Journal of Clinical Medicine · 8 authors, 5 centres
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This review examines Bruch's membrane (BrM) as a critical barrier that compartmentalizes complement activation in age-related macular degeneration (AMD). Age-related thickening and reduced permeability of BrM impede complement protein diffusion, influencing disease pathogenesis and therapeutic delivery. Understanding BrM properties is essential for optimizing complement-based therapies, including systemic, intravitreal, subretinal, and suprachoroidal routes, to treat AMD effectively.
**Background:** Age-related macular degeneration (AMD) is a leading cause of irreversible blindness, affecting approximately 200 million people globally. The complement system plays a crucial role in AMD pathogenesis, with activation believed to begin in the choriocapillaris and extend to the subretinal and retinal pigment epithelium (RPE) spaces. Bruch's membrane (BrM), a 2–4 μm thick extracellular matrix layer between the RPE and choroid, acts as a selectively permeable barrier that hinders complement protein diffusion. This impediment increases with age and AMD, leading to compartmentalization of complement activation. This review comprehensively examines BrM structure, function, age-related changes, and the implications for complement-based therapies in AMD.
**Methods:** This is a narrative review synthesizing existing literature on BrM anatomy, aging changes, complement dysfunction in AMD, and therapeutic delivery strategies. The authors discuss in vivo imaging findings from optical coherence tomography (OCT) and OCT-angiography, genetic and environmental risk factors, and preclinical and clinical studies of complement inhibitors. They evaluate systemic, intravitreal, subretinal, and suprachoroidal delivery routes for conventional and gene therapy-based complement inhibitors.
**Key Results:** BrM undergoes significant age-related changes: thickening (from 2–4 μm baseline), reduced water permeability (greatest in the inner collagenous layer, especially in the macula), and decreased protein transport (almost 100% reduction in serum protein permeability from the first to ninth decades, from 3.5 × 10⁻⁶ to 0.2 × 10⁻⁶ cm/s). Calcification and stiffening occur (elasticity decreases ~1% per year from age 21). Complement proteins show differential BrM penetration: Factor H-like protein 1 (FHL-1, 49 kDa), Factor D, and C5a can cross, while C3/C3b, Factor H (155 kDa), Factor B, and Factor I cannot. The CFH p.Y402H polymorphism confers ~2-fold increased risk of late AMD. Systemic complement inhibition (intravenous eculizumab) failed to show benefit in a randomized trial for geographic atrophy (GA). Intravitreal complement inhibitors (pegcetacoplan, avacincaptad pegol) showed anatomical benefits in Phase 3 GA trials but raised safety concerns (induction of exudative AMD). Gene therapy approaches (e.g., subretinal GT005 expressing CFI, intravitreal JNJ-1887 expressing sCD59) are in clinical trials.
**Clinical Implications:** BrM's age-related structural and permeability changes critically influence complement activation compartmentalization and therapeutic delivery. Effective complement inhibition for AMD requires strategies that overcome BrM barriers. Intravitreal delivery is currently most advanced but faces challenges of frequent dosing and potential adverse events. Subretinal and suprachoroidal routes offer advantages for outer retinal targeting but involve surgical risks and immune responses. Systemic therapies are limited by BrM impermeability and systemic infection risk. Optimizing delivery—through improved vector design, route selection, and understanding of BrM transport—is essential for developing safe and effective complement-based treatments for AMD.