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 辐射诱发的角膜病变会导致严重的眼表疾病、干细胞缺乏、视力丧失、 不适以及随之而来的生活质量下降，影响了高达 23% 接受放射治疗的患者 研究指出了角膜神经元和头颈部恶性肿瘤的功能作用。 泪腺分泌细胞在辐射引起的角膜病的病因学中的作用。 研究已知的放射缓解药物醋酸鲁沙拉肽 (TP508) 的保护或修复作用 受照射小鼠模型中的角膜上皮细胞、角膜神经元和泪腺细胞的研究。 角膜病模型表明免疫稳态的破坏可归因于角膜 神经损伤可能是放射性角膜病的一个关键病理机制[2]。 显着的神经损失和白细胞的增加在几个月内表现出流入和激活 辐射并暗示慢性神经损失对角膜免疫稳态的影响[2]。 还表明，泪腺直接受到辐射的影响，导致房水分泌减少 照射后 3 天内发生并持续超过 30 天的持续性眼部炎症。 反应通常会导致自我延续的适应性免疫 T 细胞对自身抗原的反应，从而进一步 TP508 通过其精氨酸、甘氨酸和天冬氨酸 (RGD) 结合位点使病理学永久化。 整合素受体的配体，之前已被证明可以通过这种机制下调 促炎症途径并上调再生机制以减轻细胞凋亡和干细胞 本研究的假设是 TP508 的已知分子活性在 先前针对多种细胞的辐射防护研究在逆转角膜方面将产生类似的效果 研究将包括Balb/的全身和局部给药途径。 c 小鼠将接受 11 Gy 的计量辐射剂量，此前已证明对 Balb/c 小鼠而言是亚致死的 导致角膜病变 [2] 目标 1 将研究一天腹膜内注射 TP508。 照射后（24小时）对角膜上皮细胞、角膜神经元和泪腺的保护作用 200 µg/ml (5mg/kg) 和 500 µg/ml (12.5mg/kg) TP508 剂量的影响将是 分析将包括 1 个月时荧光素角膜染色是否存在病变。 2个月和免疫组织化学检测角膜神经元和泪腺细胞的免疫标记物 2 个月时泪腺结构的超微结构分析将研究局部滴眼液。 照射后两周，每天（24 小时）和每两周注射相同的 2 剂剂量 预计调查将在 1 个月和 2 个月的时间点收集相同的数据点。 表明 TP508 在减轻放射性角膜病和最佳给药途径方面的潜在作用。