Targeting NETs in Obstetric APS

Antiphospholipid syndrome (APS), an autoimmune disorder best known for causing blood clots, is also a leading cause of pregnancy loss. APS is especially common in people with lupus. Pregnant people with APS have a high risk of very severe complications, including preeclampsia (a pregnancy complication involving high blood pressure, excess protein in the urine, and other dangerous symptoms), insufficient growth of the fetus, and late-term stillbirth. There has been some progress in how APS is monitored and treated in pregnancy, but 1 in 8 APS pregnancies still result in the death of the fetus, underscoring the urgent need for improved therapies.

Dr. Knight and his team previously found neutrophil extracellular traps (NETs) in the placenta of people with APS. NETs are spider web-like tangles used by neutrophils, a type of white blood cell, to catch bacteria and other harmful invaders. However, in APS, NETs may disrupt the function of cells called trophoblasts that form part of the placenta. NETs have also been shown to cause thrombosis — the formation of blood clots. Dr. Knight will test whether the process of forming NETs (NETosis) plays a role in obstetric APS and test the effectiveness of safe, existing drugs for other conditions that could be repurposed to enable healthy and successful pregnancies for people with APS.

Dr. Knight will first determine how the formation of NETs contributes to APS fetal death and test whether blocking the formation of NETs in an APS mouse model prevents preeclampsia-like symptoms and loss of the fetus. He will then assess if colchicine (an inexpensive and easily accessible existing drug approved for other conditions) and the activation of a specific molecule called an adenosine receptor can reduce the formation of NETs and prevent fetal loss in this mouse model. Of note, colchicine has a track record of safe use during pregnancy in other diseases but has not yet been evaluated in APS. These findings could motivate clinical trials of inexpensive, existing drugs for obstetric APS.

What this study means for people with lupus

Dr. Knight’s findings will identify the specific role of NETs in pregnant people with APS. This study could lead to a clinical trial of an already existing drug that is safe to use during pregnancy. Moreover, repurposing an inexpensive drug could rapidly translate into the clinic and improve the lives of pregnant people with APS.

Antiphospholipid syndrome (APS) is an understudied thrombo-inflammatory disease that complicates up to one-third of cases of systemic lupus erythematosus, where it portends the acquisition of more organ damage over time. APS is propelled by circulating antiphospholipid antibodies (aPL) that cause obstetric complications and vascular thrombosis, not to mention other manifestations such as nephropathy and heart valve damage. Pregnant individuals with APS have a markedly increased risk of late-term stillbirth, as well as premature delivery secondary to severe preeclampsia and/or intrauterine growth restriction. Despite some progress and standardization regarding how we approach obstetric APS in the clinic—including meticulous monitoring and the routine administration of low-dose aspirin and heparin—prospective studies have found that 1 in 8 APS pregnancies will still result in fetal demise. Thrombosis is only rarely found in APS placentae. Rather, a critical role for innate immune factors has been suggested. For example, complement activation predicts obstetric morbidity in aPL-positive individuals. Furthermore, our group has detected neutrophil extracellular traps (NETs) in the intervillous space of APS placentae, where they may disrupt normal trophoblast functions. NETs are spider web-like tangles of chromatin and microbicidal proteins expelled from activated neutrophils through a process called NETosis. We have previously found that aPL-mediated NETosis is required for thrombosis in models of APS. However, whether NET-targeted therapies might prove valuable if extended to obstetric morbidity is so far unknown. Supported by preliminary data that blocking NETosis protects APS mice from fetal loss, the hypothesis shepherding this proposal is that NETosis is a potential therapeutic target in individuals at risk for APS-associated obstetric morbidity. Because the pathogenic mechanisms being explored here are distinct from those currently targeted in the clinic, there is an opportunity for these findings to motivate clinical trials that would attempt to augment standard therapies with agents such as colchicine or dipyridamole. 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.