Neovascular age-related macular degeneration (nAMD) remains a leading cause of irreversible vision loss among the elderly, affecting millions worldwide. Imagine a world where the very treatments designed to protect our sight are sub-optimal or start losing their effectiveness over time. This is the reality for many battling nAMD, as many patients exhibit incomplete responses or develop resistance over time to standard therapies . The relentless progression of nAMD, coupled with the limitations of current treatments, underscores the urgent need for novel approaches to manage this debilitating condition. But hope is on the horizon as researchers uncover new strategies to tackle this problem head-on, offering fresh avenues to preserve vision and improve quality of life.
Recent studies led by Dr. Yingbin Fu’s team from Baylor College of Medicine,explore innovative strategies to overcome this resistance. Their findings were summarized in the peer-reviewed journal, Biomolecules.
The primary approach in treating nAMD has been to inhibit vascular endothelial growth factor (VEGF), a key factor in promoting the abnormal blood vessel growth characteristic of this disease. However, up to 50% of patients exhibit persistent disease activity despite treatment. The underlying mechanisms of this resistance are not fully understood, but recent research points to the formation of arteriolar choroidal neovascularization (CNV) as a significant contributor. This type of neovascularization involves large-caliber vessels and vascular loops that are less responsive to VEGF inhibition.
“Macrophages play a key role in anti-VEGF resistance by contributing to neovascular remodeling,” Professor Fu explained, “Because inflammatory signaling occurred on lipid-rich microdomains of macrophage membrane, one effective approach is to enhance cholesterol removal from macrophages with with Apolipoprotein A-I Binding Protein (AIBP) and the cholesterol acceptor Apolipoprotein A-I. Apolipoprotein A-I is the major protrein component of HDL. This approach neutralizes macrophage’s ability in promoting neovascular remodeling. ”
It is difficult to treat anti-VEGF resistance because VEGF recruits macrophages to lesion sites of inflammation, in turn macrophages secrete additional VEGF and other pro-angiogenic factors thereby creating a vicious cycle. To address this problem, Professor Fu’s team developed a combination therapy by targeting both VEGF and macrophages. They showed promising results in animal models that a combination of current anti-VEGF therapies with AIBP and Apolipoprotein A-I provides an effective treatment strategy to ameliorating anti-VEGF resistance in AMD.
Despite these advances, the study acknowledges that further research is needed to validate these findings in clinical settings. The complexity of nAMD, influenced by factors such as age, genetic predisposition, and environmental influences, requires a multifaceted treatment approach to achieve optimal management of AMD patients. The combination therapy developed by Professor Fu’s team represents an important step toward this goal.
In summary, Dr. Fu and his team’s research underscores the need for innovative combination therapies to address the challenge of anti-VEGF resistance in nAMD. By targeting both angiogenesis and inflammation, these strategies hold promise for improving the long-term efficacy of treatments and reducing the burden of vision loss in elderly populations. The findings pave the way for future clinical trials aimed at developing more comprehensive and effective therapies for this debilitating condition.
Journal Reference
Fu, Y., Zhang, Z., Webster, K.A., & Paulus, Y.M. (2024). Treatment Strategies for Anti-VEGF Resistance in Neovascular Age-Related Macular Degeneration by Targeting Arteriolar Choroidal Neovascularization. Biomolecules, 14 (252). DOI: https://doi.org/10.3390/biom14030252
