Overcoming Drug Resistance in AMD

What: Researchers unravel the reasons why some patients have no response or diminished response over time to anti-VEGF [vascular endothelial growth factor) drugs used to treat age-related macular degeneration (AMD) and discover an innovative and effective combination therapy.

Where: Zhu et al, “Combination of apolipoprotein-A-I/apolipoprotein-A-I binding protein and anti-VEGF treatment overcomes anti-VEGF resistance in choroidal neovascularization in mice.” Communications Biology, 202

BrightFocus Connection: This project was supported by a Macular Degeneration Research (MDR) grant to senior author Yingbin Fu, PhD, of Baylor College of Medicine, Houston (see link to grant profile below)

Yingbin Fu, PhD

Why It Is Important: This study addresses a major challenge in the treatment of choroidal neovascularization (CNV), an advanced form of AMD that is sometimes referred to as “wet AMD” because of the fragile, leaky blood vessels that form on or near the retina. Anti-VEGF drugs revolutionized the treatment for CNV; however, up to one-fourth of all treated patients are unresponsive, and about one-third of the responders become resistant after repeated administration over time. Because AMD is the leading cause of blindness in the elderly, and CNV (or wet AMD) causes 80-90% of legal blindness due to AMD, developing an effective therapy for anti-VEGF non-responders in AMD represents an urgent unmet clinical need.

An international team of researchers led by Baylor College of Medicine and Houston Methodist Hospital discovered a combination approach aimed at two different targets that provides a more promising therapy. They combined a drug that targets signaling by VEGF receptor 2 (VEGFR2) with apolipoprotein A-I binding protein (AIBP) to decrease cholesterol accumulation in macrophages (immune cells), and found it was effective at suppressing CNV in animal models.

The inspiration for their study came from previous work, suggesting that macrophages may play a role in anti-VEGF resistance and that increased cholesterol accumulation in macrophages may promote CNV. In addition, these researchers and others had shown that AIBP promotes the removal of cholesterol from endothelial cells and macrophages, two cell types that are involved in the development of CNV.

This novel approach of using AIBP treatment is distinct from the current anti-VEGF therapies and opens the possibility of reducing anti-VEGF resistance in patients in the future.