Rusalatide Acetate (TP508) Mitigation Effect on Radiation Induced Keratopathy

醋酸鲁沙来肽 (TP508) 对放射诱发的角膜病变的缓解作用

• 批准号: 10605739
• 负责人: USHA P ANDLEY
• 金额: $ 34.13万
• 依托单位: AFFIRMED PHARMA, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2024-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10605739
• 关键词: Acetates; Acids; Affect; American; Animal Model; Animals; Apoptosis; Arginine; Aspartate; Autoantigens; Binding; Binding Sites; Blinded; Blindness; Cells; Chronic; Clinical Management; Cornea; Corneal Diseases; Data; Degenerative Disorder; Diagnosis; Dose; Drug Delivery Systems; Epithelial Cells; Etiology; Eye; Eyedrops; Fluorescein; Formulation; Functional disorder; Glycine; Grouping; Head and neck structure; Histocytochemistry; Homeostasis; Hour; Immune; Immunofluorescence Immunologic; Immunohistochemistry; Immunologic Markers; Inbred BALB C Mice; Inflammatory; Inflammatory Response; Injections; Integrins; Intraperitoneal Injections; Investigation; Keratopathy; Lacrimal gland structure; Lesion; Leukocytes; Ligands; Malignant Neoplasms; Molecular; Mus; Nerve; Neurons; Organ; Pathologic; Pathology; Pathway interactions; Patients; Peptides; Persons; Pharmaceutical Preparations; Quality of life; Radiation; Radiation Dose Unit; Radiation Protection; Radiation Toxicity; Radiation induced damage; Radiation therapy; Random Allocation; Recovery; Refractory; Role; Route; Saline; Secretory Cell; Stains; Surface; T cell response; Testing; Thrombin; Time; Transmission Electron Microscopy; Whole-Body Irradiation; aqueous; cell injury; corneal epithelium; corneal repair; density; design; effective therapy; experimental study; intraperitoneal; irradiation; laboratory experience; lacrimal; local drug delivery; meter; mouse model; nerve damage; ocular surface disease; protective effect; protein aminoacid sequence; radiation mitigation; radioprotected; receptor; regenerative; repaired; response; side effect; stem cells; wound healing

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.

抽象的 辐射诱导的角膜病会导致明显的眼部表面疾病，干细胞缺乏症，视力丧失， 不适以及随后的生活质量差，多达23％接受放射治疗的患者 对于头部和颈部恶性肿瘤[1]。研究指出了角膜神经元和 辐射诱导的角化病的病因中，泪腺的秘书细胞。这项研究的目的是 研究已知的射射药乙酸鲁沙拉替酯（TP508）的效果，以保护或修复 辐照小鼠模型中的角膜上皮细胞，角膜神经元和泪细胞。鼠研究 角膜病的模型表明免疫稳态分解可以归因于角膜 神经损伤可能是辐射角膜病的关键病理机制[2]。一项研究 表现出明显的神经丧失和白细胞影响和激活的增加 辐照并暗示了慢性神经丧失对角膜免疫稳态的影响[2]。研究 还表明，泪腺直接受辐射的影响，水性分泌减少 发生在辐照的3天内，持续超过30天[3]。持续的眼部炎症 反应通常会导致自我持久的适应性免疫T细胞对自我抗原的反应，进一步 永久性病理。 TP508，通过其精氨酸，甘氨酸和天冬氨酸（RGD）结合位点是一个 整联蛋白受体的配体，以前已通过该机制显示了调节 促炎的途径和上调减轻细胞凋亡和干细胞的再生机制 激活。这项研究的假设是TP508的已知分子活性 以前跨广泛细胞的放射保护研究在逆转角膜方面具有相似的作用 和泪腺辐射损伤。研究将包括全身和局部药物输送途径。 balb/ c小鼠将接受11 Gy的计量辐射剂量，以前证明是BALB/C小鼠的绝对辐射剂量， 引起角膜病[2]。 AIM 1将调查有一天管理的TP508的腹膜内注射 （24小时）辐照后，以保护角膜上皮细胞，角膜神经元和富集 腺体结构。 TP508剂量为200 µg/ml（5mg/kg）和500 µg/ml（12.5mg/kg）的影响将是 评估。分析将包括荧光素角膜染色，以在1个月内存在或不存在病变 和2个月以及用于角膜神经元和泪细胞免疫标记的免疫组织化学，并具有 2个月时泪腺结构的超微结构分析。 AIM 2将调查局部眼药水 交付相同的2剂，每天（24小时）和两周辐射后两周送达 在1个月和2个月的时间点收集相同的数据点。预计调查 提示TP508对缓解辐射角膜病变和最佳输送途径的潜在影响。