Late-breaking data presented at AAO 2025 highlighted emerging gene-independent treatment strategies for inherited retinal diseases.

Allen C. Ho, MD (Wills Eye Hospital, Philadelphia) presented the three-year extension results from the RESTORE trial evaluating MCO-010, an investigational intravitreal optogenetic therapy for severe retinitis pigmentosa. The treatment delivers a light-sensitive protein to surviving retinal bipolar cells, aiming to restore light responsiveness even in the absence of functional photoreceptors. In long-term follow-up, a meaningful proportion of treated eyes demonstrated sustained functional improvement over the three year follow up period. There was a good safety profile and no serious inflammatory events. As a mutation-agnostic approach, MCO-010 may hold a potential across a broad range of retinal degenerations.

In a complementary strategy targeting Stargardt disease, Michel Michaelides, MD (Moorfields Eye Hospital, London) presented the interim analysis of the Phase 3 DRAGON trial investigating Tinlarebant, an oral RBP4 antagonist designed to reduce accumulation of toxic bisretinoids associated with ABCA4 dysfunction. Visual function remained stable through the first treatment year, and treatment-related effects such as delayed dark adaptation were consistent with the drug’s mechanism and generally manageable. Tinlarebant has received FDA Breakthrough Therapy designation, and global regulatory discussions are ongoing.

While long-term outcomes and real-world applicability will require further study, both presentations sought to advance the broader goal of developing mutation-independent therapies for patients who currently have limited or no treatment options.

The Retina Society 58^th Annual Scientific Meeting featured two Late Breaking Sessions. On Friday September 12^th, the late breaking session involved early-phase results for novel therapeutics for neovascular age-related macular degeneration (nAMD) and central retinal occlusion (CRAO).

Dr. Arshad Khanani of Sierra Eye Associates presented the first talk, discussing first time results from the Phase I/IIa Everest Trial. The multicenter trial investigated the safety and efficacy of EXG102-031, a novel adeno-associated virus (AAV)-based gene therapeutic vector, for treating nAMD. The therapeutic vector expresses a fusion protein ABD-VEGFR, which binds to angiopoietin 2 as well as all subtypes of VEGF.

The study had a dose-escalation (Phase1) and extension (Phase IIa) design and involved assessing a single subretinal injection of EXG102-031 in patients with nAMD. The primary safety outcomes were the incidence of adverse and serious adverse events. The primary efficacy outcomes were the annualized number of supplemental anti-VEGF injections and change in best corrected visual acuity (BCVA) as well as central subfield thickness (CRT).

In phase I, cohort follow up ranged from 4 to 52 weeks to date; there were no drug related serious adverse events or dose-limiting toxicity. There was dose-dependent reduction in annualized anti-VEGF injection rates (57-96%) across cohorts 1-4 and patients had improved or stable CRT and BCVA.

In summary, the results of the Phase I/IIa Everest Trial demonstrated a favorable safety and efficacy profile of a novel subretinal injection for nAMD. The anti-VEGF injection rate reductions were of particular interest. The durability of the injection rate reduction and long-term safety profile of this new subretinal therapy will be important factors to assess in later phase trials.

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The second late breaking presentation was delivered by Dr. Richard Rosen of New York Eye and Ear Infirmary of Mount Sinai. The study evaluated a novel intravitreal therapeutic (KUS121) for patients with non-arteritic CRAO. KUS121 is a cytoprotective compound, aimed to reduce metabolic stress from ischemia. The study was a multicenter phase 2 trial.

There were 17 patients with non-arteritic CRAO presenting 3 to 48 hours from time of symptom onset were included. Patients received an intravitreal injection for three days (two dosage groups and a control sham group). Outcomes included proportion of eyes improving 15 or more ETDRS letters from presentation at Week 12 and safety measures.

There were no statistically significant differences between proportion of eyes achieving the visual acuity outcome between the experimental and control arms. Dr. Rosen did highlight that there was a numerical trend towards improved visual recovery in the patients receiving KUS121 compared to control. The study’s small sample size may be underpowered to detect differences for now. There were no concerning safety signals.

Overall, the authors recommended further evaluation of the drug in later phase trials given the favorable safety profile and trend towards visual improvements. Larger sample sizes and evaluation of patient selection (consider time to symptom onset) may be needed to better understand this novel therapeutic.

At the Retina Society 2025 meeting in Chicago, the two late-breaking sessions highlighted innovations in retinal stem cell and prosthetic technologies for central vision improvement in individuals with geographic atrophy.

First, Rajesh Rao presented new data showing the promise of RPE-stem cells (RPESC) injected as a subretinal bleb after vitrectomy for eyes with dry AMD with vision between 20/70 to 20/800. These RPESC self-renew and differentiate into RPE cells over several weeks, and as showed in a recent paper, they exhibit key physiological characteristics of native tissue (Blenkinsop et al. Retinal Cell Biology). Across the first cohort of six subjects receiving low-dose 50,000 RPESC, there was a good safety profile and the procedure overall was well tolerated, with no vision loss, no tumor formation, no significant inflammation, and no ERM formation. Importantly, on post-operative month 1, the treated eye on average gained 21 letters versus a -1.3 letter loss in the untreated eye. While the study was limited given the small number of subjects and that  procedures were done by one surgeon at a single clinical site, they are overall promising. The study results will be published soon in Cell: Stem Cell, and the trial is ongoing.

Second, Joseph Martel presented data on the PRIMA retinal implant in patients with geographic atrophy. The PRIMA retinal implant is a 2mm-wide, 30um thick wireless prosthesis which replaces the outer retina, interacts with bipolar cells, and is connected to a visual interphase which allows the patient to process the world through transparent glasses. There have been three clinical trials testing this prosthetic system across individuals with geographic atrophy, including the two feasibility studies in France (5 patients, 72 month followup) and USA (4 patients, 36 month followup), and the pivotal multicenter study PRIMAvera (38 subjects, 36 month followup). Excitingly, the PRIMAvera trial 1 year results showed a mean improvement of 23 letters across individuals with the best patient improving by 59 letters. Overall, the results suggest that integration of natural and artificial vision is possible with meaningful improvement in VA and reassuring safety and implant stability signals.

In summary, the future of vision improvement in individuals with geographic atrophy, across both retinal stem cell and prosthetic technologies, is bright. Further trials with larger sample sizes will help translate these technologies for use in patient care.