Targeting the complement system in geographic atrophy: mechanisms and therapeutics

ABSTRACT

Introduction

Geographic atrophy (GA) is an advanced form of age-related macular degeneration (AMD) and a leading cause of vision loss for which there are currently two FDA-approved treatments (pegcetacoplan and avacincaptad pegol). The complement system, a major effector arm of innate and adaptive immunity, has been implicated in the pathogenesis of GA. This review aims to provide a comprehensive overview of the mechanisms underlying complement dysregulation in GA and the current therapeutic strategies to treat GA via targeting the complement system.

Areas Covered

This review covers the pathogenesis of GA with a focus on the role of the complement system, the mechanisms of complement dysregulation in GA, current therapeutic strategies targeting the complement system for GA, and ongoing clinical trials. We also discuss the challenges and future directions of complement-targeted therapy for GA.

Expert Opinion

Despite the challenges, the complement system remains a promising target for developing novel therapeutics for GA and AMD. Further research is needed to optimize treatment strategies, identify predictive biomarkers, and understand the contributions of complement dysregulation to the pathological processes in GA and other retinal pathologies.

KEYWORDS:

• AMD
• complement
• GA
• inflammation
• therapeutics
• mechanisms
• treatment
• gene-therapy

Article highlights

• Geographic atrophy (GA) is an advanced form of age-related macular degeneration (AMD) with two FDA-approved treatments (pegcetacoplan and avacincaptad pegol)

• Dysregulation of the complement system contributes to the development and progression of GA; several clinical trials have shown potential treatment effects with complement inhibitors.

• Current therapeutic strategies targeting the complement system in GA aim to modulate complement activation and restore complement homeostasis.

• Ongoing clinical trials evaluate the efficacy and safety of complement-targeted therapeutics in GA.

• Future research directions include the identification of optimal complement system targets, the development of more specific and potent complement inhibitors, as well as the exploration of combination therapies.

Declaration of financial/other relationships

AK, Consultant to Iveric Bio, Janssen, Gyroscope and receives research funding from Apellis, Iveric Bio, Janssen, and Gyroscope. Other authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosure

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

MK, Conceptualization, Validation, Formal analysis, Investigation, Data Curation, Writing – Original Draft, Writing – Review & Editing; OEA, Conceptualization, Validation, Formal analysis, Investigation, Data Curation, Writing – Original Draft, Writing – Review & Editing; MM, Conceptualization, Validation, Formal analysis, Investigation, Data Curation, Writing – Original Draft, Writing – Review & Editing; MJT, Writing – Review & Editing; NM, Writing – Review & Editing; AMK, Project Administration, Methodology, Resources, Conceptualization, Formal analysis, Writing – Original Draft, Writing – Review & Editing.

All authors have read and agreed to the published version of the manuscript.

Additional information

Funding

This paper was not funded.