In Part 1 of this year’s round-up of landmark literature, The Ophthalmologist Power Lister Andrzej Grzybowski curates the most impactful developments across gene therapy, diabetic retinopathy, age-related macular degeneration, glaucoma, and pediatric ophthalmology to offer a broad view of how emerging therapies and tools are being translated into real-world clinical gains.
Gene therapy
Gene therapy has continued to mature in ophthalmology, targeting both hereditary and non-hereditary retinal diseases.
The retina has been a pioneer site for gene therapy in medicine, especially since the US Food and Drug Administration (FDA) approved voretigene neparvovec-rzyl (Luxturna) in December 2017 for the treatment of biallelic RPE65-mediated inherited retinal disease. Luxturna marked the first FDA-approved gene therapy for any inherited disorder, establishing a foundation for further retinal gene therapy research.
M Michaelides et al., “Phase 1/2 AAV5-hRKp.RPGR (Botaretigene Sparoparvovec) Gene Therapy: Safety and Efficacy in RPGR-Associated X-Linked Retinitis Pigmentosa,” Am J Ophthalmol., 267, 122 (2024). PMID: 38871269.
In this open-label phase I/II trial, male participants aged ≥5 years with RPGR-associated X-linked retinitis pigmentosa received subretinal AAV5-hRKp.RPGR gene therapy across escalating doses, with 36 randomized into immediate or deferred treatment arms. The therapy was generally well tolerated, with most adverse events being transient and related to surgery; inflammation was effectively managed with corticosteroids. Improvements in retinal sensitivity and functional vision were observed in the immediate treatment group, supporting progression to a phase III trial.
BL Lam et al., “XIRIUS Study Group. Assessment of Visual Function with Cotoretigene Toliparvovec in X-Linked Retinitis Pigmentosa in the Randomized XIRIUS Phase 2/3 Study,” Ophthalmology, 131, 1083 (2024). PMID: 38423215.
In this 12-month phase I/II trial (XIRIUS), 29 male patients with RPGR-associated X-linked retinitis pigmentosa were randomized to receive low-dose, high-dose, or no subretinal cotoretigene toliparvovec gene therapy. Although the primary endpoint – proportion of microperimetry responders – was not met, the low-dose group showed significant improvements in mean microperimetry sensitivity and low-luminance visual acuity (LLVA) compared to controls. The low-dose treatment also resulted in fewer ocular serious adverse events than the high-dose group, supporting further investigation of this gene therapy approach.
M Michaelides et al., “Gene therapy in children with AIPL1-associated severe retinal dystrophy: an open-label, first-in-human interventional study,” Lancet, 405, 648 (2025). PMID: 39986747.
In this single-arm UK study, four children (aged 1–2.8 years) with AIPL1-associated severe retinal dystrophy received a subretinal injection of rAAV8.hRKp.AIPL1 gene therapy in one eye. Over an average 3.5-year follow-up, treated eyes showed significant improvement in visual acuity (from light perception to ~0.9 logMAR), enhanced cortical activity, and better preservation of retinal structure compared to untreated eyes. The treatment was generally well tolerated, with no serious adverse effects aside from one case of cystoid macular edema.
P Yang et al., “Subretinal Gene Therapy Drug AGTC-501 for XLRP Phase 1/2 Multicenter Study (HORIZON): 24-Month Safety and Efficacy Results,” Am J Ophthalmol., 271:268 (2025). PMID: 39643074.
In this phase I/II open-label study, 29 male participants with X-linked retinitis pigmentosa received subretinal injections of AGTC-501 across escalating doses, targeting initially the peripheral retina and later the macula. While all participants experienced treatment-emergent adverse events, most were mild and related to the surgical procedure; serious ocular AEs occurred in 21 percent, including retinal detachment and cataract. Although the highest dose showed the greatest gains in retinal sensitivity, it was associated with concerning retinal pigment epithelial changes, leading investigators to discontinue that dose in future studies; efficacy was most promising at the maximum tolerated dose.
Non-hereditary retinal conditions
In recent years, the field has rapidly evolved, expanding interest toward gene therapies for non-hereditary retinal conditions as well. Gene therapy works by delivering a therapeutic gene into a patient’s cells, enabling sustained production of a functional protein – such as endogenous anti-vascular endothelial growth factor (VEGF) – to achieve long-lasting therapeutic effects. This approach holds promise in reducing or eliminating the need for repeated intravitreal injections. These evolving delivery techniques are being actively explored for their potential in treating common non-inherited retinal diseases such as age-related macular degeneration (AMD), diabetic macular edema (DME), and diabetic retinopathy (DR).
JS Heier et al., “Phase 1 Study of JNJ-81201887 Gene Therapy in Geographic Atrophy Secondary to Age-Related Macular Degeneration,” Ophthalmology, 12, 1377 (2024). PMID: 38909914.
In this phase I open-label study, 17 patients with geographic atrophy secondary to advanced dry AMD received a single intravitreal injection of JNJ-81201887 across three dose levels. The gene therapy was well tolerated, with no dose-limiting or serious treatment-related adverse events; mild ocular inflammation occurred in 29 percent of patients and was resolved in most cases. While geographic atrophy lesion growth was stable across all groups, the high-dose cohort showed a continued decline in lesion growth rate over 24 months, supporting further clinical investigation.
PA Campochiaro et al., “Gene therapy for neovascular age-related macular degeneration by subretinal delivery of RGX-314: a phase 1/2a dose-escalation study,” Lancet, 403, 1563 (2024). PMID: 38554726.
In this phase I/IIa multicenter US study, 42 participants with neovascular AMD received a single subretinal injection of RGX-314 across five escalating dose cohorts, following prior anti-VEGF therapy. RGX-314 was generally well tolerated, with no unexpected inflammation; one vision-related adverse event occurred at the highest dose, and pigmentary changes were observed at higher dose levels. Sustained VEGF-A suppression was achieved, leading to stable or improved visual acuity and reduced reliance on supplemental anti-VEGF injections, supporting further investigation in larger trials.
EP Rakoczy et al., “Gene therapy with recombinant adeno-associated vectors for neovascular age-related macular degeneration: 1 year follow-up of a phase 1 randomized clinical trial,” Lancet, 386, 2395 (2015). PMID: 26431823.
In this phase I randomized controlled trial, nine patients with neovascular AMD received a single subretinal injection of low- or high-dose rAAV.sFLT-1 gene therapy or no treatment, alongside standard anti-VEGF therapy. The gene therapy was safe and well tolerated, with only mild, self-limiting procedure-related adverse events and no evidence of chorioretinal atrophy. Two-thirds of treated patients required no rescue anti-VEGF injections during follow-up, supporting the potential of rAAV.sFLT-1 as a long-term treatment for wet AMD.
Stem cell–based regenerative therapies
UV Jurkunas et al., “Cultivated autologous limbal epithelial cell (CALEC) transplantation for limbal stem cell deficiency: a phase I/II clinical trial of the first xenobiotic-free, serum-free, antibiotic-free manufacturing protocol developed in the US,” Nat Commun., 16, 1607 (2025). PMID: 40038272.
In this phase I/II single-arm clinical trial, researchers evaluated a novel two-stage, xenobiotic-free process for manufacturing cultivated autologous limbal epithelial cells (CALEC) to treat unilateral limbal stem cell deficiency (LSCD). Among 15 enrolled participants, 93 percent of CALEC grafts met release criteria, and no serious safety events related to treatment were observed. The majority of patients achieved either complete or partial clinical success (92 percent by 18 months), supporting the safety, feasibility, and potential efficacy of CALEC transplantation for LSCD. Notably, all participants met complete success criteria at least once, with most maintaining that success across subsequent visits, suggesting durable ocular surface stability. Of the five participants who transitioned from complete to partial or no success, the majority had complex clinical histories or required retreatment – indicating that baseline disease severity may influence long-term graft performance.
T Soma et al., “Induced pluripotent stem-cell-derived corneal epithelium for transplant surgery: a single-arm, open-label, first-in-human interventional study in Japan,” Lancet, 404, 1929 (2024). PMID: 39522528.
In this first-in-human clinical study, four patients with limbal stem cell deficiency (LSCD) received corneal epithelial cell sheets derived from allogeneic human induced pluripotent stem cells (iCEPSs). Over a two-year follow-up, the treatment was well tolerated, with no serious adverse events such as tumor formation or immune rejection. Improvements in corneal clarity, visual acuity, and disease stage were observed in all cases – most notably in patients receiving low-dose immunosuppression – supporting the potential of iPSC-based therapies for LSCD and warranting further clinical trials.
Diabetic retinopathy treatment
AJ Barkmeier et al., “Comparative Effectiveness of Glucagon-Like Peptide-1 Receptor Agonists, Sodium-Glucose Cotransporter 2 Inhibitors, Dipeptidyl Peptidase-4 Inhibitors, and Sulfonylureas for Sight-Threatening Diabetic Retinopathy,” Ophthalmol Retina, 8, 943 (2024). PMID: 38735641.
In this large retrospective cohort study of 371,698 adults with type 2 diabetes and moderate cardiovascular risk, researchers compared the impact of different glucose-lowering therapies on the risk of developing sight-threatening diabetic retinopathy. Patients initiating SGLT2 inhibitors had a significantly lower risk of requiring treatment for diabetic macular edema or proliferative retinopathy compared to those starting GLP-1 receptor agonists, DPP-4 inhibitors, or sulfonylureas (HRs: 0.73, 0.79, and 0.61 respectively). The findings support a potential protective role of SGLT2 inhibitors in diabetic eye disease progression.
H Tesfaye et al., “Empagliflozin and the Risk of Retinopathy in Patients With Type 2 Diabetes,” JAMA Ophthalmol., 143, 62 (2025). PMID: 39636645.
In this large observational cohort study using US insurance data, researchers compared the effects of empagliflozin and DPP4 inhibitors on diabetic retinopathy (DR) risk in adults with type 2 diabetes. Initiation of empagliflozin was not associated with a reduced risk of incident nonproliferative DR, but it was linked to a significantly lower risk of DR progression (HR 0.78; 95 percent CI, 0.63–0.96). While residual confounding cannot be excluded, these findings suggest empagliflozin may offer protective effects against worsening retinal disease in this population.
D Preiss et al., “Effect of Fenofibrate on Progression of Diabetic Retinopathy,” NEJM Evid., 3, EVIDoa2400179 (2024). PMID: 38905569.
In this randomized trial of 1,151 adults with nonreferable diabetic retinopathy or maculopathy, fenofibrate (145 mg) significantly reduced progression to referable disease or the need for treatment compared to placebo over a median follow-up of 4 years. The hazard ratio for disease progression was 0.73 (P=0.006), and for macular edema, it was 0.50, though no improvements were observed in visual function or quality of life. While fenofibrate modestly reduced progression of early diabetic retinal changes, it had no effect on vision outcomes and was associated with a small decline in renal function.
S Klier et al., “Safety and Efficacy of Senolytic UBX1325 in Diabetic Macular Edema,” NEJM Evid. 4, EVIDoa2400009 (2025). PMID: 40261111.
In this sham-controlled trial, 65 patients with diabetic macular edema and suboptimal prior response to anti-VEGF therapy were randomized to receive a single intravitreal injection of UBX1325 or sham. UBX1325 was generally well tolerated, with no treatment-emergent adverse events leading to discontinuation, and safety profiles were comparable between groups. A modest visual benefit was observed with UBX1325, showing a 5.6-letter gain in visual acuity at 48 weeks versus sham, warranting further investigation in larger trials.
Age-related macular degeneration (AMD) treatment
TL Jackson et al., “Stereotactic radiotherapy for neovascular age-related macular degeneration (STAR): a pivotal, randomized, double-masked, sham-controlled device trial,” Lancet, 404, 44 (2024). PMID: 38876132.
In the STAR randomized controlled trial, 411 patients with chronic active neovascular age-related macular degeneration (nAMD) received either 16-Gy stereotactic radiotherapy (SRT) or sham treatment alongside anti-VEGF injections. Over two years, SRT significantly reduced the number of injections required (mean reduction of 2.9) without compromising visual acuity, which remained non-inferior to sham. Although microvascular changes were more common in the SRT group, they were not associated with worse vision, and the treatment offered a potential cost-saving benefit, supporting its role in reducing injection burden in nAMD.
CC Xue et al., “Omega-3 Fatty Acids as Protective Factors for Age-Related Macular Degeneration: Prospective Cohort and Mendelian Randomization Analyses,” Ophthalmology, 132, 598 (2025). PMID: 39662686.
In this large prospective cohort and Mendelian randomization study, higher plasma levels of omega-3 fatty acids and DHA were significantly associated with reduced risk of age-related macular degeneration (AMD). Over nearly 13 years of follow-up in the UK Biobank, individuals with elevated omega-3 and DHA had lower rates of AMD, and genetic analyses confirmed a likely causal relationship, particularly for both dry and wet AMD. These findings support the protective role of omega-3 and DHA against AMD and highlight the potential value of clinical trials targeting these nutrients for AMD prevention.
Pediatric ophthalmology
FA Proudlock et al. [EUPatch study group], “Extended optical treatment versus early patching with an intensive patching regimen in children with amblyopia in Europe (EuPatch): a multicenter, randomized controlled trial,” Lancet, 403, 1766 (2024). PMID: 38704172.
In the EuPatch randomized controlled trial involving 334 children with amblyopia, early patching after just 3 weeks of glasses wear led to significantly better treatment success than extended optical treatment (EOT) before patching. After 12 weeks of patching, 67 percent of the early patching group achieved successful outcomes, compared to 54 percent in the EOT group (p=0.019). The findings support initiating intensive patching earlier to improve visual outcomes and provide evidence to personalize amblyopia management strategies.
DL Li et al., “Lower indoor spatial frequency increases the risk of myopia in children,” Br J Ophthalmol., 109, 250 (2025). PMID: 39122351.
In this study of 566 children, researchers found that indoor environments exhibited significantly lower spatial frequency content than outdoor spaces, and this reduction was linked to myopia. Myopic children were more likely to have been exposed to indoor environments with lower spatial frequency slopes, while no difference was observed in outdoor spatial frequency. Regression analysis confirmed that lower indoor spatial frequency was associated with increased myopia risk, highlighting the visual environment’s potential role in myopia development. [
Glaucoma
J Jiang et al., “CRISPR-Cas9-mediated deletion of carbonic anhydrase 2 in the ciliary body to treat glaucoma,” Cell Rep Med., 5, 101524 (2024). PMID: 38670096.
A study introduced a transformative gene therapy for glaucoma by using a CRISPR-Cas9 system delivered via ShH10 AAV to permanently knock out the carbonic anhydrase 2 (Car2) gene in the ciliary body, the source of aqueous humor. The single intravitreal injection led to sustained intraocular pressure (IOP) reduction in multiple glaucoma models, surpassing conventional treatments like brinzolamide. The study presents a potential one-time, disease-agnostic gene-editing approach to manage glaucoma, though long-term safety in primates remains to be assessed before clinical use.
History of ophthalmology
CT Leffler et al., “Sir Harold Ridley (1906-2001) and His Cure for Aphakia: New Historical Insights Into the Invention of the Intraocular Lens,” Am J Ophthalmol., 273, 167 (2025). PMID: 39983943.
In 2024 we celebrated the 75th anniversary of the first intraocular lens (IOL) implantation. This historical review clarifies the pioneering development of the IOL by Harold Ridley, who implanted the first permanent IOL in 1950 following inspiration from wartime findings on inert acrylic fragments. Ridley used Transpex I, an acrylic material known for its biocompatibility, though early designs caused significant refractive errors and inflammatory reactions due to inadequate sterilization. Despite initial setbacks, Ridley’s work laid the foundation for modern cataract surgery, proving by 1951 that intraocular lenses could achieve successful visual outcomes.
