Therapeutic use of small-molecule HGF-mimetic for emphysema

小分子 HGF 模拟物治疗肺气肿

• 批准号: 7893143
• 负责人: Bert J. W. M. Oehlen
• 金额: $ 95.4万
• 依托单位: ANGION BIOMEDICA CORPORATION
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7893143
• 关键词: A-factor (Streptomyces); Affect; Alveolar; Alveolar wall; Animal Model; Animals; Apoptosis; Apoptotic; Applications Grants; Biological; Biological Availability; Biological Markers; Biological Process; Biology; Biotechnology; Blood Gas Analysis; Blood Vessels; Blood gas; Bronchi; Cause of Death; Cessation of life; Cigarette smoke-induced emphysema; Clinic; Clinical; Collagen; Cost of Illness; Data; Dependence; Desmosine; Development; Disease; Dose; Doxycycline; Drug Exposure; Drug Formulations; Elastases; Elastin; Endothelial Cells; Environment; Epithelial; Experimental Models; Exposure to; Factor V; Factor VIII; Family suidae; Fibroblasts; Future; Gene Transfer; Genes; Genetic; Grant; Healthcare; Hepatocyte Growth Factor; Histocytochemistry; Hospitals; Human Resources; Hydroxyproline; In Situ Nick-End Labeling; In Vitro; Industry; Inflammation; Internal Medicine; Intervention; Intravenous; Irrigation; Kidney Transplantation; Knowledge; Laboratories; Lead; Legal patent; Lung; Lung diseases; Measurement; Medical; Medicine; Messenger RNA; Metalloproteases; Methods; Modeling; Molecular; Molecular Weight; Monitor; Morphology; Mus; Natural regeneration; Oral; Oral Administration; Pancreatic Elastase; Paper; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase I Clinical Trials; Positioning Attribute; Pre-Clinical Model; Predisposition; Process; Production; Proliferation Marker; Property; Proteins; Publishing; Pulmonary Emphysema; Pulmonary Fibrosis; Radiation Oncology; Rattus; Regimen; Research; Research Personnel; Respiratory physiology; Role; Route; S-Phase Fraction; Sampling; Scientist; Seminal; Series; Services; Signal Pathway; Skin; Small Business Innovation Research Grant; Smoke; Smoking; Staining method; Stains; Stimulus; Symptoms; Testing; Therapeutic; Therapeutic Uses; Time; Tissue Sample; Tissues; Transgenes; Transgenic Mice; Translating; Transplant Recipients; Treatment Efficacy; Treatment Protocols; Tropoelastin; United States; Universities; Western Blotting; Work; angiogenesis; base; cigarette smoking; cigarette smoking; clinically relevant; cost; cytokine; design; disability; drug discovery; effective therapy; efficacy testing; experience; feeding; gene therapy; improved; in vitro testing; in vivo; indexing; innovation; intraperitoneal; man; medical schools; mimetics; molecular marker; mouse model; non-smoking; pancreatic elastase II; pre-clinical; professor; programs; public health relevance; regenerative; research clinical testing; research study; response; small molecule; success; therapeutic target; tissue regeneration; treatment duration

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.

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。这种疾病每年造成的医疗费用超过 25 亿美元，仅在美国每年就导致或导致 10 万人死亡。该疾病的特征是肺泡壁破坏、气腔永久性扩大以及肺反冲能力丧失。目前批准的治疗方案只能缓解症状，不能逆转疾病。迫切需要新的有效治疗方案，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、诱导血管生成以及刺激肺上皮和内皮细胞的增殖。已知肺气肿患者的肺成纤维细胞中 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，并且事实上它可以诱导已患有疾病的动物逆转肺气肿。因此，HGF 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 HGF 体内递送的缺点，我们最近开发了一种 HGF 的小分子模拟物 BB3（又名 Refanalin）。该试剂概括了体外和体内测试的 HGF 的全方位生物活性。 Refanalin 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。人们还正在研究它作为其他适应症的潜在治疗方法，在这些适应症中组织再生被认为至关重要。我们之前发现，通过与 BB3 联合治疗，可以抑制大鼠胰腺弹性蛋白酶 (PPE) 诱导的肺气肿。重要的是，我们发现每天口服 BB3 可以逆转 PPE 诱导的大鼠模型中已形成的肺气肿。此外，我们还在 TSK1/+ 小鼠（另一种已形成的肺气肿模型）中证明了 BB3 的功效。这些结果表明 BB3 作为肺气肿治疗剂的潜力，并具有逆转疾病的令人兴奋的前景。为了进一步探索 BB3 作为肺气肿治疗药物，我们建议 (1) 表征 BB3 在猪胰腺弹性蛋白酶 (PPE) 诱导的肺气肿大鼠模型中的体内功效的剂量和时间依赖性，以及反应生物标志物和分子标志物与肺的保护和再生有关。 (2) 建立BB3功效的最佳口服给药方案，并在TSK1/+小鼠模型和TGF-(1诱导的Balb/c小鼠模型，两种已建立的肺气肿和遗传决定模型)中测试BB3的体内功效。 (3) 测试 BB3 对小鼠吸烟引起的肺气肿的体内功效 通过完成这三个具体目标，我们将在广泛的实验中收集有关 BB3 功效的重要信息。此外，我们将评估与 BB3 的功效以及刺激已形成的肺气肿的肺再生的作用机制相关的分子标记。因此，数据将为 BB3 作为肺气肿治疗剂的潜在进一步开发提供基础。 公共卫生相关性：肺气肿是导致死亡和残疾的主要原因，影响了大约 200 万人和费用。每年医疗保健费用超过 25 亿美元。仅在美国，它每年就直接导致或导致 10 万人死亡。该疾病的特征是肺泡壁破坏、气腔永久性扩大以及肺反冲能力丧失。目前批准的治疗方案只能缓解症状，不能逆转疾病。迫切需要新的有效治疗方案，特别是那些逆转疾病的方案。 Angion Biomedica Corp. 已鉴定出 BB3，一种肝细胞生长因子 (HGF) 的小分子模拟物，具有优异的药物样特性。与 HGF 一样，BB3 有可能刺激肺部的再生过程，从而逆转已形成的肺气肿。在 SBIR 第一阶段资助的支持下，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形成的肺气肿。此外，我们还在 TSK1/+ 小鼠（另一种已形成的肺气肿模型）中证明了 BB3 的功效。这些有希望的结果表明 BB3 作为肺气肿治疗剂的潜力，并具有逆转病程的令人兴奋的前景。该 II 期 SBIR 应用的目的是进一步探索 BB3 作为潜在的肺气肿治疗药物。通过确定功效所需的暴露水平并测试 BB3 在具有不同遗传背景和导致疾病形成的不同分子刺激的各种已确定疾病的临床前模型中的功效，我们期望收集有关功效广度的重要信息BB3、肺气肿模型中的口服功效和潜在反应生物标志物。这将为 BB3 作为肺气肿治疗药物的进一步开发奠定基础。