Therapeutic Potential of a Small Molecule Compound for Emphysema

描述（由申请人提供）：肺气肿是死亡和残疾的主要原因，困扰着大约200万人，每年的医疗保健费用超过25亿美元，仅在美国每年就造成或促成10万人死亡。这种疾病的特征是肺泡壁的破坏，气腔的永久性扩大和肺回缩能力的丧失。目前批准的治疗方案只是治疗症状，并不能逆转疾病。迫切需要新的有效治疗方法。肝细胞生长因子（hepatocyte growth factor，HGF）是一种多效性细胞因子，具有促进弹性蛋白合成、抗凋亡、抑制炎症、诱导血管生成、促进肺上皮细胞和内皮细胞增殖、促进肺再生等作用。肺气肿患者肺成纤维细胞中HGF的产生受损。使用基因转移，HGF已被证明可以改善动物模型中的肺气肿。因此，肝细胞生长因子具有治疗肺气肿的巨大潜力。为了克服基于蛋白质或基因的HGF体内递送的缺点，我们最近开发了HGF的小分子模拟物BB 3，其概括了体外和体内测试的HGF的全部生物活性。此外，在我们的初步研究中，BB 3在共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HGF模拟物作为治疗肺气肿的药物。具体目标-1：在建立肺气肿后，在猪胰弹性蛋白酶（PPE）诱导的肺气肿大鼠模型中，通过腹膜内给药测试BB 3的体内功效（延迟治疗）;具体目标-2：探讨BB 3在PPE诱导的大鼠肺气肿中保护和再生肺的重要分子标志物特异性目标-3：测试BB 3在吸烟诱导的肺气肿小鼠模型中经由延迟处理的体内效率。通过完成上述三个具体目标，我们将收集关于BB 3在预先存在的疾病条件下在两个实验性肺气肿模型中的疗效的重要信息，以及与BB 3治疗相关的分子标志物。这些数据将为进一步开发BB 3作为肺气肿的治疗药物提供基础。 公共卫生相关性：在美国，肺气肿每年折磨大约200万人，花费25亿美元的医疗费用。目前批准的治疗方案只是治疗症状，并不能逆转疾病。迫切需要新的有效治疗方法。该SBIR I期申请的目的是评估BB 3-HGF的小分子模拟物在两种已建立的肺气肿动物模型中的疗效，并为BB 3作为肺气肿小分子化合物药物的进一步治疗开发提供坚实的基础。

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.