Reshaping Retinal Care With Gene Therapy Programs, With Christina Y. Weng, MD

Gene therapy is poised to reshape the treatment landscape in ophthalmology—not just for rare inherited retinal disorders, but increasingly for widespread conditions like neovascular (wet) age-related macular degeneration (AMD), diabetic macular edema (DME), and diabetic retinopathy. At the 2025 American Society of Cataract and Refractive Surgery (ASCRS) Annual Meeting, Christina Y. Weng, MD, MBA, a professor and the Alice R. McPherson Retina Research Foundation Chair in Ophthalmology at Baylor College of Medicine, provided a comprehensive update on the leading gene and cell therapy programs making headway.

Revakinagene taroretcel-lwey (ENCELTO)

The US Food and Drug Administration (FDA) recently approved Neurotech Pharmaceuticals’ Revakinagene taroretcel-lwey (ENCELTO), marking the first and only FDA-approved treatment for Macular Telangiectasia type 2 (MacTel). Designed to deliver continuous therapeutic doses of ciliary neurotrophic factor (CNTF) to the retina using the company’s encapsulated cell therapy (ECT) technology, implantation in two pivotal Phase 3 trials led to a significant halt in the loss of macular photoreceptors across 24 months.

Surabgene lomparvovec (sura-vec)

Regenxbio’s surabgene lomparvovec (sura-vec, ABBV-RGX-314), developed in partnership with AbbVie, is under investigation as a potential one-time alternative for wet AMD, diabetic retinopathy, and other chronic retinal conditions treated with anti-VEGF therapies.

RGX-314’s NAV® AAV8 vector encodes an antibody fragment designed to inhibit expression of VEGF—two separate routes of administration, a standardized subretinal delivery and suprachoroidal space delivery, are under investigation.

In the recent Phase 2 fellow eye sub-study of RGX-314, nine previously treated patients showed a 97% reduction in annualized anti-VEGF treatment burden at nine months post-subretinal administration. Notably, 100% of patients required zero or one supplemental injection, and 78% were completely injection-free.

Ixoberogene soroparvovec (Ixo-vec)

Ixoberogene soroparvovec (Ixo-vec), formerly known as ADVM-022, is under development by Adverum Biotechnologies as a gene therapy for wet AMD. Using a proprietary vector capsid, AAV.7m8, ixo-vec carries an aflibercept coding sequence under the control of a proprietary expression cassette.

In the OPTIC trial, a single intravitreal injection of Ixo-vec (2E11 vg/eye) led to an 81% reduction in annualized anti-VEGF injection rate overall, and a 94% reduction in patients with baseline NAbs titers <1:125. At three years, aflibercept expression was robust, with maintenance of vision and retinal anatomy—no participants required topical steroids for inflammation.

All treatment-related ocular adverse events were mild (81%) or moderate (19%), suggesting promising safety.

4D-150

4D-150 is a backbone therapy in development to provide multi-year sustained expression of aflibercept and anti-VEGF-C from the retina with a single intravitreal injection for both wet AMD and DME.

Interim data from the SPECTRA trial found 4D-150 (3E10 vg/eye) well-tolerated in patients with DME, demonstrating strong signs of clinical activity, including improvements in visual acuity and anatomy. The FDA endorsed advancing 4D-150 directly to Phase 3 for DME, with a single pivotal trial of 300–400 patients using BCVA noninferiority to aflibercept and updated, less stringent supplemental injection criteria as the primary endpoint.

After positive data in the PRISM trial, the first patients were enrolled in the Phase 3 4FRONT-1 trial evaluating 4D-150 for wet AMD, with a primary endpoint of non-inferiority in the mean change from baseline in BCVA at 52 weeks. The Phase 3 4FRONT-2 trial, set to begin in Q3 2025, mirrors 4FRONT-1 in design and will assess 4D-150 in both treatment-naïve and recently treated wet AMD patients, with topline data from both studies expected in the second half of 2027.

Watch the full interview with Weng in the above video for more insight into these gene therapy programs.

Weng reports relevant disclosures with Alcon, AbbVie, Apellis, Astellas/Iveric Bio, Genentech, Regeneron, and others.

References

Weng CY. The Current State of Gene Therapy for Retinal Diseases. Presented at: 2025 American Society of Cataract and Refractive Surgery (ASCRS) Annual Meeting. April 25-28, 2025. Los Angeles, CA.

Iapoce C. FDA approves Revakinagene Taroretcel (ENCELTO) for MacTel. HCP Live. March 6, 2025. Accessed April 22, 2025. https://www.hcplive.com/view/fda-approves-revakinagene-taroretcel-encelto-for-mactel.

REGENXBIO presents positive data from the phase II study of subretinal ABBV-RGX-314 in patients with bilateral wet AMD at AAO 2024. Regenxbio Inc. Accessed April 22, 2025. https://ir.regenxbio.com/news-releases/news-release-details/regenxbio-presents-positive-data-phase-ii-study-subretinal-abbv.

Pipeline. Adverum Biotechnologies. January 13, 2025. Accessed April 22, 2025. https://adverum.com/pipeline/.

4DMT announces first patients enrolled in 4FRONT-1 phase 3 clinical trial evaluating 4D-150 in wet AMD. 4D Molecular Therapeutics. March 10, 2025. Accessed April 22, 2025. https://ir.4dmoleculartherapeutics.com/news-releases/news-release-details/4dmt-announces-first-patients-enrolled-4front-1-phase-3-clinical.

4DMT announces positive interim data from 4D-150 spectra clinical trial in DME and alignment with FDA on registrational path. 4D Molecular Therapeutics. January 10, 2025. Accessed April 22, 2025. https://ir.4dmoleculartherapeutics.com/news-releases/news-release-details/4dmt-announces-positive-interim-data-4d-150-spectra-clinical.