The gene therapy shift: A closer look at the science powering next-generation retinal treatments

Over the past decade, intravitreal injections of anti-VEGF biologics have significantly improved the way many retinal diseases are managed, albeit with some limitations. It’s striking to consider that when neovascular age-related macular degeneration (nAMD) was first formally described as “senile macular illness” in 1885,¹ the notion of retinal cells producing their own medication would have been incomprehensible. In 2025, the concept of gene therapy is not only well understood but is also a clinical reality that may soon become a therapeutic option in the retina specialist’s armamentarium.

Gene therapy first entered the ophthalmology space in 2017 with the approval of voretigene neparvovec-rzyl (Luxturna; Spark Therapeutics) for Leber congenital amaurosis, a rare inherited retinal disease.² This landmark approval opened the door for the extension of this concept to common, noninherited retinal diseases such as nAMD, diabetic retinopathy (DR), and diabetic macular edema (DME).

Gene therapies for retinal conditions use viral vectors to transduce retinal cells with instructions to manufacture specific proteins. Following transduction, cells are programmed to either express functional proteins that are absent or defective due to genetic mutation (eg, RPE65) or to produce proteins that are not endogenously expressed but are beneficial in acquired conditions such as nAMD, DR, and DME (eg, aflibercept; Eylea; Regeneron Pharmaceuticals).^3-5 Figure 1 shows a conceptual illustration of the mechanism of retinal cell transduction by viral vectors.^3-5

Multiple ongoing clinical programs utilizing proprietary vectors have demonstrated functional and anatomic benefit while reducing the need for frequent anti-VEGF injections.^6-9 Having demonstrated clinical utility in both inherited and acquired retinal diseases, multiple gene therapy programs now have several years of clinical data to support the efficacy, tolerability, and durability of such treatments. Rightfully, the question of safety is top of mind when it comes to investigational treatments such as gene therapy. Concerns with adeno-associated virus (AAV) gene therapy programs include the risk of inflammation and immunogenicity, potential off-target effects, and the inability to turn off protein production post transduction.

Fortunately, the native characteristics of retina tissue mitigate several of these concerns. The retina is comprised of a stable, nondividing cell population, and the relatively small tissue volume of the retina (~65 mm³) allows for localized delivery.¹⁰ The blood-retina barrier helps minimize systemic exposure of therapeutics injected into the eye,¹¹ theoretically reducing the risk of inflammation-related adverse events and systemic off-target effects.

Direct comparisons between ongoing programs or vectors cannot be made at this time due to differences in study design, capsid properties, anti-VEGF gene product, and route of administration (ie, subretinal, suprachoroidal, and intravitreal). Dosing varies among clinical programs and may impact the overall safety profile of each gene therapy, as lower doses are theoretically less likely to elicit an immune response.

To minimize the risk of intraocular inflammation, phase 2 studies typically include prophylactic steroid regimens.^7,9,12,13 Active phase 3 trials of intravitreal gene therapy programs utilize a prophylactic topical steroid taper of at least 20 weeks.^7,14 The phase 3 trials with subretinal delivery do not include a prophylactic steroid regimen,¹⁵ likely due to the localization of capsids to a small, defined area in the surgical setting. Phase 1/2 nAMD gene therapy trials now have up to 4 years of follow-up, and the investigational agents have been well-tolerated overall, with evidence of ongoing, sustained treatment effects.

Current phase 3 programs are assessing anti-VEGF response prior to gene therapy treatment with the intention of providing this type of therapy only to patients most likely to benefit. Considering data supporting the benefits of consistent treatment in diseases such as nAMD and DME,^16,17 the permanence of cell transduction may be viewed as a favorable feature of the therapy for optimal long-term disease control, rather than a deterrent.

Although numerous studies have provided evidence to support the efficacy of anti-VEGF agents for treating patients with nAMD, DR, or DME, the greatest benefits are observed under highly controlled clinical trial settings with frequent, regular anti-VEGF injections vs real-world routine clinical practice where injections are often administered less frequently.¹⁸ Less-frequent injection intervals in clinical practice can lead to excessive disease activity and the potential for vision loss over time. Patients may find the frequent office visits needed to administer the injections challenging.

Barriers to anti-VEGF injection adherence include logistical issues, socioeconomic factors, medical comorbidities, and fear of injections.^19,20 Nonadherence to the recommended dosing schedule may lead to suboptimal visual outcomes in the long term due to fluctuating drug levels and resulting oscillations in retinal thickness, which may occur during unintended, extended intervals between injections.^16,21,22 Despite newly approved agents providing incremental increases in dosing intervals, duration of action may still be relatively limited, and retina specialists still cite “longer-lasting therapies” as the greatest unmet need in nAMD treatment in 2025 (Figure 2).²³

Gene therapy shows promise in solving these issues by reducing or eliminating the onerous cycle of repeated intravitreal (IVT) injections. The anti-angiogenic properties of anti-VEGF agents combined with a longer-lasting, backbone therapeutic effect have the potential to improve long-term visual outcomes, aligning with the desire for safe, efficacious, durable, and practical therapies. Indeed, in results from the 2025 ASRS Preferences and Trends Survey, gene therapy was cited as the treatment that “excites you most.” (Figure 3).²³

Three investigational gene therapy candidates are in clinical trials for nAMD treatment: 4D-150 (4FRONT-1, phase 3; 4FRONT-2, phase 3), ADVM-022 (ARTEMIS, phase 3), and ABBV-RGX-314 (ATMOSPHERE, phase 3; ASCENT, phase 3; AAVIATE, phase 2), as shown in the Table.^7,12,13,15 4D-150 and ADVM-022 are administered via IVT injection, whereas ABBV-RGX-314 is delivered via subretinal injection (phase 3) or suprachoroidal injection (phase 2).

These clinical programs utilize modified AAV vectors to transduce retinal cells to produce aflibercept (4D-150 and ADVM-022) or ranibizumab (ABBV-RGX-314). In addition to aflibercept, the genetic payload delivered by 4D-150 includes a second transgene encoding for an inhibitory RNA sequence against VEGF-C, which enhanced the production of aflibercept in preclinical models.³

4D-150, ADVM-022, and ABBV-RGX-314 are a result of decades of ongoing collaborations between physicians and study sponsors, who share the goal of optimizing long-term visual outcomes for patients with retinal diseases such as nAMD, DR, or DME. Although some retina specialists may prefer to reserve gene therapy for patients with high treatment burden, others may consider earlier intervention based on individual patient factors. Phase 3 programs for 4D-150 and ADVM-022 include both treatment-naive and previously treated patients, whereas the phase 3 ABBV-RGX-314 program exclusively enrolled individuals with prior anti-VEGF exposure.

Future analyses from these studies will help inform patient selection by clarifying which populations derive the greatest benefit and at which time gene therapy intervention is most appropriate. If approved, clinical adoption of these gene therapies will require careful consideration of overall safety and efficacy data in combination with the practicality of use and individual patient needs. The retina community is actively engaged in bringing these phase 3 programs to the finish line, with hundreds of sites currently enrolling patients globally. Phase 3 readout timelines are provided in the Table, showing when the exciting process of submission to regulatory authorities for potential approval will begin.

Carl Regillo, MD, FACS
Director of the Retina Service at Wills Eye Hospital, Philadelphia, PA

Veeral Sheth, MD, MBA, FACS, FASRS
Partner and director of clinical trials at University Retina, Chicago, IL

Lejla Vajzovic, MD
Professor of ophthalmology and director of CME at Duke University School of Medicine, Durham, NC

References

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