Scavenging IsoLGs in Autoimmune Disease: a proof-of-concept clinical study

Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease with a markedly increased prevalence of not only hypertension but also resistant hypertension. Hypertension, along with other factors, leads to a 2 to 3-fold increase in risk of cardiovascular disease in SLE. Other than glucocorticoids and immunosuppression, there are few therapeutic options for patients with SLE and none that are known to have a beneficial effect on hypertension and cardiovascular disease; in fact, glucocorticoids have substantial deleterious effects. The increased prevalence of hypertension and its greater severity in SLE patients are unexplained; however, work from our group and others increasingly implicates activation of the immune system in the pathogenesis of hypertension. Moreover, our data suggest that downstream products of oxidative stress, specifically isolevuglandins (IsoLGs), drive immune activation and hypertension. IsoLGs are highly reactive dicarbonyl products of oxidative stress that bind covalently to proteins causing conformational changes rendering them immunogenic and proinflammatory. Two decades of work at Vanderbilt led to the identification of 2-hydroxybenzylamine (2-HOBA) as a highly effective scavenger of reactive dicarbonyls such as IsoLGs. Scavenging reactive dicarbonyls is preferable to using antioxidants because reactive oxygen species are necessary for normal cellular function. In animal models of SLE, hypertension, and atherosclerosis 2-HOBA reduced inflammation, neutrophil extracellular traps (NETosis), blood pressure, and atherosclerosis, and in human phase I clinical studies with healthy volunteers it was well tolerated. We propose a mechanistic, proof-of-concept phase II study with a randomized, placebo- controlled, double-blind, cross-over design to determine the effect of IsoLG scavenging by 2- HOBA on blood pressure and immune activation in patients with SLE. 42 patients with stable SLE and elevated blood pressure will be randomized to treatment sequence to receive placebo or 750mg 2-HOBA three times a day for 8 weeks followed by a 4-week washout and then 8 weeks of the other agent. Comparing 2-HOBA and placebo arms, Aim 1 will determine the change in 24- hour blood pressure and Aim 2 will determine the change in immune activation measured by NETosis and type 1 interferon score. This study will provide mechanistic information on the role of IsoLGs in autoimmune disease-associated hypertension and immune activation. In the long-term it may lead to a new therapeutic with novel mechanism of action to treat both hypertension and autoimmune diseases.