It is well recognized that ocular surface inflammation plays a prominent role in dry eye disease (DED) symptom development and amplification. Our laboratory has discovered that numerous neutrophils are present on the ocular surface of patients with severe tear-deficient DED subtypes and that they release their nuclear chromatin complex as a type of biologic spider's web. These extracellular DNA (eDNA) webs are termed neutrophil extracellular traps (NETs). Although NETs are part of the innate immune defense, they may contribute to pathology of chronic inflammatory diseases like rheumatoid arthritis and systemic lupus erythematosus. We showed that in severe tear-deficient DED patients, including chronic ocular graft-vs.-host- disease (oGVHD) patients, there were excessive amounts of extracellular DNA (eDNA) and molecular components of neutrophil extracellular traps (NETs) over the ocular surface. NETs accumulate on the ocular surface of DED patients either because of increased formation (due to hyperosmolarity) and/or reduced clearance (due to tear deficiency and consequent nuclease deficiency). Based on our data, we hypothesize that clinical strategies that reduce the abundance of neutrophils and their extracellular products (eDNA and NETs) on the ocular surface have the potential to reduce signs and symptoms of tear-deficient DED. To test this hypothesis, we will perform a phase I/II, randomized, double masked clinical trial using clinical endpoints to determine the therapeutic potential of recombinant human DNase I eye drops in 72 patients with tear-deficient DED due to oGVHD (Specific Aim A). We will prospectively follow patients who receive allogeneic hematopoietic stem cell transplant (HSCT) and determine if the changes that occur in tear fluid components (eDNA abundance and nuclease activity) and peripheral blood neutrophils (formation of NETs and chemotaxis) can be used to predict onset and progression of oGVHD (Specific Aim B). This research may lead to the development of a novel therapy for oGVHD - a condition that greatly impacts quality of life after HSCT and for which no specific therapies exist. Identifying biomarkers will be crucial for predicting which patients are at high risk for developing oGVHD after HSCT and this ability may help in designing personalized treatment strategies.
Dry eye disease (DED) is a disorder of tears and the ocular surface that affects millions of people worldwide. Based on a previously unexplored mechanism of inflammation in DED, namely excessive extracellular DNA (eDNA) in the tear fluid, we propose a clinical trial to determine whether DNase I eye drops are an effective treatment for ocular graft-vs.-host-disease (oGVHD) patients. We will also determine whether increase in tear fluid eDNA content is a biomarker that predicts development of oGVHD after hematopoietic stem cell transplant. This research may lead to the development of a novel therapy for treating oGVHD.
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