Therapeutic use of small-molecule HGF-mimetic for emphysema

描述（由申请人提供）：肺气肿是死亡和残疾的主要原因，约有200万人受到影响。这种疾病每年花费超过25亿美元的医疗保健费用，仅在美国每年就导致或导致10万人死亡。这种疾病的特点是肺泡壁的破坏，永久扩大的空气空间和损失的肺回缩能力。目前批准的治疗方案仅提供症状缓解，并不能逆转疾病。迫切需要新的有效治疗方案，特别是那些扭转疾病进程的方案。最近的研究表明，肝细胞生长因子（HGF），一个多效性细胞因子，具有多种活动，导致肺再生。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增殖。已知肺气肿患者的肺成纤维细胞中的HGF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，并且它实际上可以在已建立疾病的动物中诱导肺气肿的逆转。因此，用HGF进行的实验证明了靶向HGF信号传导途径用于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（a.k.a. Refanalin）。该试剂概括了体外和体内测试的HGF的全部生物活性。瑞法那林目前正处于临床开发阶段，用于肾移植患者的短期静脉注射。它也被研究作为一种潜在的治疗在其他适应症，其中组织再生被认为是至关重要的。我们之前发现，与BB 3联合治疗可以抑制大鼠给予猪胰腺弹性蛋白酶（PPE）诱导的肺气肿。重要的是，我们发现每天口服BB 3可以逆转PPE诱导的大鼠模型中建立的肺气肿。此外，我们证明了BB 3在TSK 1/+小鼠中的功效，TSK 1/+小鼠是另一种已建立的肺气肿模型。这些结果表明BB 3作为肺气肿治疗剂的潜力，具有逆转该疾病的令人兴奋的前景。为了进一步研究BB 3作为肺气肿治疗剂，我们提出（1）表征BB 3在猪胰弹性蛋白酶（PPE）诱导的已建立肺气肿大鼠模型中体内功效的剂量和时间依赖性，以及与肺保护和再生相关的响应生物标志物和分子标志物。(2)建立BB 3功效的最佳口服给药方案，并在TSK 1/+小鼠模型和TGF-β 1诱导的Balb/c小鼠模型中测试BB 3的体内功效，这两种模型是用于已建立的肺气肿的遗传确定的模型，和（3）测试BB 3在小鼠中已建立的香烟烟雾诱导的肺气肿中的体内功效。通过完成这三个具体目标，我们将收集有关BB 3在广泛的实验模型中的疗效的重要信息，这些模型适用于不同的物种，具有不同的遗传背景和分子刺激，有助于疾病的建立。此外，我们还将评估与BB 3疗效相关的分子标志物，以及与刺激肺气肿患者肺再生的作用机制相关的分子标志物。因此，这些数据将为BB 3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，影响约200万人，每年的医疗保健费用超过25亿美元。仅在美国，它每年直接导致或导致10万人死亡。这种疾病的特点是肺泡壁的破坏，永久扩大的空气空间和损失的肺回缩能力。目前批准的治疗方案仅提供症状缓解，并不能逆转疾病。迫切需要新的有效治疗选择，特别是那些扭转这种疾病的治疗选择。Angion Biomedica Corp.已经鉴定出BB 3，一种具有良好药物样性质的肝细胞生长因子（HGF）小分子模拟物。像HGF一样，BB 3有可能刺激肺的再生过程，从而逆转已建立的肺气肿。在SBIR第1阶段资助的支持下，我们发现每天口服BB 3确实可以逆转PPE诱导的大鼠模型中已建立的肺气肿。此外，我们证明了BB 3在TSK 1/+小鼠中的功效，TSK 1/+小鼠是另一种已建立的肺气肿模型。这些有希望的结果显示了BB 3作为肺气肿治疗剂的潜力，具有逆转疾病过程的令人兴奋的前景。该II期SBIR申请的目的是进一步寻求BB 3作为潜在的肺气肿治疗药物。通过建立疗效所需的暴露水平，并通过在具有不同遗传背景和不同分子刺激的已确立疾病的各种临床前模型中测试BB 3的疗效，我们预计将收集有关BB 3疗效范围、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BB 3作为肺气肿治疗剂的潜在进一步开发提供基础。

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.