2025). Retinitis Pigmentosa: From Genetic Insights to Innovative Therapeutic Approaches-A Literature Review. Medicina (Kaunas), 61(7). https://doi.org/10.3390/medicina61071179.
  19. Baz-Redon, N., Sanchez-Bellver, L., Fernandez-Cancio, M., Rovira-Amigo, S., Burgoyne, T., Ranjit, R., Aquino, V., Toro-Barrios, N., Carmona, R., Polverino, E., Cols, M., Moreno-Galdo, A., Camats-Tarruella, N., & Marfany, G. (2024). Primary Ciliary Dyskinesia and Retinitis Pigmentosa: Novel RPGR Variant and Possible Modifier Gene. Cells, 13(6). https://doi.org/10.3390/cells13060524
  20. Louie, C. M., Caridi, G., Lopes, V. S., Brancati, F., Kispert, A., Lancaster, M. A., Schlossman, A. M., Otto, E. A., Leitges, M., Grone, H. J., Lopez, I., Gudiseva, H. V., O'Toole, J. F., Vallespin, E., Ayyagari, R., Ayuso, C., Cremers, F. P., den Hollander, A. I., Koenekoop, R. K.,…Gleeson, J. G. (2010). AHI1 is required for photoreceptor outer segment development and is a modifier for retinal degeneration in nephronophthisis. Nat Genet, 42(2), 175–180. https://doi.org/10.1038/ng.519
  21. Chew, L. A., & Iannaccone, A. (2023). Gene-agnostic approaches to treating inherited retinal degenerations. Front Cell Dev Biol, 11, 1177838. https://doi.org/10.3389/fcell.2023.1177838
  22. Dong, J. Y., Fan, P. D., & Frizzell, R. A. (1996). Quantitative analysis of the packaging capacity of recombinant adeno-associated virus. Hum Gene Ther, 7(17), 2101–2112. https://doi.org/10.1089/hum.1996.7.17-2101
  23. Doudna, J. A., & Charpentier, E. (2014). Genome editing. The new frontier of genome engineering with CRISPR-Cas9. Science, 346(6213), 1258096. https://doi.org/10.1126/science.1258096
  24. Gaudelli, N. M., Komor, A. C., Rees, H. A., Packer, M. S., Badran, A. H., Bryson, D. I., & Liu, D. R. (2017). Programmable base editing of A*T to G*C in genomic DNA without DNA cleavage. Nature, 551(7681), 464–471. https://doi.org/10.1038/nature24644
  25. Komor, A. C., Kim, Y. B., Packer, M. S., Zuris, J. A., & Liu, D. R. (2016). Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature, 533(7603), 420–424. https://doi.org/10.1038/nature17946
  26. Nishida, K., Arazoe, T., Yachie, N., Banno, S., Kakimoto, M., Tabata, M., Mochizuki, M., Miyabe, A., Araki, M., Hara, K. Y., Shimatani, Z., & Kondo, A. (2016). Targeted nucleotide editing using hybrid prokaryotic and vertebrate adaptive immune systems. Science, 353(6305). https://doi.org/10.1126/science.aaf8729
  27. Maeder, M. L., Stefanidakis, M., Wilson, C. J., Baral, R., Barrera, L. A., Bounoutas, G. S., Bumcrot, D., Chao, H., Ciulla, D. M., DaSilva, J. A., Dass, A., Dhanapal, V., Fennell, T. J., Friedland, A. E., Giannoukos, G., Gloskowski, S. W., Glucksmann, A., Gotta, G. M., Jayaram, H.,…Jiang, H. (2019). Development of a gene-editing approach to restore vision loss in Leber congenital amaurosis type 10. Nat Med, 25(2), 229–233. https://doi.org/10.1038/s41591-018-0327-9
  28. Pierce, E. A., Aleman, T. S., Jayasundera, K. T., Ashimatey, B. S., Kim, K., Rashid, A., Jaskolka, M. C., Myers, R. L., Lam, B. L., Bailey, S. T., Comander, J. I., Lauer, A. K., Maguire, A. M., & Pennesi, M. E. (2024). Gene Editing for CEP290-Associated Retinal Degeneration. N Engl J Med, 390(21), 1972–1984. https://doi.org/10.1056/NEJMoa2309915
  29. Murakami, Y., Nakabeppu, Y., & Sonoda, K. H. (2020). Oxidative Stress and Microglial Response in Retinitis Pigmentosa. Int J Mol Sci, 21(19). https://doi.org/10.3390/ijms21197170
  30. Sahel, J. A., Boulanger-Scemama, E., Pagot, C., Arleo, A., Galluppi, F., Martel, J. N., Esposti, S. D., Delaux, A., de Saint Aubert, J. B., de Montleau, C., Gutman, E., Audo, I., Duebel, J., Picaud, S., Dalkara, D., Blouin, L., Taiel, M., & Roska, B. (2021). Partial recovery of visual function in a blind patient after optogenetic therapy. Nat Med, 27(7), 1223–1229. https://doi.org/10.1038/s41591-021-01351-4
  31. Marie, M., Churet, L., Gautron, A. S., Farjo, R., Mizuyoshi, K., Stevenson, V., Khabou, H., Leveillard, T., Sahel, J. A., & Lorget, F. (2025). Preclinical safety and biodistribution of SPVN06, a novel gene- and mutation-independent gene therapy for rod-cone dystrophies. Gene Ther. https://doi.org/10.1038/s41434-025-00556-3
  32. Vingolo, E. M., Casillo, L., Contento, L., Toja, F., & Florido, A. (2022). Retinitis Pigmentosa (RP): The Role of Oxidative Stress in the Degenerative Process Progression. Biomedicines, 10(3). https://doi.org/10.3390/biomedicines10030582
  33. Bianco, L., Navarro, J., Michiels, C., Sangermano, R., Condroyer, C., Antonio, A., Antropoli, A., Andrieu, C., Place, E. M., Pierce, E. A., El Shamieh, S., Smirnov, V., Kalatzis, V., Mansard, L., Roux, A. F., Bocquet, B., Sahel, J. A., Meunier, I., Bujakowska, K. M.,…Zeitz, C. (2025). Identification of IDH3G, encoding the gamma subunit of mitochondrial isocitrate dehydrogenase, as a novel candidate gene for X-linked retinitis pigmentosa. Genet Med, 27(6), 101418. https://doi.org/10.1016/j.gim.2025.101418
  34. Campochiaro, P. A., & Mir, T. A. (2018). The mechanism of cone cell death in Retinitis Pigmentosa. Prog Retin Eye Res, 62, 24–37. https://doi.org/10.1016/j.preteyeres.2017.08.004
  35. Hu, C., Ren, C., Wu, Y., Lin, R., Shen, T., Li, T., Yu, D., Jiang, L., Wan, Z., Luo, Y., Su, T., Yu, J., & Qiu, Y. (2025). ZLN005, a PGC-1alpha agonist, delays photoreceptor degeneration by enhancing mitochondrial biogenesis in a murine model of retinitis pigmentosa. Neuropharmacology, 269, 110361. https://doi.org/10.1016/j.neuropharm.2025.110361
  36. Kim, S., Han, J., Kim, H. A., Lim, B. C., Seo, J. E., Choi, M., Kim, K. J., Lee, I. G., & Chae, J. H. (2018). Neuropathy, Ataxia, Retinitis Pigmentosa-like Phenotype Associated with a Mitochondrial G8363A Mutation in a Family. Ann Clin Lab Sci, 48(4), 546–548.
  37. Bacherini, D., Maggi, L., Faraldi, F., Sodi, A., Vannozzi, L., Mazzoni, A., Capone, M., Virgili, G., Vicini, G., Falsini, B., Cosmi, L., Viggiano, P., Rizzo, S., Annunziato, F., Giansanti, F., & Liotta, F. (2024). CD3+CD4-CD8- Double-Negative Lymphocytes Are Increased in the Aqueous Humor of Patients with Retinitis Pigmentosa: Their Possible Role in Mediating Inflammation. Int J Mol Sci, 25(23). https://doi.org/10.3390/ijms252313163
  38. Brahimi, F., Nassour, H., Galan, A., Guruswamy, R., Ortiz, C., Nejatie, A., Nedev, H., Trempe, J. F., & Saragovi, H. U. (2025). Selective inhibitors of the TrkC.T1 receptor reduce retinal inflammation and delay neuronal death in a model of retinitis pigmentosa. PNAS Nexus, 4(2), pgaf020. https://doi.org/10.1093/pnasnexus/pgaf020
  39. Canto, A., Martinez-Gonzalez, J., Almansa, I., Lopez-Pedrajas, R., Hernandez-Rabaza, V., Olivar, T., & Miranda, M. (2022). Time-Course Changes in Oxidative Stress and Inflammation in the Retinas of rds Mice: A Retinitis Pigmentosa Model. Antioxidants (Basel), 11(10). https://doi.org/10.3390/antiox11101950
  40. Sahni, J. N., Angi, M., Irigoyen, C., Semeraro, F., Romano, M. R., & Parmeggiani, F. (2011). Therapeutic challenges to retinitis pigmentosa: from neuroprotection to gene therapy. Curr Genomics, 12(4), 276–284. https://doi.org/10.2174/138920211795860062
  41. Pfau, K., Callizo, J., Rossouw, P., Gabrani, C., Holz, F., Charbel Issa, P., Kellner, U., Strauss, R., Kuhlewein, L., Stingl, K., Feltgen, N., & Pfau, M. (2025). [Correction: N-Acetylcysteine (NAC) for Retinitis pigmentosa]. Klin Monbl Augenheilkd, 242(3), e2. https://doi.org/10.1055/a-2587-6864 (Original work published Erratum: N-Acetylcystein (NAC) bei Retinitis pigmentosa.)
  42. Ait-Ali, N., Fridlich, R., Millet-Puel, G., Clerin, E., Delalande, F., Jaillard, C., Blond, F., Perrocheau, L., Reichman, S., Byrne, L. C., Olivier-Bandini, A., Bellalou, J., Moyse, E., Bouillaud, F., Nicol, X., Dalkara, D., van Dorsselaer, A., Sahel, J. A., & Leveillard, T. (2015). Rod-derived cone viability factor promotes cone survival by stimulating aerobic glycolysis. Cell, 161(4), 817–832. https://doi.org/10.1016/j.cell.2015.03.023
  43. Grainok, J., Pitout, I. L., Chen, F. K., McLenachan, S., Heath Jeffery, R. C., Mitrpant, C., & Fletcher, S. (2024). A Precision Therapy Approach for Retinitis Pigmentosa 11 Using Splice-Switching Antisense Oligonucleotides to Restore the Open Reading Frame of PRPF31. Int J Mol Sci, 25(6). https://doi.org/10.3390/ijms25063391
  44. Kaltak, M., Corradi, Z., Collin, R. W. J., Swildens, J., & Cremers, F. P. M. (2023). Stargardt disease-associated missense and synonymous ABCA4 variants result in aberrant splicing. Hum Mol Genet, 32(21), 3078–3089. https://doi.org/10.1093/hmg/ddad129
  45. Kaltak, M., de Bruijn, P., Piccolo, D., Lee, S. E., Dulla, K., Hoogenboezem, T., Beumer, W., Webster, A. R., Collin, R. W. J., Cheetham, M. E., Platenburg, G., & Swildens, J. (2023). Antisense oligonucleotide therapy corrects splicing in the common Stargardt disease type 1-causing variant ABCA4 c.5461-10T>C. Mol Ther Nucleic Acids, 31, 674–688. https://doi.org/10.1016/j.omtn.2023.02.020
  46. Kaltak, M., de Bruijn, P., van Leeuwen, W., Platenburg, G., Cremers, F. P. M., Collin, R. W. J., & Swildens, J. (2024). QR-1011 restores defective ABCA4 splicing caused by multiple severe ABCA4 variants underlying Stargardt disease. Sci Rep, 14(1), 684. https://doi.org/10.1038/s41598-024-51203-7
  47. Naessens, S., Ruysschaert, L., Lefever, S., Coppieters, F., & De Baere, E. (2019). Antisense Oligonucleotide-Based Downregulation of the G56R Pathogenic Variant Causing NR2E3-Associated Autosomal Dominant Retinitis Pigmentosa. Genes (Basel), 10(5). https://doi.org/10.3390/genes10050363
  48. Chen, H., Liang, Y., Liang, Y., Chen, Y., Li, X., Zhang, R., Duan, C., Li, W., Cui, Z., Gu, J., Ding, C., Sun, X., & Chen, J. (2025). Generation of a gene-corrected isogenic human iPS cell line (CSUASOi006-A-2) from a retinitis pigmentosa patient using CRISPR/Cas9 technology. Stem Cell Res, 86, 103727. https://doi.org/10.1016/j.scr.2025.103727
  49. Diakatou, M., Dubois, G., Erkilic, N., Sanjurjo-Soriano, C., Meunier, I., & Kalatzis, V. (2021). Allele-Specific Knockout by CRISPR/Cas to Treat Autosomal Dominant Retinitis Pigmentosa Caused by the G56R Mutation in NR2E3. Int J Mol Sci, 22(5). https://doi.org/10.3390/ijms22052607
  50. Du, W., Li, J., Tang, X., Yu, W., & Zhao, M. (2023). CRISPR/SaCas9-based gene editing rescues photoreceptor degeneration throughout a rhodopsin-associated autosomal dominant retinitis pigmentosa mouse model. Exp Biol Med (Maywood), 248(20), 1818–1828. https://doi.org/10.1177/15353702231199069
  51. Feehan, J. M., Chiu, C. N., Stanar, P., Tam, B. M., Ahmed, S. N., & Moritz, O. L. (2017). Modeling Dominant and Recessive Forms of Retinitis Pigmentosa by Editing Three Rhodopsin-Encoding Genes in Xenopus Laevis Using Crispr/Cas9. Sci Rep, 7(1), 6920. https://doi.org/10.1038/s41598-017-07153-4
  52. Koster, C., van den Hurk, K. T., Lewallen, C. F., Talib, M., Ten Brink, J. B., Boon, C. J. F., & Bergen, A. A. (2021). The Lrat(-/-) Rat: CRISPR/Cas9 Construction and Phenotyping of a New Animal Model for Retinitis Pigmentosa. Int J Mol Sci, 22(13). https://doi.org/10.3390/ijms22137234
  53. Li, P., Kleinstiver, B. P., Leon, M. Y., Prew, M. S., Navarro-Gomez, D., Greenwald, S. H., Pierce, E. A., Joung, J. K., & Liu, Q. (2018). Allele-Specific CRISPR-Cas9 Genome Editing of the Single-Base P23H Mutation for Rhodopsin-Associated Dominant Retinitis Pigmentosa. CRISPR J, 1(1), 55–64. https://doi.org/10.1089/crispr.2017.0009
  54. Liang, Y., Sun, X., Chen, H., Cui, Z., Gu, J., Duan, C., Mao, S., Chen, Y., Li, X., Xiong, S., & Chen, J. (2024). CRISPR/Cas9-mediated generation of a human induced pluripotent stem cell line with PRPF6 c.2699 G > A mutation to model retinitis pigmentosa. Stem Cell Res, 81, 103581. https://doi.org/10.1016/j.scr.2024.103581
  55. Mirzaei, F., Eslahi, A., Karimi, S., Alizadeh, F., Salmaninejad, A., Rezaei, M., Mozaffari, S., Hamzehloei, T., Pasdar, A., & Mojarrad, M. (2024). Generation of Zebrafish Models of Human Retinitis Pigmentosa Diseases Using CRISPR/Cas9-Mediated Gene Editing System. Mol Biotechnol, 66(10), 2909–2919. https://doi.org/10.1007/s12033-023-00907-8
  56. NCT0662719, C. g. I. (2024). Study to evaluate Ultevursen in subjects with Retinitis Pigmentosa (RP) Due to Mutations in Exon 13 of the USH2A Gene (LUNA).
  57. Nolan, N. D., Cui, X., Robbings, B. M., Demirkol, A., Pandey, K., Wu, W. H., Hu, H. F., Jenny, L. A., Lin, C. S., Hass, D. T., Du, J., Hurley, J. B., & Tsang, S. H. (2024). CRISPR editing of anti-anemia drug target rescues independent preclinical models of retinitis pigmentosa. Cell Rep Med, 5(4), 101459. https://doi.org/10.1016/j.xcrm.2024.101459
  58. Parain, K., Lourdel, S., Donval, A., Chesneau, A., Borday, C., Bronchain, O., Locker, M., & Perron, M. (2022). CRISPR/Cas9-Mediated Models of Retinitis Pigmentosa Reveal Differential Proliferative Response of Muller Cells between Xenopus laevis and Xenopus tropicalis. Cells, 11(5). https://doi.org/10.3390/cells11050807
  59. Schellens, R., de Vrieze, E., Graave, P., Broekman, S., Nagel-Wolfrum, K., Peters, T., Kremer, H., Collin, R. W. J., & van Wijk, E. (2021). Zebrafish as a Model to Evaluate a CRISPR/Cas9-Based Exon Excision Approach as a Future Treatment Option for EYS-Associated Retinitis Pigmentosa. Int J Mol Sci, 22(17). https://doi.org/10.3390/ijms22179154
  60. Shahin, S., Xu, H., Lu, B., Mercado, A., Jones, M. K., Bakondi, B., & Wang, S. (2022). AAV-CRISPR/Cas9 Gene Editing Preserves Long-Term Vision in the P23H Rat Model of Autosomal Dominant Retinitis Pigmentosa. Pharmaceutics, 14(4). https://doi.org/10.3390/pharmaceutics14040824
  61. Wu, W. H., Tsai, Y. T., Huang, I. W., Cheng, C. H., Hsu, C. W., Cui, X., Ryu, J., Quinn, P. M. J., Caruso, S. M., Lin, C. S., & Tsang, S. H. (2022). CRISPR genome surgery in a novel humanized model for autosomal dominant retinitis pigmentosa. Mol Ther, 30(4), 1407–1420. https://doi.org/10.1016/j.ymthe.2022.02.010
  62. Wu, W. H., Tsai, Y. T., Justus, S., Cho, G. Y., Sengillo, J. D., Xu, Y., Cabral, T., Lin, C. S., Bassuk, A. G., Mahajan, V. B., & Tsang, S. H. (2018). CRISPR Repair Reveals Causative Mutation in a Preclinical Model of Retinitis Pigmentosa: A Brief Methodology. Methods Mol Biol, 1715, 191–205. https://doi.org/10.1007/978-1-4939-7522-8_13
  63. Wu, W. H., Tsai, Y. T., Justus, S., Lee, T. T., Zhang, L., Lin, C. S., Bassuk, A. G., Mahajan, V. B., & Tsang, S. H. (2016). CRISPR Repair Reveals Causative Mutation in a Preclinical Model of Retinitis Pigmentosa. Mol Ther, 24(8), 1388–1394. https://doi.org/10.1038/mt.2016.107
  64. Xi, Z., Vats, A., Sahel, J. A., Chen, Y., & Byrne, L. C. (2022). Gene augmentation prevents retinal degeneration in a CRISPR/Cas9-based mouse model of PRPF31 retinitis pigmentosa. Nat Commun, 13(1), 7695. https://doi.org/10.1038/s41467-022-35361-8
  65. Beryozkin, A., Samanta, A., Gopalakrishnan, P., Khateb, S., Banin, E., Sharon, D., & Nagel-Wolfrum, K. (2022). Translational Read-Through Drugs (TRIDs) Are Able to Restore Protein Expression and Ciliogenesis in Fibroblasts of Patients with Retinitis Pigmentosa Caused by a Premature Termination Codon in FAM161A. Int J Mol Sci, 23(7). https://doi.org/10.3390/ijms23073541
  66. Gopalakrishnan, P., Beryozkin, A., Banin, E., & Sharon, D. (2023). Morphological and Functional Comparison of Mice Models for Retinitis Pigmentosa. Adv Exp Med Biol, 1415, 365–370. https://doi.org/10.1007/978-3-031-27681-1_53
  67. Guerin, K., Gregory-Evans, C. Y., Hodges, M. D., Moosajee, M., Mackay, D. S., Gregory-Evans, K., & Flannery, J. G. (2008). Systemic aminoglycoside treatment in rodent models of retinitis pigmentosa. Exp Eye Res, 87(3), 197–207. https://doi.org/10.1016/j.exer.2008.05.016
  68. Gomez-Escribano, A. P., Garcia-Garcia, G., Perez-Santamarina, E., Aller-Manas, E., Vazquez-Manrique, R. P., & Millan-Salvador, J. M. (2025). Innovative therapies for inherited retinal dystrophies: navigating DNA, RNA, and protein approaches. EBioMedicine, 116, 105751. https://doi.org/10.1016/j.ebiom.2025.105751
  69. Duebel, J., Marazova, K., & Sahel, J. A. (2015). Optogenetics. Curr Opin Ophthalmol, 26(3), 226–232. https://doi.org/10.1097/ICU.0000000000000140
  70. Chen, Z., & Zhang, Y. A. (2015). Cell therapy for macular degeneration--first phase I/II pluripotent stem cell-based clinical trial shows promise. Sci China Life Sci, 58(1), 119–120. https://doi.org/10.1007/s11427-014-4791-2
  71. da Cruz, L., Fynes, K., Georgiadis, O., Kerby, J., Luo, Y. H., Ahmado, A., Vernon, A., Daniels, J. T., Nommiste, B., Hasan, S. M., Gooljar, S. B., Carr, A. F., Vugler, A., Ramsden, C. M., Bictash, M., Fenster, M., Steer, J., Harbinson, T., Wilbrey, A.,…Coffey, P. J. (2018). Phase 1 clinical study of an embryonic stem cell-derived retinal pigment epithelium patch in age-related macular degeneration. Nat Biotechnol, 36(4), 328–337. https://doi.org/10.1038/nbt.4114
  72. Kashani, A. H., Lebkowski, J. S., Rahhal, F. M., Avery, R. L., Salehi-Had, H., Dang, W., Lin, C. M., Mitra, D., Zhu, D., Thomas, B. B., Hikita, S. T., Pennington, B. O., Johnson, L. V., Clegg, D. O., Hinton, D. R., & Humayun, M. S. (2018). A bioengineered retinal pigment epithelial monolayer for advanced, dry age-related macular degeneration. Sci Transl Med, 10(435). https://doi.org/10.1126/scitranslmed.aao4097
  73. Mandai, M. (2023). Pluripotent stem cell-derived retinal organoid/cells for retinal regeneration therapies: A review. Regen Ther, 22, 59–67. https://doi.org/10.1016/j.reth.2022.12.005
  74. Mandai, M., Watanabe, A., Kurimoto, Y., Hirami, Y., Morinaga, C., Daimon, T., Fujihara, M., Akimaru, H., Sakai, N., Shibata, Y., Terada, M., Nomiya, Y., Tanishima, S., Nakamura, M., Kamao, H., Sugita, S., Onishi, A., Ito, T., Fujita, K.,…Takahashi, M. (2017). Autologous Induced Stem-Cell-Derived Retinal Cells for Macular Degeneration. N Engl J Med, 376(11), 1038–1046. https://doi.org/10.1056/NEJMoa1608368
  75. Mehat, M. S., Sundaram, V., Ripamonti, C., Robson, A. G., Smith, A. J., Borooah, S., Robinson, M., Rosenthal, A. N., Innes, W., Weleber, R. G., Lee, R. W. J., Crossland, M., Rubin, G. S., Dhillon, B., Steel, D. H. W., Anglade, E., Lanza, R. P., Ali, R. R., Michaelides, M., & Bainbridge, J. W. B. (2018). Transplantation of Human Embryonic Stem Cell-Derived Retinal Pigment Epithelial Cells in Macular Degeneration. Ophthalmology, 125(11), 1765–1775. https://doi.org/10.1016/j.ophtha.2018.04.037
  76. Schwartz, S. D., Regillo, C. D., Lam, B. L., Eliott, D., Rosenfeld, P. J., Gregori, N. Z., Hubschman, J. P., Davis, J. L., Heilwell, G., Spirn, M., Maguire, J., Gay, R., Bateman, J., Ostrick, R. M., Morris, D., Vincent, M., Anglade, E., Del Priore, L. V., & Lanza, R. (2015). Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt's macular dystrophy: follow-up of two open-label phase 1/2 studies. Lancet, 385(9967), 509–516. https://doi.org/10.1016/S0140-6736(14)61376-3
  77. Song, M. J., & Bharti, K. (2016). Looking into the future: Using induced pluripotent stem cells to build two and three dimensional ocular tissue for cell therapy and disease modeling. Brain Res, 1638(Pt A), 2–14. https://doi.org/10.1016/j.brainres.2015.12.011
  78. Gagliardi, G., Ben M'Barek, K., & Goureau, O. (2019). Photoreceptor cell replacement in macular degeneration and retinitis pigmentosa: A pluripotent stem cell-based approach. Prog Retin Eye Res, 71, 1–25. https://doi.org/10.1016/j.preteyeres.2019.03.001
  79. Leinonen, H., Zhang, J., Occelli, L. M., Seemab, U., Choi, E. H., LF, L. P. M., Querubin, J., Kolesnikov, A. V., Galinska, A., Kordecka, K., Hoang, T., Lewandowski, D., Lee, T. T., Einstein, E. E., Einstein, D. E., Dong, Z., Kiser, P. D., Blackshaw, S., Kefalov, V. J.,…Palczewski, K. (2024). A combination treatment based on drug repurposing demonstrates mutation-agnostic efficacy in pre-clinical retinopathy models. Nat Commun, 15(1), 5943. https://doi.org/10.1038/s41467-024-50033-5
  80. Hartong, D. T., Berson, E. L., & Dryja, T. P. (2006). Retinitis pigmentosa. Lancet, 368(9549), 1795–1809. https://doi.org/10.1016/S0140-6736(06)69740-7
  81. Thirunavukarasu, A. J., Raji, S., & Cehajic Kapetanovic, J. (2025). Visualising treatment effects in low-vision settings: proven and potential endpoints for clinical trials of inherited retinal disease therapies. Gene Ther. https://doi.org/10.1038/s41434-025-00552-7
  82. FDA, C. f. B. E. a. R. C. (2020). Guidance - Human Gene Therapy for Retinal Disorders: Guidance for Industry

About The Author

Laura Erker, Ph.D., is a life sciences executive with more than 15 years of experience integrating molecular genetics, clinical operations, and strategic partnerships. She has led the development of global, inspection-ready quality systems for ophthalmic imaging centers and directed clinical programs advancing rare-disease and genetic-testing research. Previously at Oregon Health & Science University, Laura now works in industry, focusing on data-driven, compliant infrastructures that accelerate discovery and improve patient outcomes, bridging science, technology, and operations to advance precision medicine.