Dual-restricted AAV gene delivery via suprachoroidal administration mediates precision RPE SOCS3 restoration for dry age-related macular degeneration.

EGFR inhibition promotes functional engraftment and graft survival via donor-derived CHI3L1 in fetal RPE suspension transplantation

Summary Numerous clinical trials have highlighted the translational potential of retinal pigment epithelial (RPE) cell transplantation in retinal degeneration (RD). However, an unsolved challenge remains in addressing chronic graft dysfunction, primarily due to poor integration and cell loss. Here, we perform a single-cell transcriptomic comparison between grafted RPE cells and host RPE. Our analysis identifies EGFR expression in donor fetal RPE cells as a significant obstacle to functional integration. Through multimodal imaging and spatial transcriptomics, we demonstrate that EGFR inhibition (EGFRi) facilitates effective engraftment of fetal RPE cell suspension, leading to the functional restoration of the outer blood-retinal barrier, and restrains neurodegeneration in preclinical RD models. This effect is mechanistically linked to graft reepithelialization via the activation of intrinsic CHI3L1-IL13RA2 signaling in EGFRi-treated donor cells. Moreover, EGFRi-induced CHI3L1 secretion contributes to immunosuppression that complements anti-lymphocytic therapy, thereby extending graft survival. Thus, repurposing Food and Drug Administration (FDA)-approved EGFR inhibitor offers a safe and cost-effective approach to advancing fetal RPE suspension transplantation into clinical practice.

Generation of dual mouse models of retinal degeneration with slow and rapid progression driven by ectopic RIP3 expression

Dry age-related macular degeneration (AMD) is a leading cause of blindness, characterized by progressive loss of retinal pigment epithelium (RPE) and subsequent photoreceptor degeneration. Current experimental models, including sodium iodate-induced injury, fail to fully recapitulate the chronic, age-related progression of the human disease. Although RIP3-mediated necroptosis has been strongly implicated in RPE cell death, its direct contribution to retinal degeneration in vivo remains unclear. To address this limitation, we generated two RIP3 transgenic mouse lines with distinct patterns of RIP3 overexpression. While RIP3-Tg mice exhibit systemic RIP3 overexpression, RIP3-Tg-RPE mice display additional RPE-specific overexpression beyond the levels observed in RIP3-Tg mice. We then evaluated these transgenic lines, along with wild-type controls, for age-driven retinal degeneration by using optical coherence tomography (OCT), behavior-based visual function assays, and molecular profiling of inflammation and cell death. First, RIP3-Tg mice exhibited gradual retinal thinning, progressive visual decline, and sustained upregulation of pro-inflammatory cytokines (IL-1β, TNF-α, and IL-6) over 6–15 months, recapitulating the slow progression of dry-AMD. Second, RIP3-Tg-RPE mice, which exhibit further RPE-specific increases in RIP3 expression, showed markedly accelerated retinal degeneration, with significant structural and functional deficits evident as early as 2 months of age. These findings indicate that ectopic RIP3 expression in the RPE contributes to inflammatory responses and subsequent retinal degeneration. Collectively, our results highlight RIP3 as a potential contributing factor in the progression of retinal degeneration and introduce biologically relevant transgenic models that capture both slow and accelerated disease progression. These models provide a valuable platform for investigating disease mechanisms and developing therapeutic strategies targeting necroptosis in dry-AMD.

Encapsulated cell technology delivers ciliary neurotrophic factor to promote JAK/STAT-dependent photoreceptor survival in retinal degeneration

A therapeutic dose-response relationship linking NT-501–derived CNTF levels to JAK/STAT3 activation and photoreceptor protection in human retinal tissue is established, and an optimal concentration range for efficacy is suggested.

Optogenetic vision restoration: translational barriers and emerging therapeutic strategies.

Preclinical evaluation of AL-001, a gene therapy for wet age-related macular degeneration

Frequent intravitreal administration of antivascular endothelial growth factor Vascular endothelial growth factor agents remains a major limitation in the management of wet age-related macular degeneration (wAMD). This study evaluated whether suprachoroidal delivery of an engineered recombinant adeno-associated viral (rAAV)-aflibercept vector could achieve sustained, targeted expression with improved efficacy and safety compared with intravitreal administration. AL-001, an engineered rAAV vector expressing aflibercept, was developed and characterized. Its expression profile was first assessed in New Zealand white rabbits following suprachoroidal space (SCS) injection. Efficacy, pharmacokinetics, and safety were then evaluated in a nonhuman primate model of laser-induced choroidal neovascularization (CNV), comparing SCS and intravitreal (IVT) administration routes. AL-001 efficiently expressed aflibercept in relevant ocular cells in vitro . In rabbits, SCS administration produced sustained aflibercept levels in ocular tissues. In the nonhuman primate CNV model, a single SCS injection of AL-001 showed favorable efficacy to IVT injection and a notable mild inflammatory response. At week 4, grade IV lesion incidence was 0% (0/48) after SCS administration versus 14.3% (6/42) after IVT administration (absolute difference, −14.3 percentage points; 95% CI, 3.7%–27.8%; P = 0.0258). Throughout follow-up, mean leakage area and grade IV lesion incidence remained 0 with SCS, versus IVT peaks of approximately 0.3 mm 2 and 33.0%, respectively, declining to 0.03 mm 2 and 2.0% by day 100. Both the medium and high doses decreased pathological vascular leakage and subretinal hyperreflective material. Vector administration preceded laser-induced CNV modeling, demonstrating that sustained intraocular aflibercept expression in the retina and choroid provided durable antiangiogenic protection. Pharmacokinetic analysis confirmed distinct ocular exposure profiles between routes, with viral genomes confined predominantly to the injected eye and no significant systemic accumulation. AL-001 was well tolerated, without sustained intraocular pressure elevation or severe ocular inflammation, and only mild-to-moderate treatment-emergent adverse events. Low pre-existing anti-AAV2 immunity and time-dependent neutralizing antibody responses postdosing, informing a translational model for patient stratification and redosing feasibility. Suprachoroidal administration of AL-001 is well tolerated and provides durable, targeted aflibercept expression with pronounced antiangiogenic efficacy. These results support AL-001 as a promising, long-acting therapeutic candidate for wAMD.

Drug Delivery Across the Blood-Retinal Barrier: Biological Gateways for Posterior Segment Therapy.

Posterior-segment retinal diseases remain a leading cause of irreversible vision loss worldwide, yet effective treatment continues to be limited by the challenge of achieving sufficient and durable drug exposure within target ocular tissues. Although intravitreal injection has transformed the management of retinal diseases, therapeutic success is determined not only by drug potency but also by transport across retinal interfaces, intraocular distribution, and long-term tissue exposure. Traditionally, these challenges have been attributed primarily to the restrictive nature of the blood-retinal barrier (BRB). In this review, we propose a shift from a barrier-centric view of ocular drug delivery toward a biological gateway framework. We examine how the inner and outer BRB actively regulate therapeutic access through coordinated mechanisms including paracellular restriction, transcellular transport, receptor-mediated trafficking, and disease-associated remodeling. Building upon this biological foundation, we discuss how route-specific delivery strategies-including systemic, intravitreal, suprachoroidal, and subretinal administration-interact with distinct BRB interfaces and influence therapeutic exposure. We further review clinically established and emerging delivery platforms, including sustained-release implants, refillable port-based systems, gene-based therapies, hydrogels, polymeric and lipid-based carriers, biomimetic systems, inorganic and hybrid nanomaterials, and stimulus-responsive platforms. Particular emphasis is placed on how material properties, pharmacokinetic behavior, and biological interactions collectively determine drug localization, retention, and efficacy. Finally, we discuss disease-adaptive delivery systems, cell-specific targeting, quantitative exposure modeling, and translational challenges that influence clinical implementation. By integrating retinal biology, pharmacokinetics, materials science, chemistry, and clinical ophthalmology, this review provides a gateway-centered framework for the rational design of next-generation drug delivery strategies for posterior-segment diseases.