NOT-NS-20-030: Use of anchored biologics to treat vesicant induced neovascularization

点击翻译按钮获取中文摘要

We have a long-standing interest in host-pathogen interactions in ocular microbial keratitis with the ultimate goal of developing better treatment strategies. Severe keratitis is a very damaging sequela of chemical injuries and causes vision impairment or loss after exposure to sulfur mustard, which has been used in warfare and by terrorist organizations such as ISIS. This application is in response to the NOT-NS-20-030 FOA, which is directed to supplement existing awards to expand research into developing countermeasures to chemical threats including sulfur mustard exposure, and is in accord with our desire to expand our work to chemically- induced keratitis. Corneal vascularization reduces transparency and furthermore drives inflammation by facilitating entry of various immune cells. Vascularization is therefore an appealing therapeutic target for treating keratitis. Anti-VEGF biologics have in recent years been remarkably successful in treating wet age-related macular degeneration and diabetic retinopathy, which naturally has led to interest in using these reagents to manage corneal neovascularization. The difficulty is that these biologics, which are soluble macromolecules, are washed out within minutes when applied topically to the eye and therefore have little or no efficacy. Our solution is to attach an “anchor” to the biologic i.e. a domain that binds to the cornea and therefore prevents wash-out. Currently we are using wheat germ agglutinin an anchor, which binds to GlcNAc and sialic acid that are very abundant on cell surfaces and extracellular matrix. This prolongs the residency time from a few minutes to at least 24 hours, and we have previously shown efficacy in a dry eye model by applying an anchored biologic just once daily. The hypothesis of this study is that targeted inactivation of VEGF using anchored biologics can prevent neovascularization in chemically challenged mouse corneas. The research plan is to 1) produce and validate biochemically a wheat germ agglutinin-conjugated antibody to mouse VEGF, 2) measure effects of application of the anchored antibody on vascularization in vivo in an established model of neovascularization, and 3) use the procedure to determine the extent that anchored anti-VEGF antibodies reduces neovascularization in response to nitrogen mustard. The long-term goal of this supplement is to generate preliminary data to guide further work and to obtain grant support under the CounterACT program to develop a biologic to block VEGF for use in humans.