Ocular gene therapy enters the age of precision engineering: How molecular tools and delivery platforms are shaping next-generation treatments

The eye has long been considered one of the most promising organs for gene therapy. Its small size, compartmentalized structure, relative accessibility, and suitability for local administration make it a favorable target for nucleic acid-based treatments. For many inherited eye diseases, the cause can often be traced to specific genetic mutations, giving gene therapy the possibility of addressing the molecular basis of disease rather than only managing symptoms.

Yet the clinical development of ocular gene therapy has not been straightforward. According to the review, around 3,900 gene therapy clinical trials had been conducted worldwide by 2023, but only 63 of them, or 1.6%, were related to ocular diseases. At the same time, at least 295 million people globally live with vision impairment, and more than 340 genes have been associated with inherited retinal diseases. This gap between clinical need and translational progress suggests that ocular gene therapy still has substantial room to grow, but also faces significant technical and clinical barriers.

In a review published in Eye Discovery, Lingyun Kong, Changchang Xin, Mingrui Cheng, Shuangyu Ma and co-authors, with corresponding authors Jia Chen from ShanghaiTech University and Xujiao Zhou from the Eye & ENT Hospital of Fudan University, provide a broad overview of the field. The article examines ocular gene therapy across three closely connected areas: molecular tools, delivery platforms, and applications in specific eye diseases. Together, these areas show how the field is moving beyond early gene replacement approaches toward a more precise and integrated form of therapeutic engineering.

One major shift is the growing diversity of molecular tools. Early gene therapy strategies often focused on delivering a functional copy of a missing or defective gene, an approach particularly suited to loss-of-function disorders. The approval of Luxturna® for RPE65-associated inherited retinal dystrophy provided an important clinical proof of concept for in vivo ocular gene therapy. However, not all eye diseases can be treated by simply adding back a normal gene.

Different genetic mechanisms require different interventions. Gain-of-function or dominant-negative mutations may need allele silencing or gene disruption. Splicing defects or RNA-level abnormalities may be better addressed through antisense oligonucleotides, siRNA, or RNA-targeting systems such as Cas13. Point mutations may require more precise in situ correction, including base editing or prime editing.

The review groups these strategies into three broad categories: gene silencing, gene upregulation, and in situ correction. Gene silencing approaches include CRISPR/Cas9-mediated knockout, CRISPR interference, Cas13, antisense oligonucleotides, and siRNA, all of which can reduce harmful gene expression or degrade disease-related transcripts. Gene upregulation includes gene augmentation and CRISPR activation, with the goal of restoring insufficient gene function. In situ correction aims to repair disease-causing mutations directly, using approaches such as CRISPR/Cas9-mediated HDR or HITI, base editors, and prime editors. Each tool offers distinct advantages, but also comes with limitations in efficiency, precision, durability, safety, and deliverability.

Having a molecular tool, however, is only part of the challenge. A therapy must also reach the right cells in the eye. Although the eye is well suited to local treatment, it contains complex anatomical and physiological barriers. The corneal epithelium, conjunctival-scleral route, blood–ocular barrier, vitreous body, layered retina, and retinal pigment epithelium can all influence whether a therapeutic molecule or vector reaches its intended target.

For this reason, delivery route is itself a major part of treatment design. The review discusses topical eye drops, subconjunctival injection, intrastromal injection, intracameral injection, intravitreal injection, subretinal injection, and suprachoroidal injection. Each route has its own target tissues, distribution patterns, invasiveness, and safety considerations. Intravitreal injection is widely used clinically, but efficient delivery to photoreceptors and the retinal pigment epithelium remains difficult because vectors must cross multiple retinal layers. Subretinal injection offers more direct access to the outer retina, but requires surgical intervention and carries local risks. Future ocular gene therapies will therefore need to define not only which molecular tool to use, but also where and how it should enter the eye, which tissue layer it should reach, and how long its activity should last.

Vector choice is another key issue. Adeno-associated virus remains the main platform for ocular gene delivery. AAV can support relatively long-term expression in non-dividing ocular tissues and has been studied extensively for safety and tissue tropism. However, its packaging capacity is limited, typically to less than 4.7 kb. This creates challenges for delivering large genes or complex genome-editing systems. Researchers are addressing these constraints through engineered AAV capsids, dual-AAV systems, compact Cas proteins, and truncated or mini-gene strategies.

At the same time, virus-like particles and lipid nanoparticles are expanding the delivery toolbox. Virus-like particles can transiently deliver RNA, proteins, or ribonucleoprotein complexes, making them useful for editing applications where long-term expression is not desired. Lipid nanoparticles offer a non-viral route with tunable composition, flexible cargo capacity, and potential for repeat dosing. For therapies involving RNA, proteins, or editing complexes with transient activity, LNPs provide an alternative to viral vectors. However, their efficiency in different ocular cell types, duration of action, immune profile, and scalability still require further optimization.

These tools and delivery systems are being explored across a wide range of ocular diseases. For inherited retinal disorders, the review covers therapeutic strategies for Leber congenital amaurosis, retinitis pigmentosa, Stargardt disease, Usher syndrome, choroideremia, and other conditions. Depending on the disease mechanism, approaches may involve gene augmentation, allele silencing, or precise genome editing. In glaucoma, gene therapy studies are examining pathways related to intraocular pressure regulation, trabecular meshwork function, ciliary body activity, and retinal ganglion cell protection. In age-related macular degeneration, strategies include long-term anti-VEGF expression, complement regulation, CRISPR-based suppression, and RNA-targeting approaches. Herpetic stromal keratitis has also emerged as a potential application area for gene-editing strategies designed to disrupt viral replication genes.

This broader disease landscape shows that ocular gene therapy is no longer limited to a small number of monogenic disorders. It is increasingly being explored for acquired and complex diseases as well. However, broader application also raises the level of difficulty. Many inherited eye diseases are highly heterogeneous: the same clinical disorder may be caused by different genes, and a single gene may contain numerous disease-causing variants. Therapies targeting common mutations may benefit some patient groups first, but broader coverage will require either more generalizable strategies or more precise genetic diagnosis and patient selection.

The review also emphasizes several remaining barriers to clinical translation. Genome-editing tools must minimize off-target effects and genomic instability. Viral and non-viral delivery systems must reduce immunogenicity while improving tissue specificity. AAV capacity limits the delivery of large genes and complex editing systems. VLPs and LNPs need stronger evidence of reliable and controllable delivery in ocular tissues. Clinical translation will also depend on predictive human-relevant disease models, scalable manufacturing, and long-term safety monitoring.

The next stage of ocular gene therapy is therefore unlikely to be defined simply by applying more editing tools to the eye. Instead, progress will depend on integrating molecular tools, delivery platforms, administration routes, disease mechanisms, and clinical requirements. For each disease, researchers must determine whether the best strategy is to silence, supplement, activate, or correct a gene; whether the most appropriate platform is AAV, VLP, LNP, or another system; whether delivery should be intravitreal, subretinal, suprachoroidal, topical, or through another route; and how therapeutic duration and safety risks should be balanced.

This is what precision engineering means in ocular gene therapy. The future of the field will not depend on any single technology alone, but on designing the right therapeutic combination for the right disease, mutation, and ocular tissue. As molecular tools and delivery systems continue to improve, the eye may become an increasingly important setting in which gene therapy moves from proof of concept toward more precise and clinically assessable treatments.

DOI:10.1016/j.edisc.2026.100040

Read the full article: https://doi.org/10.1016/j.edisc.2026.100040

About Eye Discovery

Eye Discovery is an open-access, peer-reviewed international academic journal, with ISSN 3117-4167. It is published quarterly by Elsevier and serves as the official journal of Eye & ENT Hospital of Fudan University, China. 

Eye Discovery  is dedicated to creating a high-end platform for ophthalmologists, scientists, and scholars worldwide to focus on innovative achievements in ophthalmology and interdisciplinary fields, and to promote academic dissemination and exchange.

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