Radiation induced keratopathy results in significant ocular surface disease, stem cell deficiency, vision loss,discomfort, and subsequent poor quality of life, affecting up to 23% of patients receiving radiation therapyfor head and neck malignancies [1]. Studies have pointed out functional roles of corneal neurons andsecretory cells of the lacrimal gland in the etiology of radiation induced keratopathy. This study is aimed toinvestigate the effect of a known radio-mitigating drug, rusalatide acetate (TP508), to protect or repaircorneal epithelial cells, corneal neurons and lacrimal cells in an irradated mouse model. Studies in a murinemodel of keratopathy indicate that the breakdown of immune homeostasis can be attributed to cornealnerve damage which may be a key pathologic mechanism of radiation keratopathy [2]. One studydemonstrated significant nerve loss and increase in leukocyte influx and activation within months ofirradiation and implicated the effects of chronic nerve loss on corneal immune homeostasis [2]. Studieshave also shown that the lacrimal gland is directly affected by radiation with decreased aqueous secretionoccurring within 3 days of irradiation and persisting beyond 30 days [3]. A persistent ocular inflammatoryresponse often leads to a self-perpetuating adaptive immune T-cell response to self-antigens that furtherperpetuates the pathology. TP508, through its Arginine, Glycine, and Aspartate (RGD) binding site is aligand for integrin receptors and has been previously shown through this mechanism to down regulateproinflammatory pathways and upregulate regenerative mechanisms for apoptosis mitigation and stem cellactivation. The hypothesis for this study is that the known molecular activity of TP508 demonstrated inprevious radioprotection studies across a wide range of cells will have a similar effect in reversing cornealand lacrimal gland radiation damage. Studies will include systemic and topical routes of drug delivery. Balb/c mice will receive a metered radiation dose of 11 Gy, previously shown to be sublethal to Balb/c mice andto cause keratopathy [2]. Aim 1 will investigate an intraperitoneal injection of TP508 administered one day(24 hours) post irradiation for effects in protecting corneal epithelial cells, corneal neurons and lacrimalgland structure. Effects from TP508 doses of 200 µg/ml (5mg/kg) and 500 µg/ml (12.5mg/kg), will beevaluated. Analysis will include fluorescein corneal staining for presence or absence of lesions at 1 monthand 2 months and immunohistochemistry for immune markers for corneal neurons and lacrimal cells withultrastrucural analysis of lacrimal gland structure at 2 months. Aim 2 will investigate a topical eye dropdelivery of the same 2 doses, administered one day (24 hours) and biweekly for two weeks post irradiationwith the same data points collected at the 1- and 2-month time points. Investigations are expected tosuggest potential effects of TP508 in mitigation of radiation keratopathy and optimal routes of delivery.
Public Health Relevance Statement: Keratopathy, a degenerative disease of the cornea, is a frequent adverse side effect of radiation therapy
for 23% of the 65,000 Americans diagnosed each year with head and neck malignancies. Clinical
management of radiation keratopathy is complicated by the lack of effective therapies with chronic
conditions generally thought to be permanent and irreversible. This animal study will evaluate an
investigational radio-mitigating drug, rusalatide acetate (TP508), for its protective effects on cellular
markers of radiation keratopathy.
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