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Published on: October 26, 2018
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.
Insights
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.
Abstract:
The complement system is a key component of innate immunity, but impaired regulation influences disease susceptibility, including age-related macular degeneration and some kidney diseases. While complete complement inhibition has been used successfully to treat acute kidney disease, key unresolved challenges include strategies to modulate rather than completely inhibit the system and to deliver therapy potentially over decades. Elevating concentrations of complement factor I (CFI) restricts complement activation in vitro and this approach was extended in the current study to modulate complement activation in vivo. Sustained increases in CFI levels were achieved using an adeno-associated virus (AAV) vector to target the liver, inducing a 4- to 5-fold increase in circulating CFI levels. This led to decreased activity of the alternative pathway as demonstrated by a reduction in the rate of inactive C3b (iC3b) deposition and more rapid formation of C3 degradation products. In addition, vector application in a mouse model of systemic lupus erythematosus (NZBWF1), where tissue injury is, in part, complement dependent, resulted in reduced complement C3 and IgG renal deposition. Collectively, these data demonstrate that sustained elevation of CFI reduces complement activation in vivo providing proof-of-principle support for the therapeutic application of AAV gene delivery to modulate complement activation.
