Humanized C3 Mouse: A Novel Accelerated Model of C3 Glomerulopathy

Area of Science:

• Nephrology
• Immunology
• Genetics

Background:

• C3 glomerulopathy (C3G) involves alternative complement pathway (AP) hyperactivation.
• Current mouse models for C3G progress slowly, limiting research.
• Novel models are crucial for understanding C3G mechanisms and treatments.

Purpose of the Study:

• To develop and characterize a novel, rapidly progressing murine model of C3G.
• To utilize this model for evaluating therapeutic interventions.

Main Methods:

• Humanized C3 (C3^hu/hu) mice were created using VelociGene technology.
• Functional, histologic, and molecular assays were employed.
• Pharmacologic interventions were tested in the C3^hu/hu model.

Main Results:

• C3^hu/hu mice exhibited early morbidity and mortality (5-6 months).
• Key C3G biomarkers (glomerulosclerosis, C3/C5b-9 deposition) were elevated.
• C5 or AP blockade improved survival and kidney function.

Conclusions:

• C3^hu/hu mice serve as a valuable C3G model, sharing human disease features.
• The model's accelerated course aids preclinical therapeutic assessment.
• Dysregulated human C3 interaction with mouse complement proteins likely drives the phenotype.