The case for complement component 5 as a target in neurodegenerative disease

• Published in: Expert opinion on therapeutic targets Vol. 27; no. 2; pp. 97 - 109
• Main Authors: Stennett, Amelia, Friston, Kallie, Harris, Claire L., Wollman, Adam J. M., Bronowska, Agnieszka K., Madden, Katrina S.
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 01.02.2023
• Subjects: Complement Activation; Complement C5 - metabolism; Complement C5a; complement component 5; Complement pathway; drug discovery; Humans; neurodegenerative disease; Neurodegenerative Diseases - drug therapy; neuroinflammation; Complement pathway; neurodegenerative disease; drug discovery; neuroinflammation; complement component 5
• ISSN: 1472-8222; 1744-7631
• DOI: 10.1080/14728222.2023.2177532

Complement-based drug discovery is undergoing a renaissance, empowered by new advances in structural biology, complement biology and drug development. Certain components of the complement pathway, particularly C1q and C3, have been extensively studied in the context of neurodegenerative disease, and established as key therapeutic targets. C5 also has huge therapeutic potential in this arena, with its druggability clearly demonstrated by the success of C5-inhibitor eculizumab. We will discuss the evidence supporting C5 as a target in neurodegenerative disease, along with the current progress in developing different classes of C5 inhibitors and the gaps in knowledge that will help progress in the field. Validation of C5 as a therapeutic target for neurodegenerative disease would represent a major step forward for complement therapeutics research and has the potential to furnish disease-modifying drugs for millions of patients suffering worldwide. Key hurdles that need to be overcome for this to be achieved are understanding how C5a and C5b should be targeted to bring therapeutic benefit and demonstrating the ability to target C5 without creating vulnerability to infection in patients. This requires greater biological elucidation of its precise role in disease pathogenesis, supported by better chemical/biological tools.