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Complement C3-targeted therapy in C3 glomerulopathy, a prototype of complement-mediated kidney diseases
Marie-Sophie Meuleman1, Anne Grunenwald1, Sophie Chauvet2
1Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Paris, France.
Insights
C3 glomerulopathy (C3G) is a rare kidney disease caused by complement system overactivation. New therapies targeting C3 and C3 convertase are needed due to limitations of current anti-C5 treatments.
Area of Science:
- Nephrology
- Immunology
- Complement System Biology
Background:
- C3 glomerulopathy (C3G) is a rare kidney disease affecting young adults with poor prognosis.
- The disease stems from uncontrolled alternative complement pathway activation, often acquired.
- C3G serves as a model for complement-mediated kidney diseases.
Purpose of the Study:
- To review the complement activation mechanisms in C3G.
- To discuss current and emerging therapeutic strategies for C3G.
- To emphasize the potential of C3 and C3 convertase inhibition.
Main Methods:
- Review of literature on complement activation in C3G.
- Analysis of functional complement abnormalities in patients and models.
- Evaluation of therapeutic interventions targeting the complement system.
Main Results:
- The roles of C3 and C5 convertases in C3G pathogenesis are established.
- Anti-C5 therapy shows limited efficacy, indicating disease complexity.
- Targeting the C3 and C3 convertase axis presents a promising therapeutic avenue.
Conclusions:
- Understanding complement dysregulation is key to managing C3G.
- Inhibition of C3 and C3 convertase offers a novel therapeutic strategy.
- Further research into C3-targeted therapies is warranted for C3G.
Abstract:
C3 glomerulopathy (C3G) is a rare and complex kidney disease that primarily affects young adults. Renal outcomes remain poor in the absence of specific treatment. C3G is driven by uncontrolled overactivation of the alternative complement pathway, which is mainly of acquired origin. Functional characterization of complement abnormalities (i.e., autoantibodies targeting complement components and variants in complement genes) identified in patients and experimental models of the disease improved the understanding of the disease, making C3G a prototype of complement-mediated diseases. The contribution of C3 convertase, as well as C5 convertase, in disease occurrence, phenotype, and severity is now well established, offering various potential therapeutic interventions. However, the lack of sufficient efficiency in anti-C5 therapy highlights the extreme complexity of the disease and the need for new therapeutic approaches based on C3 and C3 convertase axis inhibition. Here, we provide an overview of the complement activation mechanism involved in C3G and discuss therapeutic options based on complement inhibitors, with a specific focus on C3 inhibition.
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