Mr ANDRE ESPIRITU1, Dr BELINDA THOMAS2, Dr LU LU1, Dr KIM O’SULLIVAN1
1Monash University, Clayton, Australia, 2Hudson Institute of Medical Research, Clayton, Australia
Biography:
Bio to come
Aim:
To evaluate the safety and efficacy of SKQ1 compared to standard care cyclophosphamide (CYC) in treating anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV).
Background:
AAV is a systemic autoimmune disease that affects the kidneys, leading to renal failure if left untreated. It is characterised by loss of tolerance to myeloperoxidase (MPO), with neutrophil extracellular traps (NETs) playing a key pathogenic role. NETs are released by activated neutrophils in response to inflammation. Current treatments broadly suppress immunity, increasing risk of infection. We sought an alternative therapy that would maintain efficacy without compromising host immune defence. SKQ1 is a small molecule antioxidant that limits NET formation by scavenging excess mitochondrial reactive oxygen species, offering a targeted and potentially safer alternative.
Methods:
A well-established 20-day mouse model of MPO-AAV was used to compare SKQ1 (1250 nmol, intraperitoneal) and cyclophosphamide (50 mg/kg, intraperitoneal). Kidney injury was evaluated through histology and albuminuria, while immune cell infiltration was assessed by immunohistochemistry. In vitro assays with human neutrophils assessed SKQ1’s effects on NET inhibition using confocal microscopy. To examine effects on host defence, a mouse influenza model was used, assessing viral clearance and lung inflammation 3- and 10-days post-infection following treatment.
Results:
SKQ1 inhibited NET production in both mouse and human neutrophils leaving the phagocytic capability of neutrophils intact. In vivo, SKQ1 significantly reduced ANCA levels, glomerular injury, leukocyte infiltration, and albuminuria compared to vehicle controls (all P<0.05). In flu models, SKQ1-treated mice showed no impairment in viral clearance or increased lung inflammation compared to CYC-treated mice.
Conclusions:
SKQ1 has potential as a safe and targeted induction treatment for MPO-AAV that is as efficient as CYC without increased risk of infection.
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