Current anti-VEGF (vascular endothelial growth factor) therapies for wet age-related macular degeneration (AMD) may be limited by the overexpression of ANGPTL4, a protein that stimulates abnormal blood vessel growth in the retina. The discovery, published in the Proceedings of the National Academy of Sciences, could explain why a significant proportion of patients do not experience substantial vision improvements with anti-VEGF treatment.
The Paradox of Anti-VEGF Therapy
Wet AMD, characterized by excessive blood vessel growth in the retina, is typically treated with anti-VEGF drugs to slow the formation of new vessels. However, researchers at Johns Hopkins University School of Medicine found that anti-VEGF treatment can paradoxically increase ANGPTL4 levels, potentially counteracting the intended benefits. According to Dr. Akrit Sodhi, associate professor of ophthalmology at Johns Hopkins, "the anti-VEGF therapy itself turned on expression of this protein."
Study Details and Findings
The study involved analyzing VEGF and ANGPTL4 levels in the eye fluid of 52 wet AMD patients undergoing anti-VEGF treatment. Results indicated that while VEGF levels decreased post-treatment, ANGPTL4 levels increased. This ANGPTL4 activity could foster further damaging blood vessel overgrowth, hindering vision improvement.
Targeting HIF-4 to Reduce ANGPTL4
To mitigate ANGPTL4 levels, researchers tested an experimental drug targeting HIF-4, a protein known to promote VEGF production in wet AMD, in mice models. The experimental drug reduced both VEGF and ANGPTL4 levels, limiting blood vessel overgrowth. Combining this drug with existing anti-VEGF medications proved more effective than either treatment alone.
Implications for Wet AMD Treatment
These findings suggest a potential strategy to enhance anti-VEGF therapy by also targeting ANGPTL4. This approach could benefit patients who experience vision loss despite receiving anti-VEGF treatment. Dr. Sodhi hopes this research will "make current therapies as effective as possible, identify new therapies and prevent people from ever getting wet AMD."
