February 13, 2026-
A newly published review in Gene Therapy examines how adeno-associated virus (AAV)-based gene therapy could reshape treatment for neovascular age-related macular degeneration (nAMD)—while emphasizing that several scientific and translational challenges still stand between promising trial concepts and routine clinical use.
Immunity remains a front-line constraint
The review highlights preexisting neutralizing antibodies (NAbs) against AAV capsids as a major factor that can reduce treatment effectiveness and limit patient eligibility. Because many people are naturally exposed to wild-type AAV over their lifetime, antibody-mediated neutralization may prevent therapeutic vectors from reaching retinal target tissues at adequate levels, lowering transduction efficiency and narrowing the pool of patients who can receive treatment.
Re-dosing is still a difficult problem to solve
Another key concern is immune priming after first exposure. Even if initial dosing is successful, the immune response generated against the capsid can complicate future re-dosing, which is an important practical consideration for chronic retinal disease management. The authors underscore the need for strategies that enable retreatment without triggering meaningful safety risks or losing efficacy due to rapid neutralization.
Delivery route trade-offs shape feasibility in real-world retina care
The paper summarizes how route of administration influences both performance and practicality:
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Subretinal delivery can achieve strong transduction by directly targeting retinal pigment epithelium (RPE) and photoreceptors, but it requires a surgical procedure that may limit routine adoption.
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Intravitreal injection fits standard clinic workflows and is less invasive, yet anatomical barriers (e.g., the internal limiting membrane) and immune factors in the vitreous can reduce the vector’s ability to reach target retinal cells efficiently.
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Suprachoroidal delivery is discussed as an emerging “middle ground” that could offer improved access with less invasiveness than subretinal surgery, but it still needs further validation to establish a clear efficacy and safety profile.
Expression control, AAV payload limits, and CMC readiness remain pivotal
Beyond delivery and immunity, the review also calls attention to transgene overexpression risk, especially where higher vector doses are used to achieve therapeutic protein levels—raising concerns around retinal homeostasis and inflammation. The authors note that AAV’s limited packaging capacity can restrict inclusion of regulatory elements that would otherwise improve cell specificity and expression tuning.
On the translational side, the paper points to ongoing challenges in manufacturing scalability, including yield, batch variability, and purity attributes—factors that will materially affect cost, access, and the ability to support larger nAMD patient populations.
What it means for the field
The overall message is optimistic but practical: AAV gene therapy for nAMD is advancing quickly, yet the next leap will depend on immune-evasive capsids, delivery improvements, tighter expression control, and more scalable CMC solutions that can support broad clinical deployment.
