Hammadi Sarah, Tzoumas Nikolaos, Ferrara Mariantonia, Meschede Ingrid Porpino, Lo Katharina, Harris Claire, Lako Majlinda, Steel David H
Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
Sunderland Eye Infirmary, Queen Alexandra Rd., Sunderland SR2 9H, UK.
J Clin Med. 2023 Apr 14;12(8):2870. doi: 10.3390/jcm12082870.
The complement system is crucial for immune surveillance, providing the body's first line of defence against pathogens. However, an imbalance in its regulators can lead to inappropriate overactivation, resulting in diseases such as age-related macular degeneration (AMD), a leading cause of irreversible blindness globally affecting around 200 million people. Complement activation in AMD is believed to begin in the choriocapillaris, but it also plays a critical role in the subretinal and retinal pigment epithelium (RPE) spaces. Bruch's membrane (BrM) acts as a barrier between the retina/RPE and choroid, hindering complement protein diffusion. This impediment increases with age and AMD, leading to compartmentalisation of complement activation. In this review, we comprehensively examine the structure and function of BrM, including its age-related changes visible through in vivo imaging, and the consequences of complement dysfunction on AMD pathogenesis. We also explore the potential and limitations of various delivery routes (systemic, intravitreal, subretinal, and suprachoroidal) for safe and effective delivery of conventional and gene therapy-based complement inhibitors to treat AMD. Further research is needed to understand the diffusion of complement proteins across BrM and optimise therapeutic delivery to the retina.
补体系统对于免疫监视至关重要，是机体抵御病原体的第一道防线。然而，其调节因子失衡会导致不适当的过度激活，引发诸如年龄相关性黄斑变性（AMD）等疾病，AMD是全球不可逆失明的主要原因，影响约2亿人。AMD中的补体激活被认为始于脉络膜毛细血管，但它在视网膜下和视网膜色素上皮（RPE）间隙也起着关键作用。 Bruch膜（BrM）作为视网膜/RPE与脉络膜之间的屏障，阻碍补体蛋白扩散。这种阻碍随着年龄增长和AMD而增加，导致补体激活的区域化。在这篇综述中，我们全面研究了BrM的结构和功能，包括通过体内成像可见的与年龄相关的变化，以及补体功能障碍对AMD发病机制的影响。我们还探讨了各种给药途径（全身、玻璃体内、视网膜下和脉络膜上）在安全有效地递送传统和基于基因疗法的补体抑制剂以治疗AMD方面的潜力和局限性。需要进一步研究以了解补体蛋白在BrM上的扩散情况，并优化向视网膜的治疗性递送。
