Researchers from the Wilmer Eye Institute at Johns Hopkins Medicine have uncovered why some patients with wet age-related macular degeneration (wet AMD) don’t experience vision improvement despite treatment. They also highlight a potential new treatment approach that could enhance current therapies and preserve vision for more patients. The study, published in Proceedings of the National Academy of Sciences, examines the role of a specific protein, ANGPTL4, in undermining existing treatments and tests a drug that could curb its effects.
Wet AMD, a progressive eye disease, is caused by an abnormal growth of blood vessels in the retina, triggered by the overproduction of the VEGF protein, which promotes blood vessel formation. These fragile vessels can leak or bleed, damaging the retina, and leading to significant vision loss. Wet AMD is the more aggressive of the two types of age-related macular degeneration, affecting millions worldwide, primarily older adults.
The standard treatment for wet AMD involves monthly injections of anti-VEGF drugs, which are designed to inhibit VEGF activity and reduce blood vessel growth. However, only about half of the patients see substantial vision improvements from this therapy, and even for those who initially benefit, the vision gains often fade over time.
Dr. Akrit Sodhi, an ophthalmology professor and senior author of the study, and his team sought to understand why anti-VEGF therapies work inconsistently. In earlier work, they identified that patients who showed limited response to anti-VEGF therapy had elevated levels of another protein, ANGPTL4. ANGPTL4 has similar effects to VEGF, also contributing to abnormal blood vessel growth in the retina. Surprisingly, they discovered that anti-VEGF injections, while reducing VEGF levels, triggered an increase in ANGPTL4.
“What we saw in this paper was a paradoxical increase of ANGPTL4 in patients that received anti-VEGF injections—the anti-VEGF therapy itself turned on expression of this protein,” Sodhi explains.
In their study, the researchers analyzed eye fluid samples from 52 patients with wet AMD who were at different stages of anti-VEGF treatment. They found that before starting anti-VEGF therapy, patients already had high levels of both VEGF and ANGPTL4. After treatment, VEGF levels decreased as expected, but ANGPTL4 levels rose, suggesting that anti-VEGF therapy inadvertently stimulates ANGPTL4 production. This unwanted rise in ANGPTL4 likely fuels the continued overgrowth of blood vessels in the retina, counteracting the intended effect of anti-VEGF treatment and preventing full vision recovery.
Seeking a solution, the team tested an experimental drug called 32-134D in mice with wet AMD. This drug targets a third protein, HIF-1, which is involved in both VEGF and ANGPTL4 production. HIF-1 is known to activate VEGF in wet AMD and diabetic eye disease, so the researchers hypothesized that inhibiting HIF-1 with 32-134D could also suppress ANGPTL4 production. The drug successfully decreased levels of HIF-1, VEGF, and ANGPTL4, which in turn reduced abnormal blood vessel growth in the retina.
The team then tested a combined therapy of 32-134D and anti-VEGF treatment in mice. This combination prevented the increase of HIF-1, VEGF, and ANGPTL4, proving to be more effective than anti-VEGF treatment alone. By inhibiting multiple pathways that lead to abnormal blood vessel growth, this dual approach showed promise for improving treatment outcomes in wet AMD.
“This work exposes a way to improve anti-VEGF therapy for all patients and potentially help a subset of patients with wet AMD who still lose vision over time despite treatment,” says Sodhi.
In the long term, the researchers aim to achieve three primary goals: to maximize the effectiveness of existing wet AMD therapies, develop new treatments, and ultimately prevent wet AMD altogether. Their findings suggest that combining anti-VEGF therapies with drugs targeting HIF-1 and ANGPTL4 pathways could help many patients retain their vision, even those with limited response to current treatments.
The study opens new doors for improving treatment for one of the most challenging eye diseases, potentially preserving the vision and quality of life for millions. Further research will be required to confirm these results in human patients and refine the approach to make it available for clinical use.