Application of CDX-MDM in Pre-Clinical Model of Murine Pulmonary Emphysema

描述（由申请人提供）：本提案的目的是利用新发现的涉及白三烯A4水解酶的氨肽酶活性的抗炎功能来治疗肺气肿。白三烯A4水解酶是具有二分相反功能的双功能酶。作为环氧化物水解酶，它在促炎过程中催化白三烯A4转化为白三烯B4。作为一种氨肽酶，它在抗炎过程中催化三肽序列如Pro-Gly-Pro的消化。我们第一次创造了一种药物（4-MDM），可以选择性地上调白三烯A4水解酶的氨肽酶活性。我们假设用4-MDM治疗将保护肺免于发生肺气肿。初步结果表明，4-MDM治疗有效地保护鼠肺免受鼻内弹性蛋白酶诱导的肺气肿。随后，我们将4-MDM配制成稳定的水溶性，作为潜在的口服剂（CDX-MDM）。CDX-MDM的水溶性增强使我们能够在肺气肿的慢性动物模型中施用该药剂。基于这一初步工作，我们建议在香烟烟雾诱导的肺气肿小鼠模型中进行CDX-MDM的疗效研究，该模型与人类疾病最为相似。肺气肿是在长时间接触触发物（香烟烟雾）后形成的。因此，开发测量药物的药物作用的生物标志物测定也可能是克服药物制剂开发期间发作持续时间长的理想工具。我们开发了一种生物标志物测定法，其可以在离体血浆中测量白三烯A4水解酶的氨肽酶活性。在本授权申请中，我们还建议使用CDX-MDM或安慰剂治疗动物的血浆样本检测该测定法。结合起来，该项目将提供必要的证据，CDX-MDM将被开发为肺气肿的潜在治疗方法。

DESCRIPTION (provided by applicant): The objective of this proposal is to exploit a newly discovered anti-inflammatory function involving the aminopeptidase activity of the leukotriene A4 hydrolase for the treatment of pulmonary emphysema. The leukotriene A4 hydrolase is a dual-functioning enzyme with dichotomously opposing functions. As an epoxide hydrolase, it catalyzes the conversion of leukotriene A4 to leukotriene B4 in pro-inflammatory processes. As an aminopeptidase, it catalyzes the digestion of the tripeptide sequences like Pro-Gly-Pro in anti-inflammatory processes. For the first time, we have created a pharmacological agent (4-MDM) with which the aminopeptidase activity of the leukotriene A4 hydrolase can be selectively up-regulated. We hypothesized that the treatment with 4-MDM will protect lungs from developing pulmonary emphysema. Preliminary results demonstrated that the 4-MDM treatment effectively protected murine lungs from emphysema induced by intra- nasal elastase. Subsequently, we formulated 4-MDM to be stably water soluble as a potential oral agent (CDX- MDM). Enhanced water solubility of the CDX-MDM has enabled us to administer this agent in a chronic animal model of pulmonary emphysema. Building upon this preliminary work, we propose to conduct the efficacy study of the CDX-MDM in a murine model of pulmonary emphysema induced by cigarettes smoke which resembles human disease most closely. Emphysema develops over a long duration of trigger (cigarette smoke) exposure. Therefore, developing a biomarker assay which measures the pharmaceutical effects of the drug could also be a desirable tool to overcome the long duration of onset during the development of a pharmaceutical agent. We developed a biomarker assay which the aminopeptidase activity of the leukotriene A4 hydrolase can be measured in plasma ex vivo. In this grant application, we also propose to test this assay with the plasma samples from the animals treated with the CDX-MDM or placebo. In combination, this project will provide necessary evidence on which the CDX-MDM will be developed as a potential therapy for emphysema.