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Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration

Lookup NU author(s): Sarah Hammadi, Nik Tzoumas, Professor Majlinda LakoORCiD, Professor David SteelORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2023 by the authors.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.

Publication metadata

Author(s): Hammadi S, Tzoumas N, Ferrara M, Meschede IP, Lo K, Harris C, Lako M, Steel DH

Publication type: Review

Publication status: Published

Journal: Journal of Clinical Medicine

Year: 2023

Volume: 12

Issue: 8

Print publication date: 02/04/2023

Online publication date: 14/04/2023

Acceptance date: 03/04/2023

ISSN (electronic): 2077-0383

Publisher: MDPI


DOI: 10.3390/jcm12082870