Abstract: TH-PO0620
Single-Dose Adeno-Associated Virus Gene Therapy for C3 Glomerulopathy in an Avatar Mouse Model of Human Complement-Mediated Kidney Disease
Session Information
- Monogenic Kidney Diseases: Glomerular
November 06, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Monogenic Kidney Diseases
Authors
- Wang, Yuan Min, Centre for Kidney Research, The Children’s Hospital at Westmead,, Sydney, New South Wales, Australia
- Shen, Victor F., Centre for Kidney Research, The Children’s Hospital at Westmead,, Sydney, New South Wales, Australia
- Chung, Edmund, Centre for Kidney Research, The Children’s Hospital at Westmead,, Sydney, New South Wales, Australia
- Shaw, Karli I., Centre for Kidney Research, The Children’s Hospital at Westmead,, Sydney, New South Wales, Australia
- Rigterink, Jennifer, Centre for Kidney Research, The Children’s Hospital at Westmead,, Sydney, New South Wales, Australia
- McCarthy, Hugh J., Centre for Kidney Research, The Children’s Hospital at Westmead,, Sydney, New South Wales, Australia
- Logan, Grant, The University of Sydney, Sydney, New South Wales, Australia
- Alexander, Ian., The University of Sydney, Sydney, New South Wales, Australia
- Lisowski, Leszek, The University of Sydney, Sydney, New South Wales, Australia
- Harris, David, The University of Sydney, Sydney, New South Wales, Australia
- Alexander, Stephen I., Centre for Kidney Research, The Children’s Hospital at Westmead,, Sydney, New South Wales, Australia
Background
Complement 3 glomerulopathy (C3G) is a rare complement-mediated kidney disease caused by uncontrolled activation of the complement alternative pathway associated with factor H (CFH) mutations. About half of the patients with C3G will eventually develop kidney failure because no effective treatment is currently available. The aim of this study was to evaluate the therapeutic potential of a liver-directed Adeno-Associated Virus (AAV) therapy to treat a mouse CFH mutant model with C3 glomerulopathy.
Methods
C3G mouse model was established with a patient-derived specific point mutation W1180R in the CFH gene. An AAV2 vector that contains the human CFH sequence with a liver specific promoter (AAV-hCFH) was generated and packaged into a liver tropic capsid AAV8 and was administered intravenously into susceptible CFH mutant mice. Four and eight weeks after treatment, hepatic vector transduction was assessed by testing the vector copy number (VCN). The therapeutic outcome was evaluated by kidney function, proteinuria, serum CFH levels and C3 deposition in kidney.
Results
CFH homozygous (CfhW1180R/W1180R) mice showed spontaneous deposition of glomerular C3, absent circulating CFH and progressive renal injury with age as compared to heterozygous (CfhW1180R/WT) mice and wild type mice. A single intravenous dose of AAV-hCFH (5x1011 vector genome per mouse) was successfully transduced and retained in liver with a high level of VCN and functional CFH expression, increased serum CFH and reduced serum C3 levels as compared with untreated mutant mice. CfhW1180R/W1180R mice treated with the AAV-hCFH demonstrated improved kidney function with lower serum creatinine (42±2.3 vs 28±2.8µmol/L, p<0.05), less proteinuria (5.2±0.8 vs 2.5±0.4mg/16h, p<0.001), less kidney injury (5.4±0.4 vs 3.6±0.6, p<0.01) and reduced C3 deposition as compared to untreated CfhW1180R/W1180R mice.
Conclusion
Human CFH was successfully delivered to the liver of CFH mutant mice using AAV. hCFH was expressed in the mouse liver and was therapeutic with reduction in kidney injury in mutant mice compared with untreated mutant mice.
Funding
- Government Support – Non-U.S.