A Novel TGF-β Receptor Antagonist to Treat Pulmonary Fibrosis

一种治疗肺纤维化的新型 TGF-β 受体拮抗剂

• 批准号: 9139002
• 负责人: SHUAN S HUANG
• 金额: $ 28.36万
• 依托单位: AUXAGEN, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9139002
• 关键词: Address; Adult Respiratory Distress Syndrome; Affect; Alveolar; Amino Acids; Animal Model; Animals; Antibodies; Appearance; Area; Atherosclerosis; Attenuated; Binding; Binding Proteins; Biopsy; Bleomycin; Blood - brain barrier anatomy; Blood Circulation; Breathing; Cells; Cessation of life; Clinical; Collagen; Complex; Defect; Deposition; Development; Diagnosis; Disease; Drainage procedure; Edema; Engineering; Epithelial; Exhibits; Extracellular Matrix; Extracellular Matrix Proteins; FDA approved; Failure; Fibroblasts; Fibronectins; Fibrosis; Fluorescein-5-isothiocyanate; Future; Glutamates; Goals; Half-Life; Hamman-Rich syndrome; Human; Hyaluronic Acid; Injury; Insulin-Like Growth Factor Binding Protein 3; Lead; Lesion; Liquid substance; Lung; Lung Transplantation; Lung diseases; Lymph; Lymphangiogenesis; Lymphatic; Lymphatic System; Lymphatic vessel; Mediating; Mediator of activation protein; Microscopic; Molecular; Mus; Pathogenesis; Pathway interactions; Patients; Penetration; Peptides; Permeability; Phosphotransferases; Plasma; Process; Production; Property; Pulmonary Edema; Pulmonary Fibrosis; Recycling; Respiratory physiology; Role; Route; Signal Transduction; Smooth Muscle Actin Staining Method; Structure; Structure of parenchyma of lung; Systemic Therapy; Therapeutic; Time; Tissues; Transforming Growth Factor beta; Transforming Growth Factor beta Receptors; Vascular remodeling; Weight; Wound Healing; base; cytokine; drug candidate; effective therapy; in vivo; indium-bleomycin; insight; lung injury; mortality; mouse model; novel; public health relevance; response; small molecule inhibitor; targeted agent; therapeutic target

 DESCRIPTION (provided by applicant): Pulmonary fibrosis (PF), including idiopathic PF (IPF), is a group of progressive incurable lung diseases with high mortality rates. PF is characterized by excessive deposition of extracellular matrix proteins in lung parenchyma via TGF-β-dependent pathways. Existing therapies only modestly slow the progression and likely only indirectly impact TGF-β-mediated pathways. Recent identification of the involvement of abnormal lymphangiogenesis in IPF and bleomycin-induced PF has provided new insights into cellular and molecular mechanisms that may limit systemic therapeutics. It is hypothesized that vascular remodeling, which occurs after lung injury, leads to deposition of hyaluronic acid, a component of lymph and a weak lymphangiogenesis factor. This results in abnormal lymphangiogenesis which produces new lymphatic vessels with functional defects (lymphatic drainage defects), leading to the vicious cycle of repeated injury and fibrosis. Abnormal lymphangiogenesis, a rate-limiting step in PF, offers an excellent target for future inhaled PF therapeutics. The molecular basis of the role of abnormal lymphangiogenesis in the formation of PF is unknown. We hypothesize that TGF-β, a potent fibrogenic cytokine produced in lung upon injury, contributes to abnormal lymphangiogenesis which occurs during vascular remodeling after lung injury, and is involved in the vicious cycle of repeated injury and fibrosis (injury→ abnormal lymphangiogenesis→ lymphatic drainage defects→ accumulation of TGF-β→)n which leads to PF. This hypothesis is based on several lines of evidence: 1) TGF-β accumulates in lung tissues of PF, including IPF. 2) TGF-β inhibits normal lymphangiogenesis in lung tissues. 3) TGF-β induces lung edema by increasing epithelial and endothelial permeability. and 4) TGF-β is a major cytokine which is responsible for production of fibrotic extracellular matrix. This hypothesis suggests that, to ameliorate PF, TGF-β antagonists targeted to the lung draining lymphatic systems by intrapulmonary administration can inhibit not only the matrix production but the cycle of repeated injury and fibrosis. In the last decade, TGF-β binding proteins (anti-TGF-β antibodies and soluble type II TGF-β receptors) and small-molecule inhibitors, which target latent-TGF-β activation and TGF-β signaling, have been developed and used to treat PF in animal models. However, the lung draining lymphatics are not specifically targeted in these treatments. This will limit their efficacy in treating human patients. In additio, these agents have systemic and off-target effects that result in narrow therapeutic windows. To address the limited efficacy and off-target effects, we generated a novel TGF-β receptor antagonist with both TGF-β-antagonist and wound healing-promoting activities. It can be effectively, safely and affordably used for the management of PF in humans. In this project, we will determine the efficacy of this antagonist in treating PF by intranasal delivery, which targets the lung lymphatic system and lung parenchyma, in two mouse models of lung fibrotic disease. We expect that the results from these proposed studies will lead to a novel effective therapy of PF in patients.

 描述（由申请人提供）：肺纤维化（PF），包括特发性PF（IPF），是一组进行性不可治愈的肺部疾病，死亡率高。PF的特征在于细胞外基质蛋白通过TGF-β依赖性途径在肺实质中过度沉积。现有疗法仅适度减缓进展，并且可能仅间接影响TGF-β介导的途径。最近发现异常淋巴管生成参与IPF和博来霉素诱导的PF，为可能限制全身治疗的细胞和分子机制提供了新的见解。据推测，肺损伤后发生的血管重塑导致透明质酸沉积，透明质酸是淋巴液的一种成分，也是一种弱的淋巴管生成因子。这导致异常的淋巴管生成，其产生具有功能缺陷（淋巴引流缺陷）的新淋巴管，导致反复损伤和纤维化的恶性循环。异常淋巴管生成是PF的一个限速步骤，为未来吸入PF治疗提供了一个很好的靶点。 异常淋巴管生成在PF形成中的作用的分子基础尚不清楚。我们推测，TGF-β是一种在肺损伤后产生的强纤维化细胞因子，其参与了肺损伤后血管重建过程中发生的异常淋巴管生成，并参与了反复损伤和纤维化的恶性循环（损伤→异常淋巴管生成→淋巴引流缺陷→ TGF-β积累→）n，导致PF。该假设基于以下几条证据：1）TGF-β在PF（包括IPF）的肺组织中积聚。2)TGF-β抑制肺组织中的正常淋巴管生成。3)TGF-β通过增加上皮和内皮通透性诱导肺水肿。TGF-β是纤维化细胞外基质产生的主要细胞因子。这一假设表明，为了改善PF，通过肺内给药靶向肺引流淋巴系统的TGF-β拮抗剂不仅可以抑制基质产生，还可以抑制重复损伤和纤维化的循环。 在过去的十年中，TGF-β结合蛋白（抗TGF-β抗体和可溶性II型TGF-β受体）和小分子抑制剂（靶向潜在TGF-β活化和TGF-β信号传导）已被开发并用于治疗动物模型中的PF。然而，在这些治疗中，肺引流药物并不是特别针对的。这将限制它们在治疗人类患者中的功效。此外，这些药剂具有导致狭窄治疗窗的全身性和脱靶效应。为了解决有限的功效和脱靶效应，我们产生了一种具有TGF-β拮抗剂和伤口愈合促进活性的新型TGF-β受体拮抗剂。它可以有效，安全和经济地用于人类PF的管理。在这个项目中，我们将确定这种拮抗剂通过鼻内给药治疗PF的疗效，其靶点是 肺淋巴系统和肺实质，在两个小鼠模型的肺纤维化疾病。我们期望这些研究的结果将为PF患者提供一种新的有效治疗方法。