Subretinal Gene Therapy for Treatment of Retinal and Choroidal Vascular Diseases

• Published in: American journal of ophthalmology 2024-12
• Main Authors: Khanani, Arshad M., Aziz, Aamir A., Khanani, Zoha A., Khan, Hannah, Mojumder, Ohidul, Sulahria, Humza, Khanani, Ibrahim, Khan, Huma, Gahn, Greggory M., Mishra, Kapil
• Format: Article
• Language: English
• Subjects: age-related macular degeneration; gene therapy; retinal vascular disease; subretinal injection
• ISSN: 0002-9394; 1879-1891; 1879-1891
• DOI: 10.1016/j.ajo.2024.12.002

•Subretinal injections are theorized to reduce risk of adverse immune response•Subretinal gene therapy mitigates risk of transgene insertion in unintentional tissues•Previous trials have demonstrated safety and tolerability of subretinal gene therapy•ABBV-RGX-314 subretinal gene therapy has been safe and efficacious in trials to date and is being evaluated in pivotal Phase III trials This review article discusses investigational subretinal gene therapies for retinal vascular diseases, including AVA-101, an adeno-associated viral (AAV) 2 vector expressing soluble vascular endothelial growth factor (VEGF) receptor 1, ABBV-RGX-314, an AAV8 vector expressing an anti-VEGF-A antibody fragment, and EXG102-031, an AAV8 vector expressing a recombinant protein that blocks VEGF family members and angiopoietin 2. Review article Subretinal injection is a commonly used delivery route for investigational gene therapy agents which is theorized to provide relative immune privilege, thereby reducing the risk of inflammation, while providing high transgene expression in photoreceptors and retinal pigment epithelium. Subretinal injection of AVA-101 demonstrated safety and tolerability in Phase I and IIa trials, but failed to maintain visual acuity and control exudation. In contrast, subretinal injection of some doses of ABBV-RGX-314 have shown evidence of controlling exudation and the maintaining vision, as well as safety and tolerability, leading to two ongoing pivotal trials comparing subretinal delivery of two different doses of ABBV-RGX-314 versus intravitreal injections of 0.5mg ranibizumab or 2mg aflibercept. These preliminary results are an encouraging and welcome development in the search for efficacious, long-duration treatments for retinal vascular diseases.