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Adeno-Associated Virus Vector Gene Delivery Elevates Factor I Levels and Downregulates the Complement Alternative
Amina Ahmad1, Mawj Mandwie1, Anna K Dreismann2
1Gene Therapy Research Unit, Children's Medical Research Institute and Sydney Children's Hospitals Network, University of Sydney, Westmead, Australia.
Human Gene Therapy
|July 9, 2021
Summary
Elevating complement factor I (CFI) using gene therapy reduces complement system activation. This approach shows promise for treating complement-mediated diseases by modulating, not inhibiting, the immune response.
Area of Science:
- Immunology
- Genetics
- Molecular Biology
Background:
- The complement system is crucial for innate immunity but its dysregulation contributes to diseases like macular degeneration and kidney disease.
- Current therapies for acute kidney injury involve complete complement inhibition, but modulating the system and long-term delivery remain challenges.
- Elevating complement factor I (CFI) concentrations inhibits complement activation in vitro.
Purpose of the Study:
- To investigate the in vivo modulation of complement activation by sustained elevation of CFI levels.
- To assess the therapeutic potential of adeno-associated virus (AAV) mediated gene delivery for complement modulation.
Main Methods:
- Adeno-associated virus (AAV) vectors were used to deliver the gene for CFI to the liver, achieving sustained 4- to 5-fold increases in circulating CFI levels.
- Complement activation was assessed by measuring inactive C3b (iC3b) deposition and C3 degradation product formation.
- A mouse model of systemic lupus erythematosus (NZBWF1) was used to evaluate the in vivo effects on complement-dependent tissue injury.
Main Results:
- Sustained elevation of CFI levels significantly reduced alternative pathway activity in vivo.
- A decrease in iC3b deposition and accelerated C3 degradation were observed, indicating reduced complement activation.
- In lupus model mice, AAV-CFI treatment led to reduced renal deposition of complement C3 and IgG.
Conclusions:
- Sustained elevation of CFI via AAV gene delivery effectively reduces complement activation in vivo.
- This study provides proof-of-principle for using AAV gene delivery to therapeutically modulate the complement system.
- The findings support CFI elevation as a potential strategy for managing complement-mediated diseases.
