![](https://assets.reachrx.ai/images/10.1038%E2%98%8Ds41433-025-04202-5/_page_0_Picture_1.jpeg) ## **BRIEF COMMUNICATION OPEN** ![](https://assets.reachrx.ai/images/10.1038%E2%98%8Ds41433-025-04202-5/_page_0_Picture_3.jpeg) # A novel modifier gene therapy to treat Stargardt disease: Phase 1 GARDian1 Trial Insights Arshad M. Khanani 1,2 1, Lejla Vajzovic³, Benjamin Bakall⁴,5, Venkata Ramana Murthy Chavali⁴ and Huma Qamar⁴ © The Author(s), under exclusive licence to The Royal College of Ophthalmologists 2026 Eye; https://doi.org/10.1038/s41433-025-04202-5 #### INTRODUCTION Stargardt disease type 1 (STGD1) is an orphan inherited macular dystrophy affecting over 100,000 individuals in the US and EU, commonly presenting in childhood or adolescence [1]. Biallelic *ABCA4* mutations lead to toxic bisretinoid lipofuscin accumulation, retinal pigment epithelium (RPE) atrophy, and progressive central vision loss [2]. With no approved treatments, STGD1 remains a significant unmet medical need. OCU410ST (AAV5-hRORA) is designed to modulate RPE and photoreceptor homeostasis, thereby preserving retinal integrity independent of *ABCA4* genotype. This first-in-human phase 1 trial (NCT05956626) evaluated safety, tolerability, and exploratory efficacy of a single subretinal dose of OCU410ST in adults with advanced STGD1. #### **METHODS** GARDian1 was a multicentre, open-label, 3+3 dose escalation study. Three patients per cohort received a single 200 $\mu$ l subretinal injection of OCU410ST (low: $3.75\times10^{10}\,\text{vg/mL}$ ; medium: $7.5\times10^{10}\,\text{vg/mL}$ ; or high: $2.25\times10^{11}\,\text{vg/mL})$ in the worse seeing study eye. Key eligibility criteria included age 18-65 years, biallelic ABCA4 variants, early to advanced bull's eve maculopathy, best corrected visual acuity (BCVA) ≥ 50 ETDRS letters, and preserved outer nuclear layer. Follow-up visits occurred at baseline and months 1, 3, 6, 9, and 12. The primary objective was to assess the safety and tolerability of OCU410ST, including treatment-related safety adverse events (AEs). Exploratory endpoints included change from baseline to Month 12 in the progression of definitely decreased autofluorescence (DDAF) lesion area (treated vs untreated fellow eyes), reported as absolute area (mm²) and square root-transformed area (\sqrt{DDAF}, mm) to account for baseline lesion size, and BCVA. Additional structural and functional measures were collected but are not reported here. Analyses were descriptive, with paired methods used for betweeneye comparisons when appropriate. #### RESULTS Nine patients with STGD1 (5 Females/4 Males; mean age $41.7\pm18.1$ years) received OCU410ST in the study eye. Eight of nine patients (89%) completed the 12-month visit; one high-dose patient was lost to follow-up. Treatment and surgery were well tolerated with no drug-related serious AEs or adverse events of special interest. Treatment-emergent AEs (TEAEs) unrelated to OCU410ST occurred in 8 of 9 patients (89%), totalling 30 events (73% Grade 1, 27% Grade 2). Efficacy was assessed in predefined evaluable subsets (Supplementary Table 1). Among six patients with gradable Fundus Auto Fluorescence images, mean atrophic lesion growth was reduced by 54%: treated eyes progressed $0.55\pm0.27\,\mathrm{mm}^2$ versus $1.19\pm0.31\,\mathrm{mm}^2$ in untreated eyes (Fig. 1a). Annual $\sqrt{\mathrm{DDAF}}$ expansion was $0.10\pm0.039\,\mathrm{mm/year}$ in treated eyes (50% lesion reduction) versus $0.19\pm0.026\,\mathrm{mm/year}$ in fellow eyes. The rate in treated eyes was below published natural history rates (0.14–0.18 mm/year). Among six BCVA-evaluable patients without confounders, treated eyes improved by $+4.5\pm2.20\,\mathrm{ETDRS}$ letters at Month 12, compared with $-1.5\pm2.33$ letters in untreated fellow eyes, yielding a +6-letter gain (Fig. 1b). All treated eyes either stabilised ( $\pm4$ letters) or improved ( $\geq5$ letters) in visual acuity. #### DISCUSSION OCU410ST demonstrated a favourable safety profile. TEAEs were mild/moderate and attributable to procedural effects, underlying disease progression, or comorbidities. Slowing of DDAF progression (0.10 mm/year √DDAF) was below published natural history rates (0.14-0.18 mm/year), a validated surrogate endpoint for RPE and photoreceptor loss that predicts functional decline in STGD1 [3]. BCVA gains in treated eyes counteract the expected natural history of decline (0.5-2.8 ETDRS letters/year overall; ~2 letters/year in advanced disease), where ≥5-letter change correlates with clinically meaningful reading and face recognition improvements. BCVA stabilisation or gain preserves central vision, critical for quality of life [4]. No globally approved therapies for STGD1 exist. Full ABCA4 replacement remains limited by viral vector packaging capacity, while other alternative strategies, such as dual-vector approaches, CRISPR, and RNA-targeting, are still in early development and face important safety and efficacy hurdles. Emerging data from Belite Bio's Tinlarebant, the only other pivotal STGD programme, showed no visual function gains, limited 2-year lesion reduction in adolescents, and safety concerns [5]. In contrast, the convergent functional and structural benefits, in addition to safety, underscore the novelty of the RORA-mediated neuropro- Received: 10 December 2025 Revised: 11 December 2025 Accepted: 18 December 2025 Published online: 10 January 2026 ^<sup>1Sierra Eye Associates, Reno, NV, USA. ²University of Nevada, Reno School of Medicine, Reno, NV, USA. ³Duke University, Durham, NC, USA. ⁴Associated Retina Consultants, Phoenix, AZ, USA. ⁵University of Arizona, College of Medicine-Phoenix, Phoenix, AZ, USA. ⁶Ocugen, Inc., Malvern, PA, USA. ^™email: arshad.khanani@gmail.com ![](https://assets.reachrx.ai/images/10.1038%E2%98%8Ds41433-025-04202-5/_page_1_Figure_2.jpeg) ![](https://assets.reachrx.ai/images/10.1038%E2%98%8Ds41433-025-04202-5/_page_1_Figure_3.jpeg) **Fig. 1 Change in Atrophic Lesion Growth and Visual Acuity at M12 following OCU410ST Treatment.** Treated eyes showed a decrease in atrophic lesion growth from baseline (**a**), and stabilisation/improvement in Visual Acuity (**b**). tection approach, offering a paradigm shift from genotypeconstrained replacement to agnostic modifcation [5]. GARDian1 trial achieved its primary objective of favourable safety and provides confrmatory evidence of functional and structural beneft, demonstrating the potential of OCU410ST to slow macular atrophic progression and transform the treatment landscape for patients with signifcant unmet need. # **Data sharing** Data from GARDian1 will be available upon reasonable request. Trial registration: NCT05956626. # **REFERENCES** - 1. Mata NL, Weng S, Michaelides M, Charbel Issa P, Quinodoz M, Rivolta C, et al. Bisretinoids as a source of early photoreceptor pathology in Stargardt disease. Ophthalmic Res. 2025;68:555–72. - 2. Fujinami K, Strauss RW, Chiang JP, Audo IS, Bernstein PS, Birch DG, et al. Detailed genetic characteristics of an international large cohort of patients with Stargardt disease: ProgStar study report 8. Br J Ophthalmol. 2019;103:390–7. - 3. Pas JAAH, Dhooge PPA, Li CHZ, Collin RWJ, Hoyng CB, IntHout J. Randomizing eyes or patients in clinical trials for Stargardt disease. Ophthalmol Sci. [https://](https://doi.org/10.1016/j.xops.2025.101021) [doi.org/10.1016/j.xops.2025.101021.](https://doi.org/10.1016/j.xops.2025.101021) - 4. Kong X, Strauss RW, Cideciyan AV, Michaelides M, Sahel JA, Munoz B, et al. Visual acuity change over 12 months in the prospective Progression of Atrophy Secondary to Stargardt Disease (ProgStar) Study: ProgStar report number 6. Ophthalmology. 2017;124:1640–51. - 5. Kong X, Fujinami K, Strauss RW, Munoz B, West SK, Cideciyan AV, et al. Visual acuity change over 24 months and its association with foveal phenotype and genotype in individuals with Stargardt disease: ProgStar study report no. 10. JAMA Ophthalmol. 2018;136:920–8. ## **AUTHOR CONTRIBUTIONS** Conception and Design: VRMC and HQ; Acquired data and played a key role in interpreting results: VRMC, HQ; Drafted and critically revised the manuscript: VRMC, HQ, LV, BB, and AMK; All authors approved the fnal version for publication. #### **FUNDING** The study was sponsored by Ocugen, Inc. Ocugen, Inc. designed and, with the assistance of its clinical trial sites (Supplementary Table 2) and vendors, conducted the study, including data collection, data management, data analysis, and supported preparation of the manuscript. ### **COMPETING INTERESTS** The authors declare no competing interests. ## **ADDITIONAL INFORMATION** **Supplementary information** The online version contains supplementary material available at [https://doi.org/10.1038/s41433-025-04202-5.](https://doi.org/10.1038/s41433-025-04202-5) **Correspondence** and requests for materials should be addressed to Arshad M. 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