Rusalatide Acetate (TP508) Mitigation Effect on Radiation Induced Keratopathy

摘要

Abstract 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 therapy for head and neck malignancies [1]. Studies have pointed out functional roles of corneal neurons and secretory cells of the lacrimal gland in the etiology of radiation induced keratopathy. This study is aimed to investigate the effect of a known radio-mitigating drug, rusalatide acetate (TP508), to protect or repair corneal epithelial cells, corneal neurons and lacrimal cells in an irradated mouse model. Studies in a murine model of keratopathy indicate that the breakdown of immune homeostasis can be attributed to corneal nerve damage which may be a key pathologic mechanism of radiation keratopathy [2]. One study demonstrated significant nerve loss and increase in leukocyte influx and activation within months of irradiation and implicated the effects of chronic nerve loss on corneal immune homeostasis [2]. Studies have also shown that the lacrimal gland is directly affected by radiation with decreased aqueous secretion occurring within 3 days of irradiation and persisting beyond 30 days [3]. A persistent ocular inflammatory response often leads to a self-perpetuating adaptive immune T-cell response to self-antigens that further perpetuates the pathology. TP508, through its Arginine, Glycine, and Aspartate (RGD) binding site is a ligand for integrin receptors and has been previously shown through this mechanism to down regulate proinflammatory pathways and upregulate regenerative mechanisms for apoptosis mitigation and stem cell activation. The hypothesis for this study is that the known molecular activity of TP508 demonstrated in previous radioprotection studies across a wide range of cells will have a similar effect in reversing corneal and 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 and to 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 lacrimal gland structure. Effects from TP508 doses of 200 µg/ml (5mg/kg) and 500 µg/ml (12.5mg/kg), will be evaluated. Analysis will include fluorescein corneal staining for presence or absence of lesions at 1 month and 2 months and immunohistochemistry for immune markers for corneal neurons and lacrimal cells with ultrastrucural analysis of lacrimal gland structure at 2 months. Aim 2 will investigate a topical eye drop delivery of the same 2 doses, administered one day (24 hours) and biweekly for two weeks post irradiation with the same data points collected at the 1- and 2-month time points. Investigations are expected to suggest potential effects of TP508 in mitigation of radiation keratopathy and optimal routes of delivery.