Targeting Corneal Schwann cells to counteract against toxin injury

Synthetic chemical toxins developed for warfare continue to be an enigma for homeland security should they be deployed to cause mass casualties. Sulfur mustard, a powerful ocular vesicant causes irreversible corneal damage affecting the epithelium and stroma, as well as the abundant network of corneal sensory nerves. Despite many studies that have examined damaging mechanisms to the epithelium and stroma caused by vesicants, little is known regarding how corneal nerves degenerate in this injury paradigm. This has led to a critical unmet medical need as no therapeutic is available to protect or regenerate the vulnerable corneal nerves from such injuries. Evidence from both human exposures and animal models of vesicant-injury reveal acute ocular pain and chronic loss of corneal sensation manifest but their mechanisms have not been investigated. Corneal axons are ensheathed by Schwann cells (SCs), a glial cell type that provides trophic support to axons. In animal models of injury conducted in other peripheral organs, SCs can actively regenerate and support the regeneration of damaged axons. Here we hypothesize that a similar axonal-supportive role may be anticipated for corneal SCs (cSCs) in vesicant injury. This gives an opportunity to pursue an innovative strategy to identify novel druggable targets in cSCs. We interrogated molecular and biological pathway information gained from our cSC-single cell RNA seq analysis and identified novel targets and biomarkers. Using a genetically labeled SC mouse model subjected to injury experiments, we have also gained important insight into the dynamic relationships of cSC and axons over acute and chronic stages of injury. This model and targeting the candidate target in cSCs have provided us preliminary data to support the idea that cSC could be targeted for axonal regeneration. In the proposed study, we now choose FDA approved drugs for testing to illuminate the most effective method of use that could support rapid and widespread application in any urgency. Because current information is lacking whether these drug candidates have therapeutic efficacy in the paradigm axonal regeneration over acute and chronic stages of vesicant injury, we include studies of extended use. Lastly, in this innovative exploratory grant proposal we will define a new therapeutic countermeasure against vesicant injury that exploits a combination treatment regimen that can restore corneal refractive function and also help to regenerate corneal sensation.