ARVO 2026: Achieving Precision Ophthalmology with Nucleic Acid Therapeutics and Advanced Preclinical Models

Nobel Keynote Summary: The Role of ASOs, siRNAs, and mRNA Therapeutics in Ophthalmic Drug Development

A defining moment of the event was the opening keynote delivered by Nobel Laureate Thomas R. Cech. His lecture, “A Farsighted Perspective on Nucleic Acid Therapeutics for Eye Disease,” set the intellectual tone for the meeting and highlighted a pivotal transition in ophthalmic drug development.

Drawing on decades of pioneering work in RNA biology, Dr. Cech traced the field from foundational discoveries to the rise of RNA as a therapeutic platform. He illustrated how nucleic acid based strategies, including antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), mRNA therapeutics, and next generation gene editing technologies, are redefining treatment approaches for inherited and degenerative retinal diseases such as Leber congenital amaurosis and age-related macular degeneration.

He emphasized that these innovations represent more than incremental progress. They signal a shift toward precise, mechanism driven interventions that act at the level of RNA to regulate or correct gene expression. This level of specificity opens new possibilities for addressing the underlying genetic causes of disease, particularly in the eye, where conventional therapies have often been limited to slowing progression rather than restoring function.

At the same time, Dr. Cech underscored the significant scientific and translational challenges associated with these approaches. Nucleic acid therapeutics require exact sequence matching in human systems, highly efficient and targeted ocular delivery, careful control of immune responses, and robust preclinical validation strategies. These requirements go well beyond those typically encountered with traditional small molecule drugs.

Figure 2. ARVO 2026 opening keynote address by Dr. Thomas R. Cech [2].

Nucleic Acid Therapy Targets: Leber Congenital Amaurosis (LCA) and Age-Related Macular Degeneration (AMD)

Among the diseases at the forefront of nucleic acid therapeutic development discussed at ARVO are Leber congenital amaurosis (LCA) and age-related macular degeneration (AMD). LCA comprises a group of rare inherited retinal dystrophies causing severe vision loss from birth due to mutations in genes essential for phototransduction, ciliary function, and photoreceptor survival. Conversely, AMD remains the leading cause of vision loss in adults over 50, involving progressive macular damage often driven by complement system dysregulation, oxidative stress, lipid metabolism defects, and abnormal angiogenesis [3]. Beyond these two conditions, a broad spectrum of other ocular pathologies similarly necessitates the development of novel interventions, such as RNA-based medicines, to address currently unmet clinical needs.

Figure 3. Various types of eye diseases [3].

From AMD Biology to Translational Preclinical Validation

For age-related macular degeneration, the translational challenge is not only to identify promising therapeutic mechanisms, but also to evaluate whether those mechanisms can protect retinal structure, preserve visual function, and modulate disease-relevant pathways in biologically meaningful preclinical systems.

AMD is a heterogeneous retinal disorder involving retinal pigment epithelium dysfunction, photoreceptor degeneration, oxidative stress, complement dysregulation, choroidal neovascularization, and, in advanced neovascular disease, fibrotic scarring. These disease processes cannot be fully captured by a single endpoint or model system. Instead, robust AMD drug development requires a structured preclinical workflow that connects disease-relevant models with functional, structural, molecular, and histological readouts.

Cyagen’s ophthalmology research platform is designed to support this evidence-building process, from mechanism-oriented model selection to in vivo pharmacology and translational data generation.

Validated AMD Preclinical Models: Dry AMD, Neovascular AMD (nAMD), and Subretinal Fibrosis

To support AMD-related therapeutic development, Cyagen has established multiple preclinical models that reflect key pathological features of dry AMD, neovascular AMD, and advanced subretinal fibrosis. These models provide practical systems for evaluating therapeutic candidates across different disease mechanisms, including retinal pigment epithelium injury, complement pathway modulation, choroidal neovascularization, vascular leakage, and fibrotic scar formation.

At ARVO 2026, Cyagen’s advanced preclinical capabilities were highlighted in a poster presentation recognized as one of the conference’s “Hot Picks,” featuring pharmacological validation in a dry AMD model.

1. Dry AMD Pharmacology: NaIO₃-Induced Retinal Degeneration Model

This presentation showcased our specialized in vivo pharmacology services for dry AMD, focusing on our NaIO₃-induced retinal degeneration model. By utilizing the systemic administration of sodium iodate to selectively induce oxidative stress in retinal pigment epithelial (RPE) cells, this model effectively mimics RPE cell death and geographic atrophy. We provide robust pharmacological validation for this model, demonstrating how therapeutics such as the C3 complement inhibitor Pegcetacoplan can preserve RPE and outer nuclear layer (ONL) structural integrity, downregulate complement activation markers, and restore visual function.

(1) Structural Protection

Pegcetacoplan significantly preserved retinal thickness and alleviated structural damage in the NaIO₃-induced dry AMD model.

Figure 4. Pegcetacoplan Alleviates Retinal Structural Damage.

(2) Retinal Function

Pegcetacoplan treatment significantly ameliorated NaIO₃-induced functional impairment.

Figure 5. A–D) ERG recordings of a-wave and b-wave responses under scotopic and photopic conditions at different time points in mice from various treatment groups (PBS control, NaIO₃+PBS, NaIO₃+Pegcetacoplan), reflecting functional changes in photoreceptors and inner retinal neurons. Pegcetacoplan treatment significantly ameliorated NaIO₃-induced retinal functional impairment.

(3) Mechanism of Action

Pegcetacoplan treatment effectively mitigated NaIO₃-induced complement hyperactivation and downregulated C3 mRNA expression.

Figure 6. C3 expression levels in the eyecups were quantified by qPCR across three groups: PBS control, NaIO₃ combined with PBS treatment (NaIO₃+PBS), and NaIO₃ combined with the C3 inhibitor Pegcetacoplan treatment (NaIO₃+Peg).

2. Wet AMD (CNV) and Subretinal Fibrosis: Laser-Induced Models and Anti-VEGF Efficacy Testing

Cyagen also offers fully validated models for neovascular AMD (nAMD) and subretinal fibrosis:

Laser-Induced CNV (Wet AMD) Model: Mimics neovascular AMD (nAMD) by using laser photocoagulation to rupture Bruch's membrane, inducing localized choroidal neovascularization and vascular leakage. This model is fully validated for evaluating anti-angiogenic potency with anti-VEGF agents like Aflibercept.

(1) Fluorescein Angiography (FFA)

Figure 7. FFA images showing fundus vascular changes.

(2) Quantitative Efficacy Analysis

Figure 8. Comprehensive statistical analysis of the angiographic data confirms the therapeutic efficacy of Aflibercept.

(3) Neovascularization Assessment

IB4 staining of RPE/choroid flatmounts on day 21 in the laser-induced wet AMD model.

Figure 9. A) IB4 immunofluorescence images showing the distribution of choroidal neovascularization in the PBS and Aflibercept groups. B) Quantitative analysis of the IB4-positive area in the flat-mounts.

（4）Fibrosis & Scarring

Figure 10. A) α-SMA immunofluorescence images showing the distribution of fibrotic areas in the PBS and Aflibercept groups. B) Quantitative analysis of the α-SMA-positive area in the flat-mounts. The α-SMA-positive area in the Aflibercept group was significantly smaller than that in the PBS group, consistent with the trend observed in IB4 staining, indicating the inhibitory effect of Aflibercept on fibrosis.

Two-Stage Laser-Induced Subretinal Fibrosis Model: Utilizes sequential laser insults to trigger a sustained inflammatory response, promoting fibrous tissue proliferation and scar formation to mimic advanced nAMD and PCV scarring.

(1) Fluorescein angiography (FFA)

Figure 11. Representative FFA images were acquired on days 0, 7, 14, and 21 after laser treatment.

Figure 12. Representative OCT images were obtained on days 7, 14, and 21 post treatment.

(2) Fibrotic Gene Expression

Figure 13. Gene Expression Analysis of Fibrosis Markers.

(3) Immunofluorescence Analysis

Figure 14. RPE/choroid flatmounts were collected from laser-induced CNV and two-stage laser-induced fibrosis models at 14 and 21 days after laser treatment.

Building a Complete Preclinical Evidence Chain: From Cells to Gene-Edited In Vivo Models

While AMD pharmacology models provide disease-relevant in vivo validation, early-stage therapeutic development often begins with cellular systems. For nucleic acid therapeutics, in vitro assays are especially important for evaluating cellular uptake, target engagement, preliminary efficacy, cytotoxicity, and potential off-target effects before advancing into animal studies.

Cyagen provides cell-based platforms that can support early mechanistic and screening studies, including retinal pigment epithelial and photoreceptor-like cell models.

After initial in vitro validation, therapeutic candidates can be advanced into in vivo systems for mechanistic and translational assessment. Knockout models can help researchers investigate gene function and disease mechanisms, while humanized gene models are particularly valuable for therapeutic modalities that depend on human-specific sequences, regulatory elements, splice sites, or target structures.

This is especially relevant for nucleic acid therapeutics discussed in Dr. Cech’s keynote, including ASOs, siRNAs, mRNA-based approaches, and next-generation gene editing strategies. These modalities often require precise interaction with human genetic targets, making humanized in vivo systems important for evaluating efficacy, specificity, and translational potential.

Through the HUGO-GT™ platform, Cyagen develops humanized genomic ortholog models that incorporate human gene structures to support studies of human-specific biology and sequence-dependent therapeutic mechanisms.

Integrated CRO Readouts for Ocular Drug Development

For ophthalmology drug development, model selection alone is not sufficient. A robust preclinical package requires integrated readouts that connect anatomical protection, visual function, molecular mechanism, and histopathological evidence.

Cyagen’s ocular CRO capabilities support this translational workflow through a combination of structural, functional, imaging, molecular, and tissue-level analyses, including:

• Optical Coherence Tomography (OCT) for retinal structural assessment
• Fundus imaging and fluorescein fundus angiography for vascular leakage and lesion monitoring
• Electroretinography (ERG) for retinal functional evaluation
• Immunofluorescence staining for cell-type-specific and pathology-associated markers
• qPCR-based gene expression analysis for pathway and mechanism studies
• RPE/choroid flatmount analysis for CNV and fibrosis quantification
• Specialized ocular disease modeling and in vivo pharmacology workflows

Together, these capabilities allow researchers to generate integrated preclinical evidence across disease progression, therapeutic response, and mechanism of action.

Partner with Cyagen: Leveraging Humanized Models and End-to-End Ocular CRO Services for Precision Vision Science

To deliver robust, translational data packages tailored to your specific research goals, our platform integrates high-resolution structural and functional readouts, including Optical Coherence Tomography (OCT), fundus imaging, Electroretinogram (ERG), and multi-marker immunofluorescence.

By partnering with Cyagen, vision scientists gain not only state-of-the-art animal models but also a trusted collaborator committed to the same goal Dr. Cech and the ARVO community championed in Denver: translating groundbreaking RNA and nucleic acid science into tangible, personalized therapies that restore sight and improve quality of life. As precision ophthalmology advances from promise to practice, Cyagen’s gene-edited mouse models stand ready to illuminate the way forward, model by model, gene by gene, vision by vision.

Reference

[1] Association for Research in Vision and Ophthalmology. About the meeting [Internet]. Rockville (MD): ARVO; [updated 2026; cited 2026 Apr 29]. Available from: https://www.arvo.org/annual-meeting/about.

[2] Association for Research in Vision and Ophthalmology. ARVO+Genentech Keynote Series [Internet]. Rockville (MD): ARVO; [updated 2026; cited 2026 Apr 29]. Available from: https://www.arvo.org/annual-meeting/program-schedule/lectures/arvo-genentech-keynote-series.

[3] He X, Fu Y, Ma L, Yao Y, Ge S, Yang Z, Fan X. AAV for Gene Therapy in Ocular Diseases: Progress and Prospects. Research (Wash D C). 2023 Dec 22;6:0291. doi: 10.34133/research.0291. PMID: 38188726; PMCID: PMC10768554.