NETs as therapeutic targets in obstetric APS

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PROJECT SUMMARY/ABSTRACT Pregnant individuals with the autoimmune disease known as antiphospholipid syndrome (APS) have a markedly increased risk of late-term stillbirth, intrauterine growth restriction, and severe preeclampsia. Despite some progress as to how we treat obstetric APS in our clinics—including the routine administration of aspirin and heparins—prospective studies have found that roughly 1 in 8 APS pregnancies will still end with fetal demise. Thrombosis is actually a rare feature of APS placental histopathology; instead, common abnormalities include deposition of complement split products, exuberant decidual neutrophil recruitment, and inadequate tissue remodeling by extravillous trophoblasts. Indeed, our group previously detected neutrophil extracellular traps (NETs) in the intervillous space of human APS placentae, where they may disrupt normal trophoblast functions. NETs are spider web-like tangles of chromatin and microbicidal proteins expelled from activated neutrophils via “NETosis.” We have previously found that antiphospholipid antibody (aPL)-mediated NETosis is required for thrombosis in models of APS—and have identified some pharmacologic strategies that can help restore neutrophil homeostasis (including colchicine, adenosine receptor agonists, selectin ligand inhibitors, and even natural supplements such as ginger). Would such approaches prove valuable if extended to APS-associated obstetric morbidity? We believe there is an urgent need to answer this question. Bolstered by new data indicating that NETosis blockade protects APS mice from fetal loss, the hypothesis shepherding this proposal is that NETosis inhibitors such as colchicine or dipyridamole could find a place in our clinics as adjuvants therapies. While this study's disruptive hypothesis means it is not without risk, the reward will hopefully be sufficient preclinical data to support a clinical trial of a drug like colchicine—which is already known to have a good safety profile in pregnancy based on its routine use in Familial Mediterranean Fever. Aim 1 will elucidate mechanisms by which NETosis may contribute to aPL-mediated obstetric morbidity. Successful completion of this Aim will identify (i) the obstetric APS patient-derived aPL most likely to trigger NETosis, (ii) the role of NETs in amplifying aPL-mediated trophoblast dysfunction, and (iii) whether blocking NETosis reduces aPL-mediated obstetric morbidity in mice. Aim 2 will determine the extent to which administering colchicine and/or adenosine receptor agonists mitigates aPL-mediated obstetric morbidity in mice. Successful completion of this translational Aim is expected to further elucidate the role of NETs in aPL-mediated obstetric morbidity, while potentially identifying new therapies that merit urgent evaluation in the clinic.