New Approach to Phospholipidosis Prediction

磷脂沉积症预测的新方法

• 批准号: 8127066
• 负责人: PIOTR W RZEPECKI
• 金额: $ 14.99万
• 依托单位: ECHELON BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8127066
• 关键词: New; Approach; Phospholipidosis; Prediction

DESCRIPTION (provided by applicant): Drug safety is a major concern for people that taking medicines as well as pharmaceutical companies, regulatory bodies, and basic researchers. Drug induced phospholipidosis (DIPL) is an adverse reaction to cationic amphiphilic drugs (CADs) resulting in excessive phospholipid accumulation, which in serious cases, leads to organ failure and death. DIPL is prevalent; for example, about 50% of patients prescribed the common anti-arrythmic amiodarone will develop DIPL and up to 17% will require withdrawal from the medicine. CADs are a significant fraction of both approved drugs and chemical compounds currently in testing, but their DIPL- inducing potential is currently evaluated by laborious electron microscopy or mass spectrometry methods. These methods have been judged unsatisfactory by the FDA. Human lysosomal phospholipase A2 (LPLA2, group XV PLA2) is a phospholipid processing enzyme central to DIPL. Inhibition of LPLA2 activity induces phospholipidosis in cells, and an LPLA2 enzymatic assay would enable high-throughput testing of candidate compounds. We propose work to develop a simple fluorogenic biochemical screening assay for LPLA2 activity and its application for testing the phospholipidosis-inducing potential of CADs. Our specific aims are: i) prepare quenched fluorogenic LPLA2-specific substrates, ii) characterize these "smart probe" substrates, specific for phospholipases, with recombinant LPLA2, iii) develop a high throughput screening (HTS) assay, and iv) validate the assay using control and phospholipidosis- inducing CADs. With approximately one-third of all drugs entering clinical trials failing because of toxicity and safety concerns, early detection of DIPL would decrease health care costs by identifying drugs that will induce DIPL prior to expensive clinical trials. Further, we envision this project leading eventually to patient screening for LPLA2 activity. This specific application of personalized medicine would identify individuals who are susceptible to DIPL for a given drug and guide treatment; thus preventing patient harm and improving the efficiency of healthcare in the U.S. PUBLIC HEALTH RELEVANCE: Drug safety is a major concern for people taking medicines as well as pharmaceutical groups, regulatory bodies, and basic researchers. We plan to develop and commercialize a biochemical test assessing one common type of drug toxicity called phospholipidosis. Detection of chemical compounds early in the drug- discovery process that cause phospholipidosis would prevent patient harm, decrease costs, and improve the efficiency of healthcare in the U.S.

药物安全性是人们服用药物以及制药公司，监管机构和基础研究人员的主要关注点。药物诱导的磷脂病（DIPL）是阳离子两亲性药物（CAD）的不良反应，导致过量的磷脂蓄积，严重时可导致器官衰竭和死亡。DIPL普遍存在;例如，约50%的患者处方的普通抗心律失常胺碘酮将发展DIPL，高达17%将需要停药。CAD是目前正在测试的批准药物和化合物的重要部分，但目前通过费力的电子显微镜或质谱法评估其DIPL诱导潜力。FDA认为这些方法不令人满意。人溶酶体磷脂酶A2（LPLA 2，第XV组PLA 2）是DIPL的核心磷脂加工酶。LPLA 2活性的抑制诱导细胞中的磷脂质病，并且LPLA 2酶测定将使得能够高通量测试候选化合物。我们建议开发一种简单的LPLA 2活性的荧光生化筛选方法，并将其应用于检测CAD的磷脂诱导潜力。我们的具体目标是：i）制备淬灭的荧光LPLA 2特异性底物，ii）用重组LPLA 2表征这些对磷脂酶特异的“智能探针”底物，iii）开发高通量筛选（HTS）测定，和iv）使用对照和磷脂质病诱导CAD验证测定。由于毒性和安全性问题，大约三分之一的药物进入临床试验失败，DIPL的早期检测将通过在昂贵的临床试验之前识别诱导DIPL的药物来降低医疗保健成本。此外，我们设想该项目最终导致患者筛选LPLA 2活性。个性化医疗的这种特定应用将识别对给定药物敏感的DIPL个体并指导治疗;从而防止患者伤害并提高美国医疗保健的效率。 公共卫生关系：药物安全是人们服用药物以及制药集团，监管机构和基础研究人员的主要关注点。我们计划开发和商业化的生化测试评估一种常见类型的药物毒性称为磷脂病。在药物发现过程的早期检测导致磷脂质病的化合物将防止患者伤害，降低成本，并提高美国医疗保健的效率。