Abstract
Diabetic retinopathy is one of the leading causes of blindness among the working-age population worldwide. Although anti-VEGF agents have revolutionized the therapeutic approach, the limitations associated with frequent and invasive dosing regimens have driven the development of a new generation of therapies currently under clinical investigation. 1 Among these, gene therapies are emerging as the most promising innovation. ABBV-RGX-314, currently in phase IIb/III, uses an AAV vector to deliver a transgene encoding an anti-VEGF fragment analogous to ranibizumab; a single intravitreal injection enables retinal cells to autonomously produce the therapeutic agent continuously, with the potential to eliminate the need for repeated treatments. 2 A similar approach is represented by ixoberogene soroparvovec, in phase II, which employs an AAV2.7m8 capsid to express aflibercept, showing disease control for up to 26 weeks after a single administration. Even more advanced is 4D-150 (SPECTRA study), a phase I/II candidate that combines the expression of aflibercept with an interferon capable of inhibiting VEGF-C, thereby providing a dual-target antiangiogenic effect. 2
An important biological innovation is represented by bispecific drugs. Faricimab (Vabysmo), already approved and available in several countries, is the first antibody capable of simultaneously binding VEGF-A and angiopoietin-2, thereby addressing both neovascularization and vascular inflammation. Thanks to this dual-target mechanism, treatment allows for longer intervals between injections and offers better clinical control compared with traditional anti-VEGF agents. 3
In parallel, neuroprotective strategies and natural approaches are emerging. Among these, resveratrol, a polyphenol with multitarget activity, stands out for its ability to modulate oxidative stress, reduce inflammation, improve mitochondrial function, and inhibit pathological neovascularization without interfering with the endogenous neuroprotective effects of VEGF. 4 Its limited ocular bioavailability remains a challenge, but nanotechnologies and sustained-release systems currently under development may help overcome this limitation. 1
Therapeutic innovation also includes modulators of signaling pathways such as SZN-413, an agonist of the FZD4 receptor. Unlike traditional therapies that focus on inhibiting aberrant angiogenesis, this agent aims to promote the regeneration of functional retinal vasculature and endothelial integration. In preclinical models, it has demonstrated reductions in neovascularization and ischemic area, with superior efficacy to aflibercept in controlling vascular permeability. 5
Another emerging area of research involves NLRP3 inflammasome inhibitors, which target the critical contribution of inflammation to the progression of diabetic retinopathy. It is known that fenofibrate and metformin slow disease progression independently of glycemic control, suggesting inflammatory mechanisms mediated in part by inflammasome inhibition. 6 Other innovative approaches include receptor tyrosine kinase inhibitors and antagonists of the angiopoietin-Tie2 pathway, which provide multitarget action on the underlying pathological mechanisms. 7
Overall, the therapeutic landscape of diabetic retinopathy is undergoing a rapid transformation. Gene therapies promise long-lasting disease control with minimal intervention, bispecific biologics enable extended treatment intervals while maintaining high efficacy, and neuroprotective and anti-inflammatory strategies address the deeper mechanisms driving the disease. As clinical research progresses, many of these emerging therapies are likely to achieve regulatory approval, offering more effective and durable options for millions of patients with diabetes.
