Reversing the ocular impact of NM and SM through novel therapies

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PROJECT SUMMARY/ABSTRACT The ocular anterior surface in conjunction with the tear film provide the first line of defense against penetration of noxious agents, which can adversely affect vision. Once this two-component system is breached, the anterior surface is capable of mounting a vigorous response, which involves a relatively rapid re- epithelialization along with a brisk inflammatory episode. A variant on the response of the anterior segment to perturbation occurs to patients following exposure to the chemical warfare agent, sulfur mustard (SM). The acute symptoms usually resolve completely without further inflammation after 2-6 weeks. However, in a subset of patients, corneal epithelial erosions, limbal ischemia, and, occasionally, peripheral corneal thinning and neovascularization may slowly progress. With respect to treatment modalities, either steroidal or non-steroidal anti-inflammatory drugs are the accepted treatment for the acute and prolonged phases. However, long-term use of topical steroids in SM ocular injuries is not ideal. Thus, additional therapies to prevent the ocular deterioration of SM victims is a major unmet need. We have recently demonstrated that topical application of synthetic, functional high-density lipoprotein nanoparticles (HDL NPs) inherently enhance re-epithelialization following corneal wounding and can act as anti-inflammatory agents following a chemical burn to the cornea. Furthermore, HDL NPs are effective vehicles for the delivery of miRNAs to the cornea. Therefore, HDL NPs will be complexed with miR-184, a highly angiostatic miRNA in the cornea, to treat the delayed phase of NM- induced corneal injury. We also have evidence that Vitamin D3 (Vit D3) and poly(lactic-co-glycolicacid) immune modifying nanoparticles (PLGA-IMPs) systemically or HDL NPs topically, administered to mice that were exposed to topical nitrogen mustard (NM), an analogue of SM, significantly reduce pro-inflammatory and angiogenic signaling. Collectively, these observations on HDLs, Vit D3, miR-184 and PLGA-IMPs have vast translational potential as novel treatment modalities for SM-induced injury to the eye. To test this idea, we will develop and assess these topical ocular therapeutics for the acute and delayed phases of NM injury to mice. We will evaluate the efficacy and mechanisms underlying these treatments with a combination of clinical, morphological, cell biological and immunological approaches. Additionally, we will evaluate a new class of HDL NPs that replace the inorganic Au core with an organic, transparent lipid-conjugated core scaffold, which will not inhibit the passage of light. We will also appraise the utility of systemic administration of Vit D3 or PLGA- IMPs to treat the delayed phase of NM-induced ocular injury. These results will establish the most effective topical and systemic regimens to treat the acute and delayed phases of NM injury. Finally, we will apply this knowledge to evaluate the efficacy of our chosen treatments for SM injury in rabbit eyes using the approaches described for NM injury. Ultimately, our studies will yield innovative treatments for SM-induced injury that will have anti-inflammatory, anti-angiogenic, pro-resolving, capabilities with minimal side effects.