Therapeutic Potential of a Small Molecule Compound for Emphysema

描述（由申请人提供）：肺气肿是造成大约200万人死亡和残疾的主要原因，每年花费超过25亿美元的医疗保健费用，仅在美国每年就造成或促成10万人死亡。这种疾病的特点是肺泡壁破坏，空气空间永久性扩大和肺后坐力丧失。目前批准的治疗方案只是治疗症状，而不能逆转疾病。迫切需要新的有效治疗方法。近年来的研究表明，肝细胞生长因子（HGF）是一种多效性细胞因子，具有促进弹性蛋白合成、抗细胞凋亡、抑制炎症、诱导肺上皮和内皮细胞血管生成和增殖，并最终促进肺再生等多种活性。肺气肿患者肺成纤维细胞中HGF的生成受损。通过基因转移，HGF在动物模型中已被证明可以改善肺气肿。因此，HGF在肺气肿的治疗中具有很大的潜力。为了克服基于蛋白质或基因的HGF在体内传递的缺点，我们最近开发了一种HGF的小分子模拟物BB3，它概括了HGF在体外和体内测试的全方位生物活性。此外，在我们的初步研究中，BB3在联合治疗设计中改善了动物模型中的肺气肿。我们的长期目标是开发一种小分子的HGF模拟物，作为治疗肺气肿的药物。为了实现这一目标，我们计划在SBIR I期申请中完成以下三个具体目标：特异性目标-1：在肺气肿建立（延迟治疗）后，通过猪胰腺弹性蛋白酶（PPE）诱导的大鼠肺气肿模型中，通过注射BB3检测其体内疗效；特异性Aim-2：研究BB3在ppe诱导的大鼠肺气肿（特异性Aim-1）和吸烟诱导的小鼠肺气肿（特异性Aim-3）中对肺的保护和再生的重要分子标志物；特异性Aim-3：通过延迟治疗，检测BB3在吸烟致肺气肿小鼠模型中的体内效率。通过完成上述三个具体目标，我们将收集BB3在两种已有疾病条件下实验性肺气肿模型中的疗效，以及BB3治疗相关的分子标记物的重要信息。这些数据将为进一步开发BB3作为肺气肿治疗药物提供基础。

DESCRIPTION (provided by applicant): Emphysema is a major cause of death and disability afflicting approximately 2 million people, costing more than $2.5 billion in yearly health care expenses and causing or contributing to 100,000 deaths per year in the United States alone. The disease is characterized by destruction of the alveolar wall, permanent enlargement of the airspaces and loss of lung recoil capability. Currently approved treatment regimens merely treat the symptoms and do not reverse the disease. New effective treatments are urgently needed. Recent studies suggest that hepatocyte growth factor (HGF), a pleiotropic cytokine, has multiple activities including promoting elastin synthesis, anti-apoptosis, suppressing inflammation, inducing angiogenesis and proliferation of lung epithelial and endothelial cells, and ultimately, lung regeneration. HGF production in pulmonary fibroblasts of emphysema patients is impaired. Using gene transfer, HGF has been shown to ameliorate emphysema in animal models. Thus HGF holds a great potential for the treatment of emphysema. To overcome drawbacks of protein- or gene-based HGF deliver in vivo, we have recently developed a small molecule mimetic of HGF, BB3, that recapitulates the full-range of bioactivities of HGF tested in vitro and in vivo. Moreover, in our pilot study, BB3 ameliorated emphysema in an animal model in a co-treatment design. Our long-range objective is to develop a small molecule mimetic of HGF as a drug for the treatment of emphysema. To pursue this endeavor, we plan to complete the following three specific aims in this SBIR Phase I application: Specific Aim-1: To test the in vivo efficacy of BB3 via i.p. administration in porcine pancreatic elastase(PPE)- induced rat model of emphysema, after emphysema is established (delayed treatment); Specific Aim-2: To investigate important molecular markers related to protection and regeneration of the lung by BB3 in PPE-induced emphysema in the rat (samples from Specific Aim-1) and cigarette smoking-induced emphysema in the mouse (samples from Specific Aim-3); Specific Aim-3: To test the in vivo efficiency of BB3 in the cigarette smoking-induced emphysema mouse model via delayed treatment. By completing the three specific aims described above, we will collect important information about the efficacy of BB3 in two experimental emphysema models under pre-existing disease condition, as well as molecular markers related to the treatment of BB3. These data will provide basis for further development of BB3 as a therapeutic for emphysema. PUBLIC HEALTH RELEVANCE: Pulmonary emphysema afflicts approximately 2 million people and costs 2.5 billion of health care expenses each year in US. Currently approved treatment regimens merely treat the symptoms and do not reverse the disease. New effective treatments are urgently needed. The objective of this SBIR Phase I application is to evaluate the efficacy of BB3 -- a small molecule mimetic of HGF in two well-established animal models of emphysema, and to provide a solid base for further therapeutic development of BB3 as a small molecule compound drug for emphysema.