Issuu

Retina’s Next Frontier posterior segment • innovation • enlightenment

P.22 Rods die, cones follow, and for years nobody knew why, until one clinician-scientist spent 26 years finding out. Dr. José-Alain Sahel’s Proctor Medal lecture is part gene therapy update, part optogenetics fever dream, part solar panel for the eye. Buckle up.

October 2026 MediaMICE.com

LETTER TO READERS

ONTO RETINA’S NEXT FRONTIER In a corner, far far away from the front of the eye, is the retina. An enigma no more… We now know that it captures light, converts them into images, then transmits the signal through the optic nerve. The brain decodes the signal, and we see a clear image. But for something so small, we continue to wonder how it does a lot. The retina is 30 to 40 mm in total circular diameter with a surface area of about 1,094 mm².* It has a thickness ranging from about 0.1 mm (100 microns) at the thinnest parts of the fovea up to 0.5 mm in certain areas, averaging around 0.2 mm to 0.3 mm.* The retina lines roughly 72% of the inside of the eyeball globe.* Still mysterious, it sounds like. In this issue we explore the dynamic, and often paradoxical, landscape of the retina. From the pressing challenges posed by the rising tide of pathologic myopia and the nuances of ‘Ozempic eye,’ to the evolving realworld outcomes of complement inhibitors, we find ourselves at the center of profound change. The depth and trajectory of these subject matters represents the next frontier in vitreoretina—a domain where experts in the field are mapping unknown territory and fundamentally altering what is possible for our patients. As we navigate these transformative developments, we are reminded of Master Yoda’s timeless wisdom: “Do, or do not. There is no try.” Experts just do. This mindset encapsulates the dedication and standard of excellence required to push the boundaries. Whether it is Dr. José-Alain Sahel’s relentless 26-year journey to finding “light in the darkness”, the expansive potential of RNA therapeutics, or the way stem cell science is redefining our approach to neurodegeneration, we are moving beyond theory into action.

In this issue, we also confront the ‘Retina Paradox’: the challenge of a specialty facing capacity constraints even as modern interventions become more sophisticated. Through the lens of the National Eye Institute (NEI)’s outlook on the next decade and Dr. Christina Weng’s ref lections on mentorship and purpose, we see that the future of ophthalmology is built, of course, on breakthrough biology, but also on the human systems that support it. Finally, as we look down the ‘Road to 2035,’ the path forward requires durability, phenotype-driven care, and a renewed commitment to our workforce. We hope this collection of insights helps you chart your own course through this rapidly advancing field. May the light (and force) be with you!

Sincerely, Gloria D. Gamat Chief Editor | PIE, CAKE and COOKIE Head, Editorial Department | Media MICE

However, innovation is only part of the story.

*Kolb H. Facts and Figures Concerning the Human Retina. 2005 May 1 [Updated 2007 Jul 5]. In: Kolb H, Fernandez E, Jones B, et al., editors. Webvision: The Organization of the Retina and Visual System [Internet]. Salt Lake City (UT): University of Utah Health Sciences Center; 1995-.

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ISSUE

In this

POSTERIOR SEGMENT

The Myopia Wave is Coming for the Macula

Ozempic and the Eye

Beyond the Trials

Why pathologic myopia deserves a bigger seat at the retina table

What weight-loss drugs are doing to the retina

Three years of complement inhibitors in real practice

INNOVATION

The Eye Is Leading the Mission

The Age of RNA

The View from NEI

How stem cell science is closing in on neurodegeneration

Where genetic code goes to work

A glimpse into vision research in the next decades

COVER STORY

Shooting in the Dark

And somehow finding the light

ENLIGHTENMENT

Beyond the Retina

The Retina Paradox

On mentors, patients and the making of a career

The Road to 2035 What retina experts expect over the next decade

Why retina’s greatest success is becoming its hardest problem

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DR. ALAY S. BANKER Banker’s Retina Clinic and Laser Centre Ahmedabad, India alay.banker@gmail.com

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PROF. GEMMY CHEUNG Singapore National Eye Centre Singapore gemmy.cheung.c.m@singhealth.com.sg

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DR. ARSHAD KHANANI Sierra Eye Associates; University of Nevada, Reno School of Medicine Nevada, USA arshad.khanani@gmail.com

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POSTERIOR SEGMENT

THE MYOPIA WAVE IS COMING FOR THE MACULA

WHY PATHOLOGIC MYOPIA DESERVES A BIGGER SEAT AT THE RETINA TABLE The world is getting more nearsighted, and the macula is footing the bill. Prof. Timothy Lai maps out what’s coming for retina specialists, and why the response starts years before patients ever reach the retina clinic. By Tan Sher Lynn

As the global prevalence of myopia continues to rise, more highly myopic patients are reaching the age when complications affecting the macula can develop and threaten their vision. For ophthalmologists, that means preparing for a future in which myopic maculopathy becomes an increasingly significant part of clinical practice. Prof. Timothy Lai from the Chinese University of Hong Kong emphasized that the first step is recognizing high myopia as a risk state rather than merely a refractive measurement. “It is important to prevent the development of high myopia as high myopia can lead to pathologic myopia, in which various ocular complications can arise,” he said. Pathologic myopia can involve progressive structural changes in the posterior segment, including macular neovascularization (MNV), myopic traction maculopathy (MTM), and progressive macular atrophy. These complications can cause irreversible

visual impairment, making early recognition and monitoring increasingly important as the highly myopic population grows. RECOGNIZING THE WARNING SIGNS One of the challenges of managing highly myopic patients is that significant pathology may develop before patients perceive a major change in their vision. Routine visual acuity alone can therefore provide an incomplete picture of macular health. When complications do become symptomatic, however, the nature of the symptoms can provide an important warning. “Macular complications…will usually result in visual symptoms such as metamorphopsia, scotoma or blurring of vision,” Prof. Lai said. “Patients should be warned of these symptoms and ask to seek ophthalmic care as soon as new symptoms arise.” This underscores the important role of patient education. Highly myopic patients should understand that new distortion, missing areas in their vision or unexplained blurring should not simply be

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attributed to their existing refractive error. Prompt assessment allows potentially treatable complications to be identified earlier, while there’s still something worth treating. WHY IMAGING CAN NO LONGER BE OPTIONAL The complexity of highly myopic eyes also makes clinical examination challenging. Pathologic changes can be subtle, and the distorted anatomy associated with high myopia can make early macular abnormalities difficult to appreciate on examination alone. Standardized documentation can help clinicians track these changes over time and improve communication between comprehensive ophthalmologists and retina specialists. Prof. Lai pointed to the META-PM classification1 as one useful approach for documenting the fundus changes associated with pathologic myopia, along with optical coherence tomography for qualitative and quantitative assessment of macular changes.

Cases of early stages of macular changes are rather difficult to be picked up on clinical examination alone - Prof. Timothy Lai

OCT offers a window into structural changes that might otherwise go undetected. “Spectral domain optical coherence tomography (SD-OCT) or swept-source optical coherence tomography (SS-OCT) can pick up early myopic traction maculopathy and document the extent of macular thickness changes,” he explained. “Cases of early stages of macular changes are rather difficult to be picked up on clinical examination alone and therefore imaging assessment like SD-OCT and SS-OCT are essential.” EARLIER TREATMENT, BETTER OUTCOMES For patients who do develop myopic MNV, anti-vascular endothelial growth factor (anti-VEGF) therapy has substantially improved the outlook. “Intravitreal anti-VEGF therapy such as ranibizumab and aflibercept has become the standard of care treatment for myopic MNV and has improved the visual outcome of patients with MNV considerably,” Prof. Lai said. “And fortunately, unlike in neovascular age-related macular degeneration or diabetic macular edema, most patients do not require multiple, frequent intravitreal anti-VEGF therapy.”

Meanwhile, MTM presents a different challenge altogether. “For myopic traction maculopathy, vitreoretinal surgery might be required and some cases might be rather challenging and can require multiple surgeries,” he said. PREPARING BEFORE THE WAVE ARRIVES The most effective response to pathologic myopia may lie further upstream than the retina clinic. Prevention and myopia control during childhood remain critical to reducing how many patients eventually progress to severe disease, which calls for closer collaboration across the entire eye-care pathway—from pediatric ophthalmologists to retina specialists. Prof. Lai pointed to low-dose atropine and defocus incorporated multiple segments (DIMS) lenses as tools to slow progression in children, particularly those with a strong family history, alongside more frequent OCT to catch macular changes early. That continuum—slowing axial myopia in childhood, monitoring high-risk eyes, educating patients on warning symptoms, and ensuring fast access to imaging and treatment—is what stands between a highly myopic patient and irreversible vision loss. For retina specialists, it means strengthening referral pathways and keeping a low threshold for imaging. For comprehensive and pediatric ophthalmologists, it means recognizing that slowing myopia today reduces the burden retina specialists face tomorrow. The number of highly myopic patients isn’t going to shrink. The question now is whether ophthalmology catches maculopathy early enough to matter, and increasingly, that means not waiting for symptoms before reaching for the OCT.

REFERENCES 1. Ohno-Matsui K, Kawasaki R, Jonas JB, et al. International photographic classification and grading system for myopic maculopathy. Am J Ophthalmol. 2015;159(5):877-883.e7. 2. Tan NW, Ohno-Matsui K, Koh HJ, et al. Long-term outcomes of ranibizumab treatment of myopic choroidal neovascularization in East-Asian patients from the RADIANCE study. Retina. 2018;38(11):2101-2109. 3. Hamilton RD, Clemens A, Minnella AM, et al. Real-world effectiveness and safety of ranibizumab for the treatment of myopic choroidal neovascularization: Results from the LUMINOUS study. PLoS One. 2020;15(1):e0227557.

CONTRIBUTOR

He pointed out that “long-term results from the post-RADIANCE trial2 and LUMINOUS study3 have also demonstrated favorable long-term outcomes following ranibizumab treatment for myopic MNV,” stressing that “it is important to detect these lesions early in order to achieve the best outcome.”

Prof. Timothy Lai Clinical professor at The Chinese University of Hong Kong. tyylai@cuhk.edu.hk

This content is intended exclusively for healthcare professionals. It is not intended for the general public. Products or therapies discussed may not be registered or approved in all jurisdictions, including Singapore.

OCTOBER 2026

POSTERIOR SEGMENT

WHAT WEIGHT-LOSS DRUGS ARE DOING TO THE RETINA “Ozempic eye” has become shorthand for two entirely different problems: one well-understood and one still under investigation. Untangling them matters, because the wrong panic could cost patients a drug that’s doing them real good elsewhere. By Dr. Sashwanthi Mohan

Glucagon-like peptide-1 (GLP-1) receptor agonists such as semaglutide, dulaglutide and liraglutide, along with the dual GIP/GLP-1 receptor agonist tirzepatide, are now prescribed on a massive scale for diabetes and obesity, delivering substantial improvements in glycemic control and weight loss. As their use has climbed, so have questions about what they might be doing to the eye. Reports linking semaglutide to diabetic retinopathy (DR) and, more recently, non-arteritic anterior ischemic optic neuropathy (NAION) have sometimes been lumped together as evidence of one emerging “eye risk.” The reality is messier, and more interesting: these are two different clinical stories, resting on two very different levels of evidence. For DR, the underlying mechanism is already well understood. For NAION, observational studies have raised a possible safety signal, but whether GLP-1 therapy itself causes the condition remains unresolved. THE DR STORY In the SUSTAIN-6 cardiovascular outcomes trial, DR complications occurred in 3.0% of patients receiving semaglutide compared with 1.8% receiving placebo.1 Most patients who developed complications, however, already had pre-existing retinopathy, and subsequent analysis showed the added risk fell mainly among patients with poorer baseline glycemic control and larger, more rapid drops in HbA1c.2

That pattern will be familiar to anyone who has watched glycemic control tighten quickly. Early worsening of DR following rapid glucose improvement predates GLP-1 drugs entirely, and has previously been documented with intensive insulin therapy in the Diabetes Control and Complications Trial, as well as after bariatric surgery.3 Bringing chronic hyperglycemia under control quickly can transiently worsen retinopathy, even though sustained glycemic control ultimately reduces long-term diabetic microvascular complications. The evidence, in other words, does not convincingly show that semaglutide is directly linked to worsening retinopathy. What’s more plausible is that potent glucose-lowering therapy produces substantial metabolic change over a short period, and an already vulnerable retina doesn’t always adjust smoothly to that transition. Real-world data back this up. An Observational Health Data Sciences and Informatics (OHDSI) network study of 810,390 new semaglutide users across 14 databases found no increased risk of proliferative DR, treatment-requiring DR or diabetic macular edema compared with other GLP-1 receptor agonists and several non-GLP-1 diabetes medications.4 A separate large observational analysis found no difference in sight-threatening DR among patients starting semaglutide, dulaglutide, liraglutide or exenatide.5 The picture isn’t perfectly uniform, though. A real-world study of tirzepatide found increased odds of new proliferative DR,

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particularly among patients with more advanced baseline retinal disease, compared with matched controls, although the same drug was associated with reduced odds of developing new retinopathy in patients without baseline DR.6

an increased risk of NAION and other optic nerve disorders among semaglutide or tirzepatide users, though the absolute risk remained low.9

The clinical message, then, is nuanced but useful. These drugs do not simply “damage the retina.” The real concern is that rapid metabolic improvement may cause early worsening in eyes that are already vulnerable. For retina specialists, baseline retinal status and the anticipated speed and magnitude of HbA1c reduction deserve close attention.

Confounding is the persistent problem here. Patients on these drugs commonly have diabetes, obesity, hypertension and obstructive sleep apnea, the same systemic conditions already associated with NAION. Pharmacovigilance databases add another layer of uncertainty—useful for flagging safety signals, but unable to establish incidence or causation, and reporting tends to rise once an adverse event gets publicity of its own.

THE NAION QUESTION The second story is considerably more controversial. Reports of NAION associated with semaglutide have drawn attention because NAION causes sudden, typically painless, vision loss with no proven treatment to reverse it.

Regulators have taken the signal seriously regardless. In 2025, the European Medicines Agency’s Pharmacovigilance Risk Assessment Committee concluded that NAION should be classified as a very rare adverse effect of semaglutide, estimating roughly one additional case per 10,000 person-years of treatment.10

The concern first emerged from retrospective studies reporting higher NAION rates among patients prescribed semaglutide. Subsequent analyses of electronic health records, insurance claims and pharmacovigilance databases have produced mixed results.

A 2026 joint consensus statement from the American Academy of Ophthalmology (AAO) and the North American NeuroOphthalmology Society (NANOS) reached a similar conclusion: current evidence suggests a possible small increase in NAION risk, likely lower than early estimates suggested. Causality, however, has not been established, and the absolute risk remains low.11

One large OHDSI analysis found a modest increase in NAION risk with semaglutide in some comparisons7, while another cohort study of GLP-1 receptor agonist users found no statistically significant increase. 8 A 2025 target-trial emulation involving more than 1.5 million eligible patients with type 2 diabetes found

That’s a meaningfully different level of certainty from the early-worsening phenomenon seen in DR. Semaglutide’s direct contribution to NAION, however, is still under investigation.

OCTOBER 2026

POSTERIOR SEGMENT

WHAT SHOULD RETINA SPECIALISTS DO NOW? For the moment, there’s no evidence-based case for discouraging GLP-1 therapy indiscriminately. Patients with diabetes should stay current with retinal screening, particularly when starting potent glucose-lowering therapy if they have longstanding diabetes, poor baseline glycemic control or pre-existing DR. Close retinal monitoring matters most for someone with moderate or severe NPDR whose HbA1c is expected to fall rapidly over a short period. A recent multidisciplinary consensus recommended DR screening before GLP-1 receptor agonist initiation along the same lines, particularly in higher-risk patients with more than 10 years of diabetes duration or poor glucose control, HbA1c greater than 10%.12 The NAION conversation calls for a different approach. Patients should know that sudden, painless loss or dimming of vision requires urgent ophthalmic assessment. For patients with a previous NAION episode or sight loss in one eye, the uncertainty warrants an individualized discussion between ophthalmologist and prescribing clinician. The AAO– NANOS statement emphasizes shared decision-making over automatic discontinuation.11

What the evidence doesn’t support is stopping GLP-1 therapy indiscriminately over possible ocular risk. These drugs deliver substantial glycemic, cardiovascular, renal and weight-loss benefits, and any ophthalmic risk needs to be weighed within that broader risk–benefit picture, individualized for each patient. The study most likely to settle the retinal question is FOCUS, a prospective Phase III randomized trial comparing semaglutide with placebo in approximately 1,500 patients with type 2 diabetes, with a primary endpoint of at least three-step ETDRS DR progression. Initiated in 2019, the 176-site study is currently expected to complete in November 2027.13 Until then, the distinction is worth holding onto. Rapid glycemic improvement can cause early worsening of DR, particularly in eyes with significant pre-existing disease, a phenomenon documented long before GLP-1 drugs existed. Whether semaglutide independently raises the risk of NAION remains, for now, an open question. For ophthalmologists, the task now is not to stand in the way of the remarkable progress of GLP-1 drugs, but to recognize which eyes may need close monitoring and to counsel the patients accordingly while the rest of the evidence catches up.

REFERENCES 1. Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375:1834-1844.

9. Wang L, et al. Semaglutide or tirzepatide and optic nerve and visual pathway disorders in type 2 diabetes. JAMA Netw Open. 2025;8(8):e2526327.

2. Vilsbøll T, Bain SC, Leiter LA, et al. Semaglutide, reduction in glycated haemoglobin and the risk of diabetic retinopathy. Diabetes Obes Metab. 2018;20:889-897.

10. European Medicines Agency Pharmacovigilance Risk Assessment Committee. PRAC concludes eye condition NAION is a very rare side effect of semaglutide medicines Ozempic, Rybelsus and Wegovy. June 6, 2025. Accessed on August 22, 2026.

3. The Diabetes Control and Complications Trial Research Group. Early worsening of diabetic retinopathy in the Diabetes Control and Complications Trial. Arch Ophthalmol. 1998;116:874-886.

11. DeParis SW, Oke I, Gaier ED, et al. Glucagon-like peptide-1 receptor agonists and the risk of non-arteritic anterior ischemic optic neuropathy: a consensus statement. Ophthalmol. 2026;133(8):1029-1035.

4. Cai CX, Nishimura A, Baxter S, et al. Semaglutide and diabetic retinopathy: an OHDSI network study. BMJ Open Diabetes Res Care. 2025;13(6):e005424.

12. Carter P, Simó R, Lövestam-Adrian M, et al. Addressing the risk of ocular complications of GLP-1RAs: a multi-disciplinary expert consensus. Diabetes Obes Metab. 2025;27:7535-7543.

5. Barkmeier AJ, Deng Y, Swarna KS, et al. Risk of sight-threatening diabetic retinopathy with glucagon-like peptide-1 receptor agonist use in routine clinical practice: comparative effectiveness of semaglutide, dulaglutide, liraglutide, and exenatide. Ophthalmol Retina. 2026;10:142-151.

13. ClinicalTrials.gov. Long-term effects of semaglutide on diabetic retinopathy in subjects with type 2 diabetes (FOCUS). NCT03811561. Accessed on August 22, 2026.

6. Buckley AJ, Tan GD, Gruszka-Goh M, Scanlon PH, Ansari I, Suliman SGI. Early worsening of diabetic retinopathy in individuals with type 2 diabetes treated with tirzepatide: a realworld cohort study. Diabetologia. 2025;68:2069-2076.

CONTRIBUTOR Dr. Sashwanthi Mohan

7. Cai CX, Hribar M, Baxter S, et al. Semaglutide and nonarteritic anterior ischemic optic neuropathy. JAMA Ophthalmol. 2025;143(4):304-314.

Specialist ophthalmologist in the Department of Ophthalmology at the Medcare Eye Centre, Dubai, United Arab Emirates.

8. Ramsey DJ, Makwana B, Dani SS, et al. GLP-1 receptor agonists and sight-threatening ophthalmic complications in patients with type 2 diabetes. JAMA Netw Open. 2025;8(8):e2526321.

sashu23@gmail.com

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BEYOND POSTERIOR SEGMENT

THE TRIALS THREE YEARS OF COMPLEMENT INHIBITORS IN REAL PRACTICE

Three years after CIs left the launch pad, the data is finally back from orbit…and it turns out slowing GA is only half the story. The other half is a rare but sightthreatening complication that trials never flagged, and a growing consensus that timing, not just molecule choice, may decide who benefits. By Hazlin Hassan

Pegcetacopla n (Sy fovre; Apel lis Pharmaceutica ls; Massachusetts, United States) became the first FDA-approved treatment for geographic atrophy (GA) in February 2023, followed by avacincaptad pegol (Izervay; Astellas Pharma; Tokyo, Japan) that August. Three years on, both drugs have left the tightly controlled orbit of clinical trials and entered the messier atmosphere of everyday practice…and the view from down here is illuminating.

While real-world experience has broadly reinforced the efficacy signal seen in the pivotal trials, it has also exposed a serious safety complication that was essentially invisible in those trials. The question now emerges: W ho should actually receive treatment? The answer is not simply “everyone with GA,” nor is it “no one.” While these drugs can slow an otherwise relentless disease, the

OCTOBER 2026

POSTERIOR SEGMENT

benefit is preventive, the effect is difficult for a patient to see, and treatment carries risks. THE EFFICACY SIGNAL SURVIVES RE-ENTRY In OAKS and DERBY, pegcetacoplan slowed GA lesion growth over 24 months, with the treatment effect increasing over time. Monthly treatment reduced growth by roughly 22% in OAKS and 19% in DERBY; every-other-month dosing reduced growth by about 18% and 16%, respectively.1 GATHER2 similarly found that monthly avacincaptad pegol slowed GA growth by 14% at 12 months compared with sham.2 Two-year GATHER2 results, published in 2026, continued to support a treatment effect over time.3 The encouraging news is that this effect appears to hold up outside the highly controlled environment of a trial. A 2026 real-world study followed 103 pegcetacoplan-treated eyes for a year and found a 37% reduction in annual GA growth rate compared with each eye’s own pretreatment rate.4 A separate community-practice comparison of 112 patients found similar 12-month anatomic and visual outcomes between pegcetacoplan and avacincaptad pegol, though the avacincaptad group received more injections.5 For avacincaptad pegol, a 461-eye real-world cohort reported no cases of intraocular inflammation or endophthalmitis over a mean follow-up of 120 days.6

One of the biggest challenges with complement in hibitors has been the inability to easily measure efficacy for the patient in the exam chair. - Dr. Paul Hahn

There is an important caveat, though: slowing GA is not the same as restoring vision, and treatment benefits can be genuinely hard to see in an individual patient. As Dr. Paul Hahn (United States), founder of phRETINA, put it, “One of the biggest challenges with complement inhibitors has been the inability to easily measure efficacy for the patient in the exam chair.”

In clinical trials, aggregate and controlled data made treatment differences visible. That kind of signal is far harder to demonstrate at the level of a single patient, he noted. “Moreover, although there have been prespecified functional vision outcomes demonstrated in clinical trial analyses, we as a community hoped for more robust functional improvements to be elucidated over time which have not meaningfully materialized,” he added. “There is still robust research trying to better understand the disease and these treatments, but our current treatment of GA patients relies on faith in the science rather than visible efficacy.” THE SAFETY SIGNAL NOBODY SAW COMING The most consequential real-world lesson has been pegcetacoplanassociated retinal vasculitis and retinal vascular occlusion. Neither complication appeared in OAKS or DERBY. Yet within months of commercial launch, cases began surfacing. The ASRS Research and Safety in Therapeutics (ReST) Committee ultimately confirmed 14 affected eyes in 13 patients in its initial case series.7 All cases followed the first pegcetacoplan injection. Eleven eyes had occlusive retinal vasculopathy, eight lost more than three lines of vision, and two were ultimately enucleated. The FDA has since added retinal vasculitis and retinal vascular occlusion to the Syfovre prescribing information, noting that cases may occur after the first dose, result in severe vision loss and warrant discontinuation of treatment if they occur.8 The mechanism remains unresolved, and the early investigation into the 19-gauge filter needle did not establish causality. “With these complement inhibitors, the most largely scrutinized difference between real-world experience and clinical trials has been the identification of retinal vasculitis as a rare but serious side effect,” said Dr. Hahn. That experience has reshaped counseling and, for some physicians, prescribing habits. Dr. Hahn’s own approach is methodical. “For those patients who start pegcetacoplan, I will start treatment in their worse eye…and have them return in two weeks for reevaluation. If we are planning to start treatment in their other eye, I will usually start treatment at that two week follow-up visit, assuming no inflammation is seen,” he said.

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“Retinal vasculitis has been observed primarily following the first injection, so the absence of inflammation at the two week visit gives me reassurance to continue treatment.” While the risk is rare, informed consent, vigilance and appropriate patient selection are essential. PATIENT SELECTION GETS SMARTER Three years in, the field has largely moved past whether to treat and on to a sharper question: when is treatment most worthwhile? Because current therapies slow progression without regenerating lost retina, disease stage and future risk have become central to that decision.

The ideal candidate for c ompl e me nt i n h i bit or therapy—and, indeed, any preventive treatment— is an individual who has early disease and is still asymptomatic.

REFERENCES 1. Heier JS, Lad EM, Holz FG, et al. Pegcetacoplan for the treatment of geographic atrophy secondary to age-related macular degeneration (OAKS and DERBY): two multicentre, randomised, double-masked, sham-controlled, phase 3 trials. Lancet. 2023;402(10411):1434–1448. 2. Khanani AM, Patel SS, Staurenghi G, et al. Efficacy and safety of avacincaptad pegol in patients with geographic atrophy (GATHER2): 12-month results from a randomised, doublemasked, phase 3 trial. Lancet. 2023;402(10411):1449–1458. 3. Iapace C. Arshad Khanani, MD: Two-Year Results from GATHER2 Trial. Available at https://www.hcplive.com/view/ arshad-khanani-md-two-year-results-gather2-trial. Accessed on August 18, 2026. 4. Shen M, Berni A, Liu J, et al. Real-world experience with intravitreal pegcetacoplan for the treatment of geographic atrophy in age-related macular degeneration. Am J Ophthalmol. 2026;281:31–41. 5. Kuhns L. Geographic atrophy therapies have similar efficacy, albeit with different dosing. Ophthalmology Advisor. Available at https://www.ophthalmologyadvisor.com/news/ avacincaptad-pegol-pegcetacoplan-efficacy-at-12-monthssimilar-but-with-different-dosing/. Accessed on August 18, 2026.

- Dr. Paul Hahn

Dr. Hahn argues for treating earlier, while patients are still relatively asymptomatic. “Current complement inhibitors are a preventive and not restorative treatment for GA,” he said. “The ideal candidate for complement inhibitor therapy—and, indeed, any preventive treatment—is an individual who has early disease and is still asymptomatic.” CIS THREE YEARS IN Complement inhibitors are not a cure for GA. What they offer is a way to slow the biological process driving irreversible retinal loss, and real-world evidence suggests the anatomic efficacy seen in trials does translate into practice. But that gain comes bundled with real risk, including a rare complication that can be devastating to vision.

6. Abou-Samra A, Barazi MD, Abbas A, et al. Real-world experience of geographic atrophy treatment with avacincaptad pegol. J Vitreoretin Dis. 2025;9(6):24741264251367100. 7. Witkin AJ, Jaffe GJ, Srivastava SK, Davis JL, Kim JE. Retinal vasculitis after intravitreal pegcetacoplan: report from the ASRS Research and Safety in Therapeutics (ReST) committee. J Vitreoretin Dis. 2023;8(1):9–20. 8. Pegcetacoplan (Syfovre™) - CAM 911. South Carolina Blues. Medical Policy. Available at https://www.medicalpolicy. southcarolinablues.com/web/public/brands/medicalpolicy/ external-policies/pegcetacoplan-syfovre/. Accessed on August 18, 2026.

CONTRIBUTOR

“We often take what we have for granted, and I think that first and foremost, it is important to keep in mind that this class of therapies represents a first-in-class treatment modality for a devastating disease,” Dr. Hahn said.

Dr. Paul Hahn Founder of phRETINA, an independent retina practice in the United States. paulhahn@gmail.com

“All decisions in medicine involve balancing opposing risks. For geographic atrophy, we balance the certainty of disease progression versus the risks of treatment,” he concluded.

OCTOBER 2026

INNOVATION

THE EYE

IS LEADING THE MISSION HOW S T E M C E L L SC I E NC E I S C L O S I NG I N O N NE U R ODE GE NE RA T I ON

Stem cells have promised to transform neurodegeneration for decades. At ARVO 2026, a pioneer in the field made the case that the promise is finally catching up with the biology… and that the eye is out in front. By Michaela Perez

The eye has spent decades being treated as medicine’s special case. A contained system. A surgical problem. A disease of aging that happens to affect vision. Dr. Sally Temple (United States) has spent just as long arguing the opposite: that the retina is a piece of brain, that neurodegeneration is neurodegeneration wherever it shows up, and that the toolkit built to crack one disease may crack them all. At ARVO 2026, she came with evidence. WHERE EVERY DISEASE BEGINS Neurodegenerative diseases all share one brutal feature: cells die and don’t come back. Dr. Temple put some numbers to that, noting that Alzheimer’s disease affects approximately five million people in the U.S., age-related macular degeneration (AMD) about 10 million, Parkinson’s disease about one million, and glaucoma about four million. Once a cell is gone, no drug can reach it. That’s the logic behind the two jobs Dr. Temple thinks stem cells are best suited for: catching disease early and replacing cells once they’re gone.

It was Dr. Temple who first demonstrated that stem cells exist in the developing mammalian brain and spinal cord, a discovery that earned her a MacArthur Fellowship and set up the science behind everything that followed. MODELING THE DISEASE Frontotemporal dementia (FTD) caused by mutations in the MAPT gene is rare, hits early, and strips patients of behavior, language and motor function in the prime of life.1 Dr. Temple argues it’s also a useful stand-in for the much more common taudriven damage seen in Alzheimer’s disease. Her lab at the Neural Stem Cell Institute, working through the Tau Consortium, took skin or blood cells from patients carrying the V337M MAPT mutation, reprogrammed them into stem cells and grew them into small lab-made brain tissue called organoids. The resulting cell resource now includes more than 120 patientderived lines, each paired with a gene-corrected version of itself as a built-in control.2 More than 6,000 of these organoids have been shipped out to collaborating labs and studied at two, four and six months of growth.

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By six months, the organoids carrying the mutation had built up significant amounts of tau, in patterns that resembled real patient brain tissue.3 Gene-expression profiling pointed to one particular neuron type, cortical glutamatergic neurons, as the most vulnerable—the same cells that die off preferentially in human FTD patients.3 That same profiling showed early activation of genes tied to glutamate signaling, which led the team to a hypothesis: that mutant neurons were oversensitive to glutamate and effectively toxifying themselves.3 The hypothesis held up. When the team added glutamate to living, labeled neurons growing inside the organoids, the mutant cells died off noticeably faster than normal ones.3 A drug called apilimod, which blocks an enzyme called PIKFYVE, slowed that death down, and a separate experiment silencing PIKFYVE directly confirmed it was the right target.3 Both are now being explored as possible tau-disease treatments—drug candidates found entirely in a dish, with no animal model involved.

TARGETING THE RISK The organoid approach doesn’t stop at FTD. As Dr. Temple outlined in her ARVO 2026 session, her group is applying the same approach to Alzheimer’s disease, but through a different door: blood vessels. Her team has been looking at how the APOE4 gene—the bestknown genetic risk factor for Alzheimer’s—affects blood vessels in the brain, using stem-cell-derived models of that vascular tissue to hunt for drug targets. The goal is the same as with the FTD work, which is to see something in human cells that animal models simply can’t show. In this framework, poor blood vessel health and brain inflammation aren’t side effects of neurodegeneration. They’re places to intervene. REPLACING WHAT’S LOST Modeling and early targeting only help while cells can still be saved. The harder question is what to do once they’re already gone, and that’s what Dr. Temple’s retinal pigment epithelium (RPE) stem cell program is built to answer.

OCTOBER 2026

INNOVATION

We are at a new era of human, mechanistic and translational neuroscience—and the eye is leading. - Dr. Sally Temple

Dry AMD affects one in five people over age 75, Dr. Temple noted, and today’s approved treatments slow the disease down without giving any function back. Her group found something unexpected, that adult human RPE tissue harbors a small, dormant population of stem cells that have been sitting inactive since about 20 weeks of gestation. Remarkably, eye tissue from donors as old as 99 still yields millions of new RPE cells, enough for thousands of patient doses from a single donor. Only 3% to 10% of the original cells end up rebuilding the tissue layer, which is exactly what you’d expect from a true stem cell population, one that stayed dormant for decades but never lost the ability to divide.

as costing a billion dollars, much of that price tag comes from projects that failed along the way, and that better tools upfront could bring that number down. A NEW ERA, LED BY THE EYE Dr. Temple closed with a line that landed with the room. “We are at a new era of human, mechanistic and translational neuroscience—and the eye is leading.” It’s no accident that her most advanced program is the one built on the eye. Because you can see into it and reach it easily, the eye has become the test bed for ideas that may later work in the brain. The brain organoid models are maturing. The blood vessel targets are defined. And the clinical trial—with patients now showing sustained vision gains—is already delivering proof of principle. Three diseases. One toolkit. And a field that, on the strength of this keynote lecture, is only just leaving the launch pad.

Editor’s Note Reporting for this article was conducted during the ARVO 2026 Annual Meeting, held May 2026 in Denver, Colorado, USA.

Earlier animal studies showed that cells at a specific “four-week” stage of development worked best for rescuing vision, young enough to have stopped dividing but not yet fully matured.4 Those cells are the basis of a therapy called RPESC-RPE-4W, now being tested in a Phase I/IIa dose-escalation trial through Luxa Biotech (United States) at the University of Michigan, Stanford University and LA Retina, all in the U.S.5

REFERENCES

Early results from the first, lowest-dose group of six patients look promising. There were no serious safety concerns. Treated eyes gained between 11 and 40 letters on the vision chart compared with the untreated eye in the same patient, and that improvement held even after patients stopped taking immune-suppressing drugs at six months.6 Higher-dose groups are being tested now.

1. Rohrer J, Ryan B, Ahmed R. MAPT-Related Frontotemporal Dementia. In: Adam MP, Bick S, Mirzaa GM, et al., eds. GeneReviews [Internet]. University of Washington, Seattle; 2000. Updated August 18, 2022. Accessed August 18, 2026. 2. Karch CM, Kao AW, Karydas A, et al; Tau Consortium Stem Cell Group. A comprehensive resource for induced pluripotent stem cells from patients with primary tauopathies. Stem Cell Reports. 2019;13(5):939-955.

THE UNIFYING THREAD What ties all three efforts together is artificial intelligence (AI).

3. Bowles KR, Silva MC, Whitney K, et al. ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids. Cell. 2021;184(17):4547-4563. e17.

Large genetic studies have turned up hundreds of genes linked to these diseases—Dr. Temple noted—around 700 for Alzheimer’s disease, 700 for glaucoma, and 70 for AMD alone. Figuring out which of those genes actually matter, and how, is a sorting job too big for humans alone. That’s where machine learning comes in.

4. Arduini B, Blenkinsop T, Naimark M, et al. INDenabling safety and efficacy of RPESC-RPE-4W, an adult RPE progenitor cell therapy for dry age-related macular degeneration. Cell Rep Med. 2026;7(5):102779. 5. Luxa Biotech. A study of RPESC-RPE-4W in patients with dry age-related macular degeneration. ClinicalTrials.gov. NCT04627428. Accessed August 18, 2026.

AI is also being used to predict how drugs might interact or cause side effects, and to iron out manufacturing problems—like inconsistent cell batches—that have made it hard to produce cell therapies at scale.

6. Rao RC, Arduini BL, Borden S, et al. Safety and tolerability of RPESC-RPE transplantation in patients with dry age-related macular degeneration: low-dose clinical outcomes. Cell Stem Cell. 2025;32(11):1659-1670.e4.

“By including AI-driven decisions, we will reduce failure,” Dr. Temple said, noting that while drug approval is often cited

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INNOVATION

THE

AGE OF

RNA

WHERE GENETIC CODE GOES TO WORK RNA can suppress a message, redirect splicing or guide an editor to its target, doing far more than simply carrying information from gene to protein. Retinal medicine is now testing what each of these roles can accomplish and where each approach meets resistance. By Kendra Bruning

Between stored genetic code and biological output lies a working layer of RNA. Some interventions in that layer can be paused or reversed; others are built to persist. Neither guarantees clinical success. Prof. Thomas Cech (United States) discovered catalytic RNA in 1982, work that earned him the 1989 Nobel Prize in Chemistry alongside molecular biologist Sidney Altman. Decades later, addressing ARVO 2026 delegates, he led with his conclusion. “The punchline,” he told the audience, “is that the 21st century is the age of RNA. That is really where all of the action in biology is”. The U.S. Food and Drug Administration (FDA) approved pegaptanib (Eyetech Pharmaceuticals; New York, United States), the first approved aptamer, for neovascular age-related macular degeneration in 2004. This RNA molecule, which targets vascular endothelial growth factor (VEGF), established that a nucleic acid can function as a drug.1

RNA DOES MORE THAN DELIVER THE MAIL “RNA must do more than just serve as a message,” Prof. Cech explained, organizing the clinical landscape around three modes of action. Antisense oligonucleotides and small interfering RNA suppress a harmful protein; splice correction, gene editing and messenger RNA delivery restore a missing one; aptamers block molecular interactions outright. Pathogenic variants in RNU4-2 and four RNU6 paralogs cause retinitis pigmentosa (RP) in patients without a previous genetic diagnosis, disrupting the base-pairing dynamics of small nuclear RNAs that direct pre-messenger RNA splicing. 2 Prof. Cech observed that “these mutations alter that pairing and unpairing cycle, creating a disease mechanism outside the protein-coding genome”. These variants may account for up to 1.4% of otherwise u nd ia g nosed R P ca ses a nd 3 .0 % of ot her w ise

OCTOBER 2026

INNOVATION

These mutations alter that pairing and unpairing cycle, creating a disease mechanism outside the protein-coding genome - Prof. Thomas Cech

undiagnosed dominant RP families, based largely on cases of European descent.2 TWO ROUTES AROUND CEP290 Leber congenital amaurosis (LCA) is among the earliest and most severe inherited retinal diseases. Pathogenic variants in 24 genes account for 70% to 80% of nonsyndromic cases, and CEP290 mutations are the single most common cause at 15% to 20% of diagnoses.3

HYPERION (NCT06891443) now retraces sepofarsen’s route in Phase III. Its eligibility criteria exclude participants with clinically significant lens opacities under Age-Related Eye Disease Study criteria, tightening control of baseline lens status after cataracts complicated earlier dosing. The first participant was dosed on October 1, 2025, and the trial was listed as recruiting in August 2026.10,11 RNA STAYS ON MESSAGE GUCY2D mutations account for 10% to 20% of LCA cases. Unlike CEP290, GUCY2D complementary DNA fits within a single conventional AAV vector, avoiding the packaging constraint that shaped the CEP290 programs.

The CEP290 complementary DNA is too large for a single conventional adeno-associated virus (AAV) vector. That packaging limit has split development into two routes: one redirecting RNA after transcription and the other editing DNA at its source.4

ATSN-101 (Atsena Therapeutics; North Carolina, United States), uses AAV5 to deliver functional human GUCY2D transgene to photoreceptors.3,12 Here, RNA keeps its day job, carrying instructions from the delivered transgene to the protein-making machinery.

Sepofarsen (QR-110; Laboratoires Théa; Clermont-Ferrand, France) took the first route. The antisense oligonucleotide is designed to correct the most frequent CEP290 splice defect by binding mutant pre-messenger RNA and redirecting splicing toward the canonical transcript.4 Because it requires repeat dosing, treatment can be stopped.

A Phase I/II trial enrolled 15 patients. In the high-dose cohort (n = 9), dark-adapted full-field stimulus testing improved by a mean of 20.3 dB in treated eyes, roughly a 100-fold gain in light sensitivity, compared with 1.1 dB in fellow eyes. Best-corrected visual acuity did not reach statistical significance (P = 0.10).12 Improvements appeared by Day 28, with an approximately 20 dB full-field stimulus testing gain sustained through 36 months.13

“RNA therapy has the advantage that it is not a permanent change in our genetic makeup,” Prof. Cech said. “It is reversible, just like a lot of medicines that we take. If the patient is not doing well on it, we stop giving it”. An exploratory Phase Ib/II study in 11 participants found that five gained 15 or more ETDRS letters. Eight developed cataracts and six required lens replacement. Dosing in the highest administered cohort was discontinued.4 ILLUMINATE, a Phase II/III trial of 36 participants, failed its primary visual acuity endpoint, along with secondary full-field stimulus testing and mobility endpoints.5,6 Reversibility, it turned out, was not enough on its own. EDIT-101 (Editas Medicine; Massachusetts, United States) took the second route, going upstream to the stored code. Two guide RNAs and Cas9, delivered via AAV, disrupted the aberrant splice site at the DNA level.7 The Phase I/II BRILLIANCE trial enrolled 14 participants. No serious treatment-related adverse events or dose-limiting toxicities were reported, and nine of 14 showed meaningful

improvement in at least one prespecified outcome. 8 Enrollment was paused in November 2022. Two months later, Editas Medicine discontinued investment in the program.9 Permanence, it turned out, was not enough either.

Atsena Therapeutics expects to begin a global pivotal Phase III trial later in 2026.14,15 In his broader comparison, Prof. Cech left the two routes open. “Both gene therapy and RNA therapy may have important uses,” he said. CAS13 COMPLICATES THE ENDING HG202 (HuidaGene Therapeutics; Shanghai, China) complicates reversibility itself by pairing an RNA target with a delivery system designed to persist. Cas13 degrades RNA rather than cutting DNA. A guide RNA directs it to VEGFA messenger RNA, reducing VEGF-A protein expression without altering the genome. In company-reported preclinical data, HG202 reduced choroidal neovascularization area by 87% in a laser-induced mouse model.16 SIGHT-I (NCT06031727), the Phase I investigator-initiated trial in China, began in September 2023 and was last verified as recruiting in March 2025.17 The FDA cleared an investigational new drug application for HG202 on November 4, 2024, but the BRIGHT Phase I trial PIE

(NCT06623279) still appeared as “Not yet recruiting” in August 2026, with its registry record unverified since September 2024.16,18 Available human efficacy signals remain limited to one conference abstract and sponsor communications.16,19 Targeting the working layer and being reversible are different propositions. HG202 reaches VEGFA messenger RNA through a single AAV-delivered system intended to sustain Cas13 expression indefinitely.16,18 Once that system has been administered, there is no repeat dose to withhold. “In closing,” Prof. Cech said, “I hope I have given you some reason to believe that maybe the 21st century is the age of RNA”. He had carried that thesis beyond the lab two years earlier in The Catalyst: RNA and the Quest to Unlock Life’s Deepest Secrets.20 HG202 suggests how complicated that age may become. Long after the message turns over, the machinery sent to destroy it may remain—a fittingly openended note for a field still writing its own script.

4. Russell SR, Drack AV, Cideciyan AV, et al. Intravitreal antisense oligonucleotide sepofarsen in Leber congenital amaurosis type 10: a phase 1b/2 trial. Nat Med. 2022;28(5):1014-1021. 5. ProQR Therapeutics. Phase 2/3 ILLUMINATE trial results of sepofarsen in CEP290-mediated LCA10. Community update. February 11, 2022. 6. ClinicalTrials.gov. A study to evaluate efficacy, safety, tolerability and exposure after a repeat-dose of sepofarsen (QR-110) in LCA10 (ILLUMINATE). NCT03913143. 7. Pierce EA, Aleman TS, Jayasundera KT, et al. Gene editing for CEP290-associated retinal degeneration. N Engl J Med. 2024;390(21):1972-1984. 8. Editas Medicine. Editas Medicine announces clinical data demonstrating proof of concept of EDIT-101 from phase 1/2 BRILLIANCE trial. Press release. November 17, 2022. 9. Editas Medicine. Editas Medicine announces strategic updates and portfolio reprioritization. Press release. January 9, 2023. 10. ClinicalTrials.gov. Study to evaluate sepofarsen in subjects with Leber congenital amaurosis (LCA) type 10 (HYPERION). NCT06891443. 11. Sepul Bio. Sepul Bio doses first participant in phase 3 HYPERION clinical trial of sepofarsen for CEP290-associated Leber congenital amaurosis type 10. Press release. October 1, 2025.

Long after the message turns over, the machinery sent to destroy it may remain—a fittingly openended note for a field still writing its own script.

12. Yang P, Pardon LP, Ho AC, et al. Safety and efficacy of ATSN101 in patients with Leber congenital amaurosis caused by biallelic mutations in GUCY2D: a phase 1/2, multicentre, openlabel, unilateral dose escalation study. Lancet. 2024;404(10456):962-970. 13. Cideciyan AV, Aleman TS, Yang P, et al. Safety and efficacy of ATSN-101 in patients with Leber congenital amaurosis caused by biallelic variants in GUCY2D (LCA1): durability through 3 years post-treatment. Invest Ophthalmol Vis Sci. 2026;67(7):4480.

- Prof. Thomas Cech

Editor’s Note The Association for Research in Vision and Ophthalmology (ARVO) 2026 Annual Meeting was held from May 3-7, 2026, in Denver, Colorado. Reporting for this article comes from Prof. Thomas Cech’s ARVO+Genentech Opening Keynote on May 3.

14. Atsena Therapeutics. Atsena presents positive clinical data from its XLRS and LCA1 gene therapy programs at ARVO 2026. Press release. May 7, 2026. 15. Atsena Therapeutics. Atsena Therapeutics receives orphan designation from the European Medicines Agency (EMA) for ATSN-101 and ATSN-201. Press release. July 23, 2026. 16. HuidaGene Therapeutics. HuidaGene Therapeutics receives the first-ever FDA clearance of CRISPR/Cas13 RNA-editing HG202 for macular degeneration. Press release. November 4, 2024. 17. ClinicalTrials.gov. CRISPR/Cas13-mediated RNA targeting therapy for the treatment of neovascular age-related macular degeneration investigator-initiated trial (SIGHT-I). NCT06031727.

REFERENCES 1. Ng EW, Shima DT, Calias P, et al. Pegaptanib, a targeted antiVEGF aptamer for ocular vascular disease. Nat Rev Drug Discov. 2006;5(2):123-132. 2. Quinodoz M, Rodenburg K, Cvackova Z, et al. De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa. Nat Genet. 2026;58(1):169-179. 3. Kumaran N, Pennesi ME, Yang P, et al. Nonsyndromic Leber congenital amaurosis/early-onset severe retinal dystrophy overview. 2018 Oct 4 [updated 2025 Dec 4]. In: Adam MP, Bick S, Mirzaa GM, et al. GeneReviews. Seattle (WA): University of Washington, Seattle; 1993-2026.

18. ClinicalTrials.gov. Open-label dose-escalation study for CRISPR/Cas13-RNA targeting therapy for the treatment of neovascular age-related macular degeneration in phase I trial (BRIGHT). NCT06623279. 19. Luk A, Xing D, Liu B, et al. World’s first CRISPR/RNAtargeting therapy (HG202) for patients with neovascular age-related macular degeneration. Invest Ophthalmol Vis Sci. 2024;65(7):4357. 20. Cech TR. The Catalyst: RNA and the Quest to Unlock Life’s Deepest Secrets. New York: W.W. Norton & Company; 2024.

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INNOVATION

THE VIEW FROM NEI A glimpse into vision research in the next decades

NEI has $824 million, 1,600 grants and a director willing to say the quiet part out loud: the science is ready, but the system to scale it isn’t. Here’s what he thinks needs to happen next. By Marhiel Garrote

What will shape vision research over the next decade? For the National Eye Institute (NEI), the answer may not be one breakthrough, but several forces converging at once: artificial intelligence (AI), regenerative medicine, new approach methodologies (NAMs) and the data infrastructure needed to support all three.

A FIELD ALREADY AHEAD Regenerative medicine is not new territory for NEI. In 2013, the institute launched its Audacious Goals Initiative, a roughly decade-long, $80 million effort focused on regenerating neurons and neural connections, particularly photoreceptors and retinal ganglion cells.

Vision science has been building toward this for years. In 2011, Eiraku and colleagues showed that mouse embryonic stem cell aggregates could self-organize into optic-cup structures in threedimensional culture, an early marker of how far a laboratory model could go in reproducing retinal development.1

As the primary funder of vision research in the U.S., NEI carries an annual budget of roughly $824 million, supporting some 1,600 grants across more than 250 institutions. That gives the institute an unusually wide vantage point on where the science is gaining momentum, and what’s worth watching next.

A decade of foundational work has changed the question, though. It’s no longer only about whether retinal cells can be regenerated or replaced. It’s about how to turn increasingly sophisticated biology into therapies that can be manufactured consistently, survive transplantation, integrate with host tissue and ultimately function in patients.

Dr. Chiang noted that this history matters. “There’s a lot of innovative work, and I think there’s going to be a lot of opportunity for the vision field to help lead the rest of science and medicine [in] how we can make better use of NAMs in the research pipeline.”

At ARVO 2026, NEI Director Dr. Michael Chiang offered a glimpse of those priorities and how they’re beginning to intersect. “You’re definitely going to hear more and more about these because of their priorities at the NIH and also at the FDA,” he said. The real question, as Dr. Chiang framed it, isn’t whether these fields keep advancing individually. It’s what happens when they start working together, and whether that convergence can move promising science closer to patients.

“One of [the next steps] is going to be addressing barriers to translating some of this foundational work that’s been developed over the last 10 years…into therapies,” Dr. Chiang said. That is where NAMs enter the picture. NIH uses the term for emerging approaches that may complement or reduce animal testing, including organoids, stemcell-based systems, microphysiological models, digital twins, in silico methods and AI-enabled tools.

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AI GETS PRACTICAL Artificial intelligence in eye care is usually discussed in the language of image interpretation, screening or prediction. Dr. Chiang pointed to a less familiar role it can play, helping determine whether a living cell product is actually good enough to become a therapy. Work from Kapil Bharti’s NEI laboratory offers one of the clearest examples. The group has developed autologous induced pluripotent stem cell-derived retinal pigment epithelium (iPSC-RPE) patches for retinal degeneration. The process starts with a patient’s own cells, reprograms

them into iPSCs, differentiates those into RPE and grows the resulting cells on a biodegradable scaffold. “How healthy is a cell and how do we know when it’s good enough for these cell therapy patches?” Dr. Chiang asked. One approach paired quantitative microscopy with deep learning to predict the functional characteristics of live RPE cells, offering a non-destructive way to assess cell quality. 2 According to Dr. Chiang, that approach was later folded into quality control for the iPSC-RPE program itself. Other research has revealed just how much biological complexity can hide beneath a seemingly uniform cell type. A single-cellresolution map of human RPE identified five statistically distinct, concentric subpopulations, with differences that may influence disease susceptibility.3 More recent work has pushed the same concept closer to clinical translation, outlining a manufacturing process for autologous iPSC-RPE patches with builtin quality checks for identity, sterility and phenotype. That work now underpins a Phase I/IIa trial evaluating the safety and feasibility of these patches in age-related macular degeneration.4 Together, these studies move AI out of the abstract. Beyond uncovering new biological signals, its value may also lie in making increasingly complex therapies measurable and reproducible in the first place. A PLAYBOOK FOR TRANSLATION Dr. Chiang also pointed to gene therapy as a useful precedent. Vision science has repeatedly served as an early testing ground for genetic medicine, most recently in vivo gene editing. A 2024 Phase I/ II study evaluated EDIT-101 (Editas Medicine; Massachusetts, United States), an in vivo gene-editing therapy, with results supporting further investigation of the approach.5

But Dr. Chiang’s interest wasn’t only in the therapy itself. It was in the infrastructure built around it. The $80 million Bespoke Gene Therapy Consortium brought together NIH institutes, the FDA, industry and other partners to develop shared platforms and standards for ultra-rare diseases, including a playbook intended to streamline regulatory pathways. NEI is now weighing whether a similar model could work for cell-based therapies. The barriers are familiar to anyone who has watched cell therapy struggle toward clinical use, inconsistent cell sourcing, product characterization, manufacturing and regulatory friction. Dr. Chiang raised the possibility of using AI to automate production and quality control, improve clinical testing and build datasets designed from the outset to support machine learning. THE DATA UNDERNEATH IT ALL That same thinking extends to big data. NIH’s Bridge2AI program is investing $130 million in its first stage to create large, multimodal, AI-ready datasets for discovery. One project is building detailed cell maps using approaches such as proteomics, cellular imaging and CRISPR-based perturbations, with datasets intended for public use.

discovery than on how well these fields learn to work together. For ophthalmologists, the next decade will likely be about whether promising science can become measurable, reproducible and scalable enough to actually reach the clinic. From NEI’s vantage point, the hardest problem left may not be making the breakthrough at all, but building the system sturdy enough to carry it forward.

REFERENCES 1. Eiraku M, Takata N, Ishibashi H, et al. Self-organizing optic-cup morphogenesis in three-dimensional culture. Nature. 2011;472(7341):5156. 2. Schaub NJ, Hotaling NA, Manescu P, et al. Deep learning predicts function of live retinal pigment epithelium from quantitative microscopy. J Clin Invest. 2020;130(2):1010-1023. 3. Ortolan D, Sharma R, Volkov A, et al. Single-cell-resolution map of human retinal pigment epithelium helps discover subpopulations with differential disease sensitivity. Proc Natl Acad Sci U S A. 2022;119(19):e2117553119. 4. Jha S, Hua F, Dejene R, Sarkar S, Sharma R, Bharti K. Development of a manufacturing process for clinical autologous hiPSC-derived retinal pigment epithelium. Adv Exp Med Biol. 2025;1486:165-178. 5. Pierce EA, Aleman TS, Jayasundera KT, et al. Gene editing for CEP290associated retinal degeneration. N Engl J Med. 2024;390(21):1972-1984.

Much of that work isn’t specific to ophthalmology, and that’s partly Dr. Chiang’s point. NEI is participating in a broader effort to build methods and datasets that cross disease boundaries, while still asking what vision science— with its head start in imaging, organoids, gene therapy and regenerative biology— can contribute to the wider effort. THE ROAD AHEAD None of this means AI, NAMs or cell therapies are about to change clinical practice overnight. Dr. Chiang’s ARVO talk reads more like a signal than a prediction, that the next phase of vision research may hinge less on any single

OCTOBER 2026

COVER STORY

Rods die, cones follow, and for years nobody knew why, until one clinician-scientist spent 26 years finding out. Dr. José-Alain Sahel’s Proctor Medal lecture is part gene therapy update, part optogenetics fever dream, part solar panel for the eye. Buckle up. By Sam McCommon

From a distance, the scientific community can look like a slime mold looking for food: constantly branching out, sending exploratory tendrils in every direction. Most of those tendrils wither, but occasionally some of them will thicken into paths that eventually lead somewhere valuable. From afar, it looks like there’s no central planner, no master map and no individuated parts—just relentless, decentralized trial and error until, somewhere, there’s a breakthrough.

When you zoom in closer, however, it’s nothing of the sort. Up close, the story of something as profound as restoring sight to people with retinal disease feels much less like a nameless organism and much more like a ship crew on a long voyage. Think The Odyssey. The goal of their long voyage is clear—prevent sight loss and restore it if possible—but they have no reliable chart for how to get there. They name their companions. They mourn those whom they lose along the way. But they keep rowing because the people waiting for them—not Odysseus’ Penelope or Telemachus,

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or his faithful hound Argos, but the patients who depend on their success. So, the voyagers row on, because they’re needed. This was the spirit Dr. José-Alain Sahel (France) took to the stage to deliver the Proctor Medal Award Lecture at ARVO 2026. He thanked the committee. He thanked the colleagues who had nominated him. But his first and warmest thanks went to his patients: the people who trust researchers to do better and faster, even when the work feels like shooting in the dark. The title of his talk was exactly that: Shooting in the Dark. He grinned as he said it, acknowledging how mad it may seem. Then he went on to provide a very thorough un-apology, explaining the wild and encouraging progress that has been made in the field of retinal degenerations.

THE MAN AND THE MISSION Dr. Sahel is the sort of clinician-scientist who seems to feel at home in any number of teams, whether in Pittsburgh, Paris or beyond. Companies spring up in his footsteps like mushrooms after the rain, with names like Gensight (Florida, United States), SparingVision (Paris, France), and Pixium Vision (Paris, France). He speaks about his late collaborator Thierry Léveillard the way a man might speak of his brother. They worked side-by-side for 26 years, which is as close to brotherhood as you can get. For those years, they wrestled with one stubborn question: Why do the cones die after the rods are gone, and is there anything that can be done about it? That question sits squarely in the center of retinitis pigmentosa and the wider family of inherited retinal degenerative conditions. Gene therapy can look like an elegant dream. Fix the bad

OCTOBER 2026

COVER STORY

The first winding stretch of this voyage began with an experiment that feels almost old-fashioned now. In Rd1 mice—animals whose rods die starting at around Day 8 and are completely gone by Day 20-30—the team transplanted a thin sheet of healthy rod photoreceptors into the degenerating retina. The transplanted rods didn’t form new connections. But, mysteriously, cones across the entire retina suddenly looked healthier. Something was coming out of those rods, like the molecules were whispering to each other to hang on.

instruction manual inside the cell and the cell should be fine, right? One therapy is indeed approved and more are on the way. But for the majority of patients there is still no gene-specific treatment available, and no cavalry on the immediate horizon. Even when the gene is known, the disease keeps moving. Rods disappear first, then the cones—the ones that give color to life. When a person can no longer read a face across the table or appreciate a painting on the wall, their quality of life takes a tumble. Secondary cone death is what actually blinds people. So, Dr. Sahel’s crew decided to fight the common pathway rather than only the individual mutations. Their goal was to protect the cones. Wake up whatever is left. Build new ways to see when the natural hardware is gone. This is gene-agnostic, stage-specific work that’s part science and part leap of faith. It depends entirely on scientists willing to take a shot in the dark—or hop on a ship that may wander, but knows its destination when it sees it. FINDING THE INVISIBLE FACTOR Dr. Sahel brought up a teaching from his Jewish background: that you shouldn’t take advice on how to get somewhere from someone who knows the way, because then you wouldn’t get lost. As he put it, “Getting lost is the best way to get somewhere.”

Getting lost is the best way to get somewhere. The phrase “shooting in the dark” had actually been aimed at him years earlier as a professional dig. After he presented the stillunfinished search for the cone-survival factor, a decorated leader of the field took the stage and announced that, unlike the previous speaker (Dr. Sahel), he would not be talking about “shooting in the dark trying to find something that nobody knows about.” Dr. Sahel kept the phrase and made it his own. And so the journey continued.

Finding that whisper required the pure slime-mold phase of the work: years of systematic, often brute-force exploration. They built a library of every gene expressed in the retina and tested the proteins in batches, narrowing from roughly 200,000 clones until only one unknown factor remained. They dubbed it rod-derived cone viability factor, or RdCVF. The short form of RdCVF is essentially a trophic bodyguard. It helps cones take up more glucose and feeds a metabolic pathway called aerobic glycolysis. Otto Warburg had spotted the same pathway in the retina a century before and had dismissed it as a laboratory artifact, believing that only cancer cells worked that way. As it turns out, the retina is one of the few normal tissues of the body that relies on aerobic glycolysis, using the carbon skeletons to keep rebuilding the light-sensitive outer segments that wear out every day. The longer form of the same gene works more like an antioxidant shield. Together, the two forms give cones a fighting chance. So, the factor itself was understood, but the receiving end of that cellular conversation—the receptor on the cone—was still in hiding. This is where the real grunt work kicked in. It took eight years of painstaking, often invisible labor to find that receptor, but they did: an orphan receptor called basigin-1. That single, eightyear stretch of the journey shows just how long the Odyssey phase can last before a useful pathway thickens…or how many shots in the dark you need to take before you hit something. The dual-gene insight that grew out of this work is now advancing as a therapy with SparingVision. Natural-history studies are under way. A first-in-human dose-escalation trial is fully enrolled. Early safety data look clean, and there are murmurs that something positive may be happening. It’s far too soon to celebrate. But after decades of shooting in the dark—including those eight grueling years chasing a single receptor—the outline of a target is visible. WHEN THE PHOTORECEPTORS GO QUIET Even if cones can be protected for a while, many patients eventually reach the stage where the outer segments are gone. The cells are still there—researchers call these “dormant cones”—but they no

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longer respond to light. For a long time, the field assumed those cells were useless.

successes, but the exploration may have stumbled on something. Land, ho!

Then the papers started stacking up showing that dormant cones persist in advanced disease more often than anyone had noticed.

HARDWARE AND OTHER BEAUTIFUL LONG SHOTS While the biological approaches mature, the hardware side of the field has been busy, too, like PRIMA (photovoltaic retina implant microarray) from Science Corporation (California, United States). It’s essentially a solar panel for the eye that sits under the retina in the exact place the photoreceptors used to live. Each of its 400 electrodes works independently.

The next idea on the voyage was almost pure science fiction—a mad scientist moment gone right. They borrowed light-sensitive proteins from algae and inserted them into the remaining retinal cells so they can once again communicate with the brain. Early attempts aimed at the cones themselves. The mouse data looked beautiful, but the primate data were less cooperative. Expression levels refused to behave. So, the crew pivoted to the ganglion cells—the last neurons in the retinal chain—which still survive even in very late disease. They needed a protein that could work with safer, red-shifted light instead of the intense, “staring at the sun in the desert” illumination earlier versions required. A molecule called ChrimsonR, developed by Prof. Ed Boyden, a neuroscientist at MIT, fits the description. Pair it with specifically designed goggles that deliver the right wavelength and, voilà, you have a combination therapy. The Gensight clinical trial, using this combination therapy, began just as COVID arrived. As astute readers may guess, that’s a way of saying almost nothing went according to plan. Most patients were lost to follow-up. But one man who lived near the hospital kept showing up. One day he reported that, with the goggles on, he could see the white lines of the crosswalk. The team brought him in, tested him carefully and watched him reach for objects he hadn’t been able to see before. Cortical recordings confirmed that the visual centers of his brain were lighting up in the same pattern you’d expect from real vision. This was progress. Encouraged, the team brought the rest of the small cohort back for the same careful evaluation. Most of those patients also showed meaningful improvement. Some even gained sensitivity without the goggles. It’s not yet the kind of vision that lets someone drive or recognize every face in the room, but it’s certainly vision that wasn’t there before. Work continues as the approach sharpens: better vectors, more precise cell targeting, even holographic stimulation of individual cells. A separate cone-reactivation program is now in the works at SparingVision. Two patients have been treated. Again, the early murmurs are encouraging. It’s too soon to crow about any

In patients with advanced dry age-related macular degeneration who’ve lost central vision but still have peripheral vision, the device has produced average gains of about 25 letters. One notable French patient gained 59 letters—a whopping 12 lines on the chart. Roughly 80% of participants in the larger European trial responded. They can use the new central vision together with whatever peripheral vision they still have. Regulatory conversations have begun. Then there’s the project that can make even the most seasoned researcher’s eyebrows climb off their face: whole-eye transplantation. Funded by the U.S. agency ARPA-H (Advanced Research Projects Agency for Health), a consortium is trying to solve every piece of an absurdly hard puzzle: keeping donor tissue alive, performing the surgery fast enough, controlling the immune response and, hardest of all, persuading the optic nerve to regenerate and reconnect to the brain. No one pretends this will be routine anytime soon. But like its military cousin DARPA (Defense Advanced Research Projects Agency), long shots are what the organization is for. The point is that the attempt itself will generate smaller, more immediate bits of knowledge that can be put to use. You can liken it to the number of inventions that came from NASA during the space race. THE UNGLAMOROUS MACHINERY OF THE VOYAGE None of these advancements matter if you can’t find the patients, measure what’s actually changing, or prove that a new therapy actually improves daily life. That’s why Dr. Sahel’s group and the Foundation Fighting Blindness have built a global registry across more than 30 sites, with more on the way. Standardized natural-history data will help define the endpoints that regulators and patients both care about. In Paris, they created a “Street Lab” that uses virtual reality to recreate the real-world tasks 1,500 respondents came up with—the kind of functional vision that doesn’t show up cleanly on an eye chart. The lab is now used in many trials. Dr. Sahel is frank about the tendrils that withered. In an award lecture, you don’t want to dwell on the failures, but

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acknowledging they happened shows the struggles along the way. Years disappeared. Ideas that looked brilliant in the mouse died in the primate. But no one stopped rowing or taking pot shots in the dark. ITHACA CAN’T WAIT Near the end of his talk, Dr. Sahel read a few lines from C.P. Cavafy’s poem Ithaca. That’s the one that tells the traveler to hope the road is long, full of adventure and discovery, and that the voyager shouldn’t hurry.

From a distance, the untrained eye may think it’s looking at a slime mold. Up close it’s an Odyssey made up by named people who refused to stop. The map remains incomplete and large stretches are still dark. But the number of places where light has appeared—a rescued cone, a crosswalk suddenly visible, a line of letters gained—keeps growing. The work is nowhere near finished. However, researchers are no longer shooting in the dark. Some of the shots are starting to land. And that, in any world of near-blind research, is a good day.

Dr. Sahel offered a polite disagreement with the poem’s takeaway. “It’s good to take time,” he said, “but our patients are not willing for us to take time. So it’s a long journey, but we have to do it faster.”

Editor’s Note The ARVO Annual Meeting was held from May 3 to 7, 2026, at the Colorado Convention Center in Denver, Colorado, United States. Reporting for this story took place during the event.

Like Odysseus, Dr. Sahel has grown older on the road, just as the poem predicted. Some of the friends who started with him, including Thierry, are gone. The list of people he wanted to thank was too long for any slide. Mentors, students, surgeons, scientists in Paris, Pittsburgh, Strasbourg, Jerusalem and a dozen other places. But the most important partners, he insisted, have always been the patients, ”who trust us and expect us to do better and faster,” as he put it.

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CLINICIAN & CREATOR

I once saw a man with no eyes

Little could have prepared me for the empty sockets

By Dr. Rida Khan

And yet he remains balanced, incomplete yet whole

Behind his large reflective frames I’ve spent all this time learning How to read a person from his gaze Exploring the ways His iris and pupil interplay Searching for something even deeper Useless now. How jarring, to have no window into this man’s soul He tells me he is lucky—after all, he is still alive He’s only just lost his sight. He is all laughter, he is all light Even though all he has known for three months is darkness. You and I know darkness too. But we could never know it as intimately as him He, who lived 36 years never thinking that one day soon

Behind the Verse Written during a third-year ophthalmology elective, this poem grew out of one unforgettable patient encounter: a man three months into blindness and still, somehow, all light. Dr. Rida Khan turns a clinical moment into a meditation on what vision really means, and what remains when it’s gone.

He would have seen his last full moon, His last favorite painting, film, person. His last reflection. This man, young and strong and full of hope Once had the globe And now has none Orbiting alone in a space without sun My hands shake at the slit lamp As I pretend to know What it is that I am looking for In these empty sockets.

Originally published in the Journal of Narrative Visions (JNV; www.narrativevisions.org). Reprinted with permission from JNV.

OCTOBER 2026

ENLIGHTENMENT | WOMEN IN OPHTHALMOLOGY

BEYOND

THE RETINA ON MENTORS, PATIENTS AND THE MAKING OF A CAREER

International retina specialist Dr. Christina Weng reflects on mentorship, resilience and purpose—and why the future of ophthalmology will always be shaped by people as much as innovation. By Chow Ee-Tan

Retina has undergone one of the most remarkable transformations in modern ophthalmology. Yet for Dr. Christina Weng (United States), the future of the specialty extends far beyond groundbreaking therapies and cutting-edge technology. While the field continues to evolve through artificial intelligence, gene therapy and personalized medicine, she believes its greatest strength has always been—and always will be—its people. This conviction has been shaped by her own journey.

residency at Johns Hopkins University and, later, fellowship training at the renowned Bascom Palmer Eye Institute.

Today, Dr. Weng is professor of ophthalmology and the Alice R. McPherson Retina Research Foundation Chair at Baylor College of Medicine. She is also a respected clinician, researcher, educator and former President of Women in Ophthalmology (WIO).

Surrounded by some of the world’s leading retina specialists, she discovered not only the technical challenge of vitreoretinal surgery but also the excitement of working in one of ophthalmology’s fastest-evolving subspecialties.

Yet despite her many accomplishments, she speaks with refreshing humility about the people who guided her career and the responsibility she now feels to guide others.

Few fields have advanced as rapidly over the past two decades, continually introducing new treatments and technologies that have transformed the outlook for patients with retinal diseases. For someone who enjoys lifelong learning and innovation, it was the ideal environment in which to build a career.

A SPECIALTY THAT FOUND HER Although Dr. Weng always knew she wanted to become a physician, ophthalmology was not her original destination. As a medical student, she found herself equally fascinated by plastic surgery for its artistry and family medicine for its l ong-term patient relationships. It was her mother, who had trained as an ophthalmologist in Taiwan, who encouraged her to explore ophthalmology as a specialty that combined the best of both worlds. She enrolled in an elective almost as a practical decision. “It was a purely rational decision at the time,” she recalled. “Fast forward 20 years later and I cannot imagine loving another specialty as much as I love ophthalmology.” If ophthalmology was the destination, retina became her true calling through the influence of exceptional mentors during

LEARNING THROUGH CHALLENGES Looking at Dr. Weng’s distinguished career today, it would be easy to assume confidence came naturally. But it did not. “Like many, I was constantly battling impostor syndrome,” she confessed. She believes many women experience similar feelings, often questioning whether they are ready for opportunities even when others recognize their abilities. She herself has passed up—or almost passed up—opportunities because she doubted whether she was good enough. “A pivotal moment came when I was invited to serve as national protocol chair of a major DRCR Retina Network clinical trial,” she recalled. Her initial response was to decline because she questioned whether she was ready.

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Fortunately, a trusted mentor, Dr. Daniel Martin. encouraged her to reconsider. And accepting that opportunity became one of the defining moments of her career.

Therapeutics; Pennsylvania, United States). Following treatment, his vision improved dramatically, allowing him to attend school, read independently and even dress himself.

Looking back, Dr. Weng says the experience not only accelerated her professional growth but also reminded her how profoundly mentors can shape a person’s future.

For Dr. Weng, the experience perfectly illustrates the extraordinary impact that scientific discovery, surgical skill and compassionate care can have on someone’s life.

That lesson continues to influence the way she mentors younger ophthalmologists today.

“I feel like I have the best job in the world,” she quipped.

PAYING MENTORSHIP FORWARD There is one initiative that reflected Dr. Weng’s passion for supporting women—a book that she co-edited with mentor and close friend Dr. Nina Berrocal—Women in Ophthalmology: A Comprehensive Guide for Career and Life.

Indeed, helping patients preserve or restore sight through medicine, surgery and compassion remains the most meaningful part of her work, reminding her every day why she chose this profession.

The project grew from a simple but powerful idea: creating a collection of stories where women could openly share their wisdom, experiences and even mistakes with one another.

LOOKING BEYOND TODAY’S RETINA Having witnessed remarkable advances such as anti-vascular endothelial growth factor therapy and optical coherence tomography (OCT), Dr. Weng believes retina is entering another exciting chapter.

“It was a two-year labor of love,” she reflected of the book that explores subjects ranging from research, teaching and public speaking to parenting and career development, offering practical guidance rarely found in traditional medical textbooks.

She sees enormous promise in personalized medicine, home OCT and artificial intelligence, technologies that may allow treatment to become increasingly tailored to each patient’s individual disease profile.

For Dr. Weng, its greatest success lies not in the publication itself but in hearing from readers who found encouragement in its pages. “I hope young ophthalmologists will realize that successful careers are rarely linear, and that even accomplished leaders encounter uncertainty, setbacks and difficult decisions along the way,” she said.

Yet she is equally mindful that innovation alone is not enough. “New therapies must remain affordable and accessible if they are to improve lives on a global scale,” she noted.

The enthusiastic response from readers—and requests for a second edition—has been especially rewarding for her. She also believes organizations such as Women in Ophthalmology and the American Society of Retina Specialists play an essential role in nurturing future leaders through mentorship, clinical research, public speaking and leadership opportunities. PURPOSE AND INSPIRATIONS FROM PATIENTS Despite her research achievements and international leadership roles, Dr. Weng says her greatest fulfilment still comes from caring for patients. “Every single patient encounter reinforces my ‘why’,” she said.

As both an educator and long-time fellowship program director, Dr. Weng has watched countless young retina specialists begin their careers. “I hope they will bring the same curiosity, compassion and commitment that have propelled the specialty forward for decades while remaining open to continuous learning as medicine evolves,” she said. So for Dr. Weng, the next frontier in retina is not defined solely by technological breakthroughs. But it is also about investing in people: learning from mentors, supporting colleagues and ensuring that every scientific advance ultimately serves the patient. That, perhaps, is the most enduring vision of all. CONTRIBUTOR

And there was one particular case that remains especially close to her heart. She treated a young boy with Leber congenital amaurosis using Luxturna gene therapy (voretigene neparvovec; Spark

Dr. Christina Weng Associate professor of ophthalmology and the Alice R. McPherson Retina Research Foundation Chair at Baylor College of Medicine. christina.weng@bcm.edu

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ENLIGHTENMENT

THE RETINA PARADOX WHY RETINA’S GREATEST SUCCESS IS BECOMING ITS HARDEST PROBLEM Anti-VEGF therapy transformed retinal medicine. Now the specialty is grappling with what that success created: a patient population that never leaves, a procedure that never stops and a workforce that can’t keep up. Dr. Reginald Sanders unpacks the imbalance, and what retina is doing about it. By Michaela Perez

Dr. Reginald Sanders (United States), has a way of making the problem vivid. “Imagine two graphs,” he said. “On the horizontal line is time. On the first graph, the vertical is demand for retinal services. How do you think that graph looks?” He answered his own question, sketching a steep line upward with his hand, “It would go up like this.” Then the second graph. This one plots the number of retinal specialists available to meet that demand. “It’s flat,” he said. “And starting to go down.” Dr. Sanders, president of the American Society of Retina Specialists (ASRS), has practiced retinal medicine for over 30 years. He is careful not to frame what he’s describing as a burnout crisis. It’s something more structural. “There’s an imbalance between our ability to meet the demand and supply in the face of an ever-increasing demand,” he said. “Retinal specialists are busy. And there are only so many hours in a day. So that imbalance can lead to those who feel like they’re burned out.”

There’s an imbalance between our ability to meet the demand and supply in the face of an ever-increasing demand - Dr. Reginald Sanders

THE DEMAND SIDE The forces pushing that first graph upward are multiple: an aging population, more chronic disease and a therapeutic pipeline Dr. Sanders described as “very rich and vast.” A large-scale analysis of anti-vascular endothelial growth factor (anti-VEGF) utilization across Medicare, Medicaid and commercial insurance from 2017 to 2023 found that aflibercept 2 mg injection rates rose from 361.3 to 913.1 per 100,000 ophthalmology encounters in six years.¹ Faricimab recorded the largest relative increase after its 2022 approval.¹ The patients are overwhelmingly elderly—73% over 65¹—and their diseases don’t resolve. They are managed, on relentless intervals, for years. Real-world data show individual retinal practices performed injection volumes in the hundreds to thousands annually.² Geographic atrophy now has approved therapies. Gene therapy candidates are advancing. Every one of those wins adds another patient to a schedule that was already full. THE SUPPLY SIDE The second graph is simpler…and grimmer. “There’s only a certain number of fellows coming out every year,” Dr. Sanders said. “I think it’s less than a hundred. And that number is not increasing.” What is increasing is retirements. “There’s a growing number of retinal specialists, the baby boomer group—I’m in that group— who are starting to retire,” he noted. “That’s a large number of people.” The specialty’s own data produces a counterintuitive finding. In one national U.S. survey that broke out burnout by ophthalmology

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subspecialty, vitreoretinal specialists reported the lowest rate: 30.8%.³ Uveitis specialists were highest at 45.4%.³ That number doesn’t mean the retina field is fine. The dominant burnout drivers were low work control, insufficient documentation time and misalignment with institutional leadership³—organizational variables, not injection-volume variables. High-autonomy private retina practices may score better on those dimensions even as the underlying workload compounds. The two graphs, in other words, are still moving apart. YOU CAN’T MANUFACTURE DOCTORS “First of all, you’ve got to recognize that there’s a gap,” Dr. Sanders said. “It’s…frustrating because you can’t manufacture doctors to meet the demand.” Remote scribes have helped at Retina Group of Washington, where Dr. Sanders is president, mainly by reducing staff turnover after the pandemic. “That doesn’t necessarily address the imbalance,” he said. “But it does address turnover, which creates its own stress in the retinal practice.” Some specialists are moving to four-day work weeks. The paradox is immediate. “If you had a certain amount of patients in a week that you saw in five days, and now you have to see those same amount of patients in four days, you’re busier.”

OR access is its own sore spot. “One of the big issues we have that adds to the frustrations, and perhaps burnout, is the lack of access to operating rooms.” ASRS has a task force focused on this specifically. The frustrations point toward something the specialty is increasingly having to confront: closing the gap requires solutions that go beyond individual practice adjustments. WHAT’S ACTUALLY BEING TRIED The responses operate on three levels: practice, workforce and pipeline. At the practice level, technology is helping with efficiency, reducing per-visit friction and administrative burden. The ASRS Preferences and Trends (PAT) Survey tracks how these adaptations are adopted annually—one of the few instruments with granularity to monitor real-time practice change. On the workforce side, physician extenders are the most substantive structural response. “Consider the use of physician extenders to do some of the work that we do, in those areas where not necessarily a physician needs to do the work,” Dr. Sanders said. “Under the aegis and supervision of physicians, a physician extender can supply more manpower.” A Moorfields Eye Hospital study of 4,000 nurse-delivered injections reported no serious complications and significant

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ENLIGHTENMENT

capacity improvement.⁴ A systematic review of more than 31,000 nurse-performed injections found endophthalmitis rates of up to 0.40‰—comparable to physician-delivered care—freeing physicians for more complex work.⁵

REFERENCES 1. Malhotra K, Colcombe J, Patil S, Vail D, Parikh R. U.S. trends of anti-vascular endothelial growth factor use from 2017–2023: an analysis of medicare, medicaid, and commercial insurance. PLoS One. 2026;21(1):e0335390.

On the pipeline side, sustained-release delivery systems— intravitreal implants, suprachoroidal platforms and gene therapy approaches—represent the field’s most ambitious attempt to reduce injection frequency fundamentally.⁶

2. Chaturvedi R, Wannamaker KW, Riviere PJ, Khanani AM, Wykoff CC, Chao DL. Real world trends in intravitreal injection practices among American retina specialists. Ophthalmol Retina. 2019;3(8):656-662. 3. Sedhom JA, Patnaik JL, McCourt EA, et al. Physician burnout in ophthalmology: U.S. survey. J Cataract Refract Surg. 2022;48(6):723-729.

“ASRS is a very powerful organization, and it recognizes that imbalance,” Dr. Sanders said. “The leadership is working hard to fight the battles for advocacy for payments and fight the battle for all the regulatory battles.”

4. DaCosta J, Hamilton R, Nago J, et al. Implementation of a nurse-delivered intravitreal injection service. Eye (Lond). 2014;28(6):734-740. 5. Rasul A, Subhi Y, Sørensen TL, Munch IC. Non-physician delivered intravitreal injection service is feasible and safe — a systematic review. Dan Med J. 2016;63(5):A5229.

WHERE THE FRONTIER IS Dr. Sanders sees two potential moderators on the demand side.

6. Rowe LW, Akotoye C, Harris A, Ciulla TA. Beyond the injection: delivery systems reshaping retinal disease management. Expert Opin Pharmacother. 2025;26(8):939-952.

GLP-1 drugs are the longer-term wildcard. “I don’t think it’d be surprising that that will, on the positive side, reduce the amount of chronic disease,” he said.

CONTRIBUTOR

The near-term frontier is durability. “There’s no drug that is much better in terms of results, visual results, than we have right now,” he noted. “Where the frontier is, is ways to make things last longer…That would help the imbalance.”

Dr. Reginald Sanders Retina specialist and vitreoretinal surgeon, president of the American Society of Retina Specialists (ASRS) and president of Retina Group of Washington, USA.

Faricimab’s rapid uptake signals the field is moving this way.¹ But durability alone doesn’t shrink the total patient population. It just makes each visit count for more.

regsanders@icloud.com

W here the f rontier is, is ways to make things last longer…That would help the imbalance.

THE QUESTION THAT DOESN’T GET ASKED ENOUGH Dr. Sanders is confident about the specialty’s resilience. “In my over 30 years of practice, issues have come up in our field that we have dealt with,” he said. “And although we’ve had our struggles, we’ve come up with effective solutions.”

- Dr. Reginald Sanders

But he raises one challenge unprompted, and it isn’t about physician workload. “How do we provide care for those who don’t have the insurance or the income, or those who are underinsured?” he said. “That’s a big issue in the United States. We have great treatments, but not everybody has access to these great treatments.” Medicaid patients in the 2017–2023 analysis showed markedly different utilization patterns, with minimal faricimab uptake despite its rapid rise elsewhere.¹ Insurance structure already shapes who gets which treatment. Any widening of the supply gap will not be felt equally. The demand graph keeps rising. The supply graph is flat and is starting to slide. Recognizing the gap, plainly and without flinching, is where any honest response has to begin.

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ENLIGHTENMENT

THE

ROAD

TO 2035 WHAT RETINA EXPERTS EXPECT OVER THE NEXT DECADE The future of retina, according to the people who’ll build it: durability over dosing, phenotypes over diagnosis codes, and a capacity problem nobody’s quite solved yet. By Sam McCommon

When you’re predicting the future, especially the future of eye care, a crystal ball can be murky and easily misinterpreted. A time machine is too complicated to build and operate. Believe us, we tried, and we’ll never get that intern back. Instead, it’s far more effective to ask the experts in the field what they think, so that’s what we did. We had a burning, broad question in mind: What will retina care look like in 2035? The field has come leaps and bounds over the last few decades, and the specialists we interviewed—including PIE advisory board members—converged on a few key points. Dr. Arshad Khanani (United States) summed it up well, and enthusiastically. “Overall, I believe we are entering one of the most exciting eras in retina,” he said. “The convergence of sustained delivery, gene therapy, regenerative medicine, vision restoration and AI-driven personalized medicine has the potential to fundamentally transform how we treat retinal diseases and deliver care to our patients.” There’s much good to expect, yes. But there are also some potential pitfalls, which we’ll cover towards the end. Let’s lead with optimism. FEWER JABS, LONGER CONTROL By 2035, the measuring stick itself is expected to change. Instead of obsessing over how many letters a patient gains, the real metric will be how many times a year a patient actually needs treatment.

Dr. Veeral Sheth (United States) framed it cleanly. “The last decade in retina was about efficacy. The next one is about durability and burden,” he said. “We are at or near the ceiling for visual acuity gains in exudative disease…What is changing is how often we treat and who we treat.” He continued, “By 2035 I expect the standard of care in neovascular AMD and diabetic macular edema to be measured in treatments per year rather than per month, through some combination of longer-acting biologics, sustained delivery like tyrosine kinase inhibitors (TKIs) and gene therapy.” Dr. Khanani sees the same shift already picking up steam: “I envision a future where sustained-delivery therapies dramatically reduce treatment burden and the need for frequent clinic visits, while potentially improving long-term outcomes.” Fewer visits, longer-acting options, and a lighter treatment load lead to exactly the kind of future patients (and clinics) can get behind. PERSONALIZATION FINALLY GETS PERSONAL One-size-fits-all treatment may be going the way of the dodo. Dr. Christina Weng (United States) puts her chips firmly in the pot: “The future of retina treatment will step into the era of personalized medicine…The ability to utilize imaging biomarkers, aqueous sampling or genetic testing to gain insight into the individual’s unique disease profile will be increasingly important as more and more drugs are available.”

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ENLIGHTENMENT

She further envisions AI-assisted tools like home OCT letting patients “receive an anti-VEGF injection when, and only when, their disease is active,” adding, “We are not far off from this, and important clinical trials such as Protocol AO from the DRCR Retina Network will be critical in taking us to the next level of individualized patient care.” Dr. Sashwanthi Mohan (United Arab Emirates) echoes the move towards personalization, and points out that treatments can begin earlier. “By 2035, I think retina care will become much more proactive, individualized and technology-driven,” she said. “Instead of treating disease after vision is affected, we’ll be identifying patients earlier, monitoring and predicting progression more accurately, and intervening before any permanent structural damage occurs.” Dr. Sheth is thinking along the same lines. “I expect we will finally be selecting patients by phenotype rather than by diagnosis code,” he predicted. “Imaging biomarkers combined with AI-driven segmentation should tell us earlier on in the treatment process who is a non-responder, who recurs quickly and who can safely be extended…We’re headed towards a more personalized medicine story in retina, and I think it is closer than most people presume.” Unsurprisingly, AI is set to become everyday infrastructure rather than a novelty. Dr. Mohan expects it to be, “an adjunct to routine part of retina practice, helping us analyze imaging, identify subtle biomarkers, predict treatment response and support clinical decision-making.” Prof. Gemmy Cheung (Singapore) points to the practical enablers already falling into place—home OCT, smartphone-

based monitoring and wearable technology—that should make proactive, on-demand care the norm rather than the exception. FROM PRESERVING VISION TO RESTORING IT The harder problems—geographic atrophy, non-perfusion, inherited retinal diseases—are where things get interesting. Dr. Khanani is notably energized by the restorative potential. “Geographic atrophy remains a major unmet need in retina,” he said. “I am particularly excited about the potential of emerging approaches including gene therapy, stem cell therapies, optogenetics and vision-restoration implants to not only preserve vision but potentially restore meaningful visual function.” Dr. Barbara Parolini (Italy) hopes the field will achieve “the ability to implant new artificial retinas with more satisfactory results,” and, ultimately, “to generate unreproducible tissues and implant them with satisfactory results.” She sees this happening not only with the retina, but with choroid and the ciliary body, too. FUTURE PLOT TWISTS The optimism is real, but these same experts are quick to flag potential friction ahead. Capacity sits on top of the list. “Capacity is the first,” Dr. Sheth said. “AI screening will identify far more disease than the workforce can absorb, and the number of retina specialists is not growing to meet it. Finding disease and being able to treat it are separate problems, and we are solving the first considerably faster than the second.” Dr. Mohan tacks on demographic pressure to the mix: “We may also face a growing burden of retinal disease as populations age and diabetes becomes more common.” Access and cost are also potential speedbumps. “One of the biggest challenges will be ensuring equitable access to new technologies,”

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she noted. “Many of the most promising treatments are likely to be expensive, and it is very important that innovation benefits all patients, not just those in well-resourced settings.” Dr. Weng agrees. “The therapeutic pipeline is very promising, but will be of little value if these treatments can only help a few people.” Data volume is another double-edged sword. As any internet user knows, a large volume of data doesn’t mean a large volume of good data. As Dr. Sheth anticipates, “By 2035 nearly every treated eye will be generating structured real-world data… My concern is not that we will lack evidence in 2035, it is that we will have far too much of it and no shared discipline about which signals should actually change practice.”

On the human side, Dr. Khanani raises a quieter risk. Home imaging and virtual care expanding, he warns, can mean less patient-physician interaction. “As we move towards more decentralized care, we must ensure that greater convenience does not come at the expense of patient engagement, education and adherence,” he said. THE BOTTOM LINE The specialists we spoke with see the road to 2035 as one of the most promising stretches retina care has ever faced. Turning that promise into reality will depend on the less glamorous work: building capacity, ensuring equity, handling evidence responsibly and keeping the human connection intact. The science is lining up, but the work is never over.

CONTRIBUTOR Prof. Gemmy Cheung

Dr. Barbara Parolini

gemmy.cheung.c.m@singhealth.com.sg

Dr. Arshad Khanani

parolinibarbara@gmail.com

Dr. Veeral Sheth

arshad.khanani@gmail.com

vsheth@gmail.com

Dr. Sashwanthi Mohan

Dr. Christina Weng

sashu23@gmail.com

christina.weng@bcm.edu

OCTOBER 2026