Therapeutic use of small-molecule HGF-mimetic for emphysema

描述(申请人提供)：肺气肿是导致死亡和残疾的主要原因，约有200万人患有肺气肿。这种疾病每年造成超过25亿美元的医疗费用，仅在美国每年就导致或促成了10万人的死亡。这种疾病的特征是肺泡壁被破坏，空气空间永久性扩大，肺后坐能力丧失。目前批准的治疗方案只能提供症状缓解，并不能逆转疾病。迫切需要新的有效的治疗方案，特别是那些逆转病程的方案。最近的研究表明，肝细胞生长因子(HGF)是一种多效性细胞因子，具有多种导致肺再生的活性。这些活性包括促进弹性蛋白合成、抑制细胞凋亡、抑制炎症、诱导血管生成和刺激肺上皮细胞和内皮细胞的增殖。已知肺气肿患者肺成纤维细胞中HGF的产生受到损害。通过基因转移，HGF已被证明可以改善动物模型中的肺气肿，事实上，它可以诱导患有既定疾病的动物的肺气肿逆转。因此，HGF的实验证明了靶向HGF信号通路治疗肺气肿的巨大潜力。为了克服基于蛋白质或基因的体内HGF传递的缺点，我们最近开发了一种HGF的小分子模拟物BB3(又名。Refanalyin)。该试剂概括了HGF在体外和体内测试的全部生物活性。瑞法林目前正在临床开发中，用于肾移植患者的短期静脉注射。在组织再生被认为至关重要的其他适应症中，它也被研究为一种潜在的治疗方法。我们先前已经发现，猪胰腺弹性酶(PPE)在大鼠体内引起的肺气肿可以通过与BB3共同治疗而被抑制。重要的是，我们发现每天口服BB3可以逆转PPE诱导的大鼠模型中已建立的肺气肿。此外，我们还在另一种已建立的肺气肿模型TSK1/+小鼠身上展示了BB3的疗效。这些结果表明，BB3作为一种治疗肺气肿的潜在药物，具有逆转这种疾病的令人兴奋的前景。为了进一步探索BB3作为肺气肿的治疗药物，我们建议：(1)研究BB3在猪胰腺弹性酶(PPE)诱导的大鼠肺气肿模型中的体内疗效的剂量和时间依赖性，以及与肺保护和再生相关的反应生物标志物和分子标志物。(2)建立BB3的最佳口服给药方案，并在TSK1/+小鼠模型和转化生长因子-(1)诱导的Balb/c小鼠模型上检测BB3的体内疗效。通过完成这三个特定目标，我们将收集有关BB3在广泛的实验模型中、在不同物种中以及在不同遗传背景和有助于疾病建立的分子刺激下的有效性的重要信息。此外，我们将评估与BB3的疗效相关的分子标记，以及在已建立的肺气肿中刺激肺再生的作用机制。因此，这些数据将为BB3作为肺气肿治疗药物的潜在进一步开发提供基础。公共卫生相关性：肺气肿是死亡和残疾的主要原因，影响到大约200万人，每年花费超过25亿美元的医疗保健费用。仅在美国，它每年就直接导致或促成了10万人的死亡。这种疾病的特征是肺泡壁被破坏，空气空间永久性扩大，肺后坐能力丧失。目前批准的治疗方案只能提供症状缓解，并不能逆转疾病。迫切需要新的有效的治疗方案，特别是那些扭转这种疾病的方案。Angion Biomedica Corp.已经确定BB3是一种肝细胞生长因子(HGF)的小分子模拟物，具有良好的类药物特性。与HGF一样，BB3有可能刺激肺内的再生过程，从而逆转已建立的肺气肿。在SBIR第一阶段拨款的支持下，我们发现每天口服BB3确实可以逆转PPE诱导的大鼠模型中已建立的肺气肿。此外，我们还在另一种已建立的肺气肿模型TSK1/+小鼠身上展示了BB3的疗效。这些有希望的结果表明，BB3作为一种治疗肺气肿的药物具有潜在的潜力，具有逆转病程的令人兴奋的前景。这一第二阶段SBIR应用的目的是进一步寻求BB3作为潜在的肺气肿治疗药物。通过确定疗效所需的暴露水平，并通过在各种已建立的疾病的临床前模型中测试BB3的有效性，这些模型具有不同的遗传背景和有助于疾病建立的不同分子刺激，我们预计将收集关于BB3疗效的广度、肺气肿模型中的口服疗效和潜在反应生物标志物的重要信息。这将为进一步开发BB3作为肺气肿的治疗药物提供基础。

DESCRIPTION (provided by applicant): Emphysema is a major cause of death and disability and afflicts approximately 2 million people. The disease cost more than $2.5 billion in annual health care expenses and causes or contributes to the death of 100,000 people each 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 offer symptomatic relief and do not reverse the disease. New effective treatment options are urgently needed, particularly those which reverse the course of disease. Recent studies suggest that hepatocyte growth factor (HGF), a pleiotropic cytokine, has multiple activities that lead to lung regeneration. Such activities include promotion of elastin synthesis, suppression of apoptosis, suppression of inflammation, induction of angiogenesis and stimulation of proliferation of lung epithelial and endothelial cells. HGF production in pulmonary fibroblasts of emphysema patients is known to be impaired. Using gene transfer, HGF has been shown to ameliorate emphysema in animal models, and it can in fact induce a reversal of emphysema in animals with established disease. Thus, experiments with HGF demonstrate the great potential for targeting the HGF signaling pathway for the treatment of emphysema. To overcome the drawbacks of protein- or gene-based HGF delivery in vivo, we have recently developed a small-molecule mimetic of HGF, BB3 (a.k.a. Refanalin). This agent recapitulates the full-range of bioactivities of HGF tested in vitro and in vivo. Refanalin is currently in clinical development for short term intravenous use in kidney transplant patients. It is also being studied as a potential therapeutic in other indications where tissue regeneration is thought to be of critical importance. We have previously found that induction of emphysema by porcine pancreatic elastase (PPE) administration in the rat can be suppressed by co-treatment with BB3. Importantly, we found that daily oral administration of BB3 can reverse established emphysema in the PPE-induced rat model. Additionally, we demonstrated efficacy of BB3 in the TSK1/+ mouse, another model of established emphysema. These results suggest the potential of BB3 as a therapeutic for emphysema with the exciting prospect of reversal of the disease. To further pursue BB3 as emphysema therapeutic, we propose to (1) characterize dose and time dependence of the in vivo efficacy of BB3 in the porcine pancreatic elastase (PPE)-induced rat model of established emphysema, as well as response biomarkers and molecular markers related to protection and regeneration of the lung. (2) Establish the optimal oral dosing regimen for efficacy of BB3 and test the in vivo efficacy of BB3 in the TSK1/+ mouse model and the TGF-(1-induced Balb/c mouse model, two genetically determined models for established emphysema and (3) Test the in vivo efficacy of BB3 in established cigarette smoke-induced emphysema in the mouse. By completing these three specific aims, we will collect important information about the efficacy of BB3 in a breadth of experimental models, in different species and with different genetic backgrounds and molecular stimuli contributing to the establishment of the disease. Furthermore, we'll evaluate molecular markers related to the efficacy of BB3 and to the mechanism of action to stimulate lung regeneration in established emphysema. These data will therefore provide a basis for potential further development of BB3 as a therapeutic for emphysema. PUBLIC HEALTH RELEVANCE: Pulmonary emphysema is a major cause of death and disability that affects approximately 2 million people and costs more than $2.5 billion in annual health care expenses. It directly causes or contributes to the deaths of 100,000 people 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 offer symptomatic relief and do not reverse the disease. New effective treatment options are urgently needed, particularly those which reverse the disease. Angion Biomedica Corp. has identified BB3, a small molecule mimetic of hepatocyte growth factor (HGF) with excellent drug-like properties. Like HGF, BB3 has the potential to stimulate regenerative processes in the lung and thus reverse established emphysema. With support of an SBIR Phase 1 grant, we have found that daily oral administration of BB3 can indeed reverse established emphysema in the PPE-induced rat model. Additionally, we demonstrated efficacy of BB3 in the TSK1/+ mouse, another model of established emphysema. These promising results show the potential of BB3 as a therapeutic for emphysema with the exciting prospect of reversal of the course of disease. The objective of this phase II SBIR application is to further pursue BB3 as potential emphysema therapeutic. By establishing the exposure levels required for efficacy and by testing efficacy of BB3 in a variety of preclinical models of established disease with different genetic backgrounds and different molecular stimuli contributing to the establishment of the disease, we anticipate to collect important information about the breadth of efficacy of BB3, the oral efficacy in emphysema models and potential response biomarkers. This will provide a basis for potential further development of BB3 as a therapeutic for emphysema.