Pathways to reducing the burden of corneal ulcer in India and beyond

Corneal ulcer caused by invading bacteria or fungi (microbial keratitis, MK) is a silent epidemic, disproportionately affecting low-middle income countries (LMICs), and is a major cause of blindness. Despite being a WHO priority disease area it has not explicitly been covered by Vision2020 frameworks and as such, it has garnered little policy, research or development focus over the last 20+ years. In India alone, 1.5-2 million people experience corneal ulcer per year, predominantly affecting the rural-poor. Corneal ulcer is an "ophthalmic emergency" and the longer the delay to seek appropriate treatment, the worse the outcome. Even where gold-standard diagnostics and treatments are available, over 60% of MK patients are still left with visual impairment across India, and >10% of patients require expensive and often unsuccessful surgical interventions such as corneal transplant. These permanent, debilitating outcomes are often attributed to an excessive and uncontrolled inflammatory response, leading to scarring and corneal perforation. Furthermore, these bleak statistics are for the minority of patients who are able to access specialist care in large cities. The rural-poor are, in reality, much worse off. A radical re-development of the entire healthcare pathway, from diagnosis to treatment, is required to improve the prognosis for these patients.

Due to the large-scale neglect of corneal ulcer, the fundamental molecular mechanisms driving disease, which are required for developing better diagnostics and new therapeutic strategies have been understudied. These molecular "fingerprints" could hold the key to predicting who will heal or who will suffer long lasting visual impairment and require a different therapeutic strategy. To date, tears (a non-invasive, readily available sample) have proven pivotally important in biomarker discovery for a number of eye disorders such as dry-eye, keratoconus and blepharitis, and non-ocular diseases such as cancer and multiple sclerosis; and have led to the development of commercial diagnostic platforms. Surprisingly, molecular signatures within tears have been relatively understudied in the context of MK, and the translation pipeline is bare. Here, through the development of a series of escalating in vitro and ex vivo models, and through the interrogation of MK patient tears by sophisticated proteomic and metabolomic techniques, the molecular signatures of bacterial and fungal, and resolving and non-resolving MK will be mapped. The key targets identified by the research will feed into diagnostic assay development, which will include the synthesis of novel activatable fluorescent chemistries (SmartProbes), which can be used as a tool to non-invasively capture the molecular "fingerprint" of the infection when coupled with simple optical devices at the point-of-care. Furthermore, targeted approaches to modulate the molecular mechanisms driving "non-resolution" pathways, such as neutrophil activation or clearance, will be investigated to identify novel therapeutic strategies for precision medicine based approaches to treatment.

Often translation of such diagnostic technologies and interventional strategies, particularly in low-resource environments, fail or under-perform at the point-of-care. This can partly be attributed to a poor understanding of the intended health-system and lack of end-user engagement during the development process. To mitigate against this, I will work with the world's largest eye-care provider, the Aravind Eye Care System in South India to map MK patient pathways from primary to tertiary care, patient engagement, and how these relate to MK clinical outcomes. Not only will this identify ways to contribute to health-system strengthening, but this insight will feed directly into technology design and provide a route for the clinical evaluation and implementation of the user-appropriate diagnostic and treatment strategies for MK developed within this programme.