{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T01:31:57Z","timestamp":1792805517620,"version":"4.5.0"},"reference-count":314,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2023,4,14]],"date-time":"2023-04-14T00:00:00Z","timestamp":1681430400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Newcastle University","award":["ACF-2021-01-008"],"award-info":[{"award-number":["ACF-2021-01-008"]}]},{"name":"Newcastle University","award":["#GR602"],"award-info":[{"award-number":["#GR602"]}]},{"name":"Newcastle University","award":["#GR601"],"award-info":[{"award-number":["#GR601"]}]},{"name":"Gyroscope Therapeutics, a Novartis company","award":["ACF-2021-01-008"],"award-info":[{"award-number":["ACF-2021-01-008"]}]},{"name":"Gyroscope Therapeutics, a Novartis company","award":["#GR602"],"award-info":[{"award-number":["#GR602"]}]},{"name":"Gyroscope Therapeutics, a Novartis company","award":["#GR601"],"award-info":[{"award-number":["#GR601"]}]},{"name":"NIHR Academic Clinical Fellowship","award":["ACF-2021-01-008"],"award-info":[{"award-number":["ACF-2021-01-008"]}]},{"name":"NIHR Academic Clinical Fellowship","award":["#GR602"],"award-info":[{"award-number":["#GR602"]}]},{"name":"NIHR Academic Clinical Fellowship","award":["#GR601"],"award-info":[{"award-number":["#GR601"]}]},{"name":"Retina UK","award":["ACF-2021-01-008"],"award-info":[{"award-number":["ACF-2021-01-008"]}]},{"name":"Retina UK","award":["#GR602"],"award-info":[{"award-number":["#GR602"]}]},{"name":"Retina UK","award":["#GR601"],"award-info":[{"award-number":["#GR601"]}]},{"name":"Macular Society UK","award":["ACF-2021-01-008"],"award-info":[{"award-number":["ACF-2021-01-008"]}],"id":[{"id":"https:\/\/ror.org\/02j172648","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Macular Society UK","award":["#GR602"],"award-info":[{"award-number":["#GR602"]}],"id":[{"id":"https:\/\/ror.org\/02j172648","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Macular Society UK","award":["#GR601"],"award-info":[{"award-number":["#GR601"]}],"id":[{"id":"https:\/\/ror.org\/02j172648","id-type":"ROR","asserted-by":"crossref"}]},{"name":"companies developing complement therapeutics","award":["ACF-2021-01-008"],"award-info":[{"award-number":["ACF-2021-01-008"]}]},{"name":"companies developing complement therapeutics","award":["#GR602"],"award-info":[{"award-number":["#GR602"]}]},{"name":"companies developing complement therapeutics","award":["#GR601"],"award-info":[{"award-number":["#GR601"]}]},{"name":"Gyroscope Therapeutics (a Novartis company) (relevant to work under consideration), Alcon, Boehringer Ingelheim, Bayer, DORC, and Roche","award":["ACF-2021-01-008"],"award-info":[{"award-number":["ACF-2021-01-008"]}]},{"name":"Gyroscope Therapeutics (a Novartis company) (relevant to work under consideration), Alcon, Boehringer Ingelheim, Bayer, DORC, and Roche","award":["#GR602"],"award-info":[{"award-number":["#GR602"]}]},{"name":"Gyroscope Therapeutics (a Novartis company) (relevant to work under consideration), Alcon, Boehringer Ingelheim, Bayer, DORC, and Roche","award":["#GR601"],"award-info":[{"award-number":["#GR601"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>The complement system is crucial for immune surveillance, providing the body\u2019s 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\u2019s 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.<\/jats:p>","DOI":"10.3390\/jcm12082870","type":"journal-article","created":{"date-parts":[[2023,4,14]],"date-time":"2023-04-14T02:28:12Z","timestamp":1681439292000},"page":"2870","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["Bruch\u2019s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration"],"prefix":"10.3390","volume":"12","author":[{"given":"Sarah","family":"Hammadi","sequence":"first","affiliation":[{"name":"Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolaos","family":"Tzoumas","sequence":"additional","affiliation":[{"name":"Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"},{"name":"Sunderland Eye Infirmary, Queen Alexandra Rd., Sunderland SR2 9H, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariantonia","family":"Ferrara","sequence":"additional","affiliation":[{"name":"Manchester Royal Eye Hospital, Manchester M13 9WL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid Porpino","family":"Meschede","sequence":"additional","affiliation":[{"name":"Gyroscope Therapeutics Limited, a Novartis Company, Rolling Stock Yard, 6th Floor, 188 York Way, London N7 9AS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Lo","sequence":"additional","affiliation":[{"name":"Gyroscope Therapeutics Limited, a Novartis Company, Rolling Stock Yard, 6th Floor, 188 York Way, London N7 9AS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Harris","sequence":"additional","affiliation":[{"name":"Gyroscope Therapeutics Limited, a Novartis Company, Rolling Stock Yard, 6th Floor, 188 York Way, London N7 9AS, UK"},{"name":"Clinical and Translational Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Majlinda","family":"Lako","sequence":"additional","affiliation":[{"name":"Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8734-3089","authenticated-orcid":false,"given":"David H.","family":"Steel","sequence":"additional","affiliation":[{"name":"Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK"},{"name":"Sunderland Eye Infirmary, Queen Alexandra Rd., Sunderland SR2 9H, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e106","DOI":"10.1016\/S2214-109X(13)70145-1","article-title":"Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: A systematic review and meta-analysis","volume":"2","author":"Wong","year":"2014","journal-title":"Lancet Glob. 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