Development of biomarker of aging as predictor of AKI due to cardiac surgery

开发衰老生物标志物作为心脏手术引起的 AKI 的预测因子

• 批准号: 8904943
• 负责人: Natalia Mitin
• 金额: $ 22.46万
• 依托单位: SAPERE BIO, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8904943
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Admission activity; Aging; Area; Atherosclerosis; Biological Assay; Biological Markers; Bypass; CDKN2A gene; Cardiac; Cardiac Surgery procedures; Cardiovascular Surgical Procedures; Cardiovascular system; Cell Aging; Cells; Cisplatin; Clinical; Clinical Research; Clinical Trials; Contrast Media; Coronary Artery Bypass; Coupling; Cytotoxic Chemotherapy; Data; Development; Diabetes Mellitus; Diagnostic; Dialysis procedure; Disease; Elderly; Epithelial Cells; Funding; Glaucoma; Homeostasis; Hospitals; Human; Imaging Techniques; Immune system; In Vitro; Incidence; Injury; Injury to Kidney; Kidney; Kidney Failure; Malignant Neoplasms; Marketing; Measures; Medical Imaging; Messenger RNA; Multi-Institutional Clinical Trial; Natural regeneration; Operative Surgical Procedures; Organ Transplantation; Organism; Patient Care; Patients; Phase; Pilot Projects; Population; Prevention; Procedures; Proliferating; Risk; Risk Factors; Shock; Small Business Innovation Research Grant; Stratification; Stress; Stroke; Supportive care; T-Lymphocyte; Technology; Testing; Therapeutic; Tissues; Validation; age related; base; clinical risk; cohort; commercialization; high risk; improved; mortality; novel; peripheral blood; post gamma-globulins; predictive modeling; public health relevance; regenerative; research study; senescence; tissue repair

 DESCRIPTION (provided by applicant): Acute kidney injury (AKI) is common, expensive to treat, and is associated with >50% mortality despite advances in supportive care. Each year, millions of patients undergo cardiovascular surgery, medical imaging procedures, or cytotoxic chemotherapy, placing them at significant risk for developing AKI. However, while there is an immense clinical need to identify patients at high risk for developing AKI, predictive models do not currently exist. To make matters worse, there are no pharmacologic therapies available for the prevention or treatment of AKI, despite a $6.3 billion market opportunity in the US. A principal reason for the lack of therapies is the lack of biomarkers capable of identifying patient at high risk for AKI that can be used as an enrichment strategy to power phase 2/3 clinical trials. HealthSpan Dx has identified a biomarker that has potential to predict patients at risk for AKI. Our findings in a human clinical trial point to a marker of senescence, p16INK4a as predictor of risk of AKI in patients undergoing cardiovascular procedures. Senescent cells lack replicative capacity and, therefore, cannot contribute to tissue repair and homeostasis. In kidney, where normally quiescent epithelial cells need to rapidly proliferate to recover from ischemic shock, accumulation of senescent cells hinders regeneration and leads to kidney injury. A test to measure expression of p16INK4a mRNA in peripheral blood has been developed in the Sharpless lab and evaluated in various clinical scenarios in >1,000 human patients. IP around this marker was issued in 2012 and is the core technology of HealthSpan Dx. HealthSpan Dx is developing the assay for commercialization and is actively exploring areas of clinical need. In this proposal, we will perform proof-of-concept experiments to determine the utility of p16INK4a assay for prediction of AKI after cardiac bypass surgery. Completion of this Phase I proposal will provide the requisite data to seek Phase II funding for multi-center clinical trials to further validate clinical utility of the p16INK4a diagnostic as a predictor of AKI in patients undergoing cardiovascular procedures. Ultimately, validation of the p16INK4a diagnostic as a predictor of AKI would catalyze the clinical development of novel preventative and treatment approaches for AKI.

 描述(由申请人提供)：急性肾损伤(AKI)是常见的，治疗费用昂贵，并与50%的死亡率相关，尽管支持性治疗取得了进展。每年，数以百万计的患者接受心血管手术、医学成像程序或细胞毒性化疗，使他们面临患AKI的巨大风险。然而，尽管有巨大的临床需求来确定发生AKI的高危患者，但目前还不存在预测模型。更糟糕的是，尽管美国有63亿美元的市场机会，但目前还没有预防或治疗AKI的药物疗法。缺乏治疗的一个主要原因是缺乏能够识别AKI高危患者的生物标记物，这些生物标记物可以用作支持2/3期临床试验的补充策略。 Health Span Dx已经确定了一种生物标记物，它有可能预测有AKI风险的患者。我们在一项人类临床试验中的发现指出，衰老的标志物p16INK4a是心血管手术患者AKI风险的预测指标。衰老的细胞缺乏复制能力，因此不能促进组织修复和动态平衡。在肾脏中，通常静止的上皮细胞需要快速增殖才能从缺血性休克中恢复，衰老细胞的积累阻碍了再生，并导致肾脏损伤。夏普莱斯实验室已经开发了一种检测外周血中p16INK4a mRNA表达的测试，并在1000名人类患者的不同临床场景中进行了评估。围绕这一标志的IP发布于2012年，是HealthSpan Dx的核心技术。HealthSpan Dx正在为商业化开发这种检测方法，并积极探索临床需要的领域。在这项提案中，我们将进行概念验证实验，以确定p16INK4a检测在预测心脏搭桥术后急性心肌梗死中的作用。这一第一阶段提案的完成将为寻求多中心临床试验的第二阶段资金提供必要的数据，以进一步验证p16INK4a诊断作为心血管手术患者AKI预测指标的临床实用性。最终，确认p16INK4a诊断为AKI的预测因子将促进AKI新的预防和治疗方法的临床发展。