Systemic Lupus Erythematosus (SLE) is an autoimmune disorder that can result in end stage renal failure if left untreated but current treatments are non-specific contributing to significant morbidity and mortality. A characteristic feature of this multisystem disease is plasma anti-nuclear antibodies and their co-deposition with complement C3 in diseased kidneys. Additionally, kidneys from lupus patients also exhibit neutrophil extracellular traps (NETs), which comprise extracellular DNA (ecDNA) and proteins released from dead and dying cells. Based on these and other observations there is compelling incentive to develop the enzyme DNase I as a non-toxic therapeutic to clear DNA both as an antigenic source of anti-nuclear antibodies and to disrupt NETs in diseased kidneys. To test therapeutic potential of DNase I, an AAV vector encoding murine DNase I under the transcriptional control of a powerful liver-specific promoter was packaged into serotype 8 capsid to transduce the murine liver and induce high levels of plasma DNase I . Vector performance was confirmed in HuH7 in vitro and in mice in vivo, the latter showing a 150-fold increase in plasma DNase I levels over control treated animals. Vector was also injected into lupus prone NZBWF1 mice and animals were monitored long term (>8 months). While there was no improvement in endpoints such as anti-nuclear antibody levels, kidney function or life span, there was a significant decrease in renal IgG and C3 co-deposition in treated mice. Further studies are in progress to also investigate the incidence of NETS in diseased kidneys but the current outcomes demonstrate the vector system requires further development to confer therapeutic efficacy in the NZBWF1 mouse model.