Preclinical development of a novel Nrf2-activator formulation for the treatment of idiopathic pulmonary fibrosis

用于治疗特发性肺纤维化的新型 Nrf2 激活剂制剂的临床前开发

基本信息

批准号：
9224281
负责人：
LOUISE HECKER
金额：
$ 18.87万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9224281
关键词：
Acetylcysteine Advair Adverse effects Age Aging Air Antioxidants Biochemical Biological Biological Assay Biological Availability Breathing Cell Culture Techniques Cell Membrane Permeability Cell Survival Cellular Membrane Cicatrix Clinical Clinical Trials Collagen Data Devices Diagnosis Disease Disease Progression Dose Drug Kinetics Effector Cell Excipients Excretory function Exhibits FDA approved Fibroblasts Fibrosis Formulation Fumarates Gases Genes Half-Life Hamman-Rich syndrome Histopathology Homeostasis Human Human Characteristics Hydroxyproline In Vitro Inhalators Lead Liquid substance Lung Lung diseases Measures Medical Metabolism Methods Modeling Molecular Morbidity - disease rate Multiple Sclerosis Mus Myofibroblast Nanotechnology Oral Oxidation-Reduction Patients Permeability Pharmaceutical Preparations Pharmacodynamics Pharmacotherapy Phase III Clinical Trials Powder dose form Property Pulmonary Fibrosis Quality of life Resolution Respiratory Failure Route Safety Site Specific qualifier value Structure of parenchyma of lung Survival Rate Therapeutic Time Tissues absorption aged biomaterial compatibility design disorder prevention efficacy study efficacy testing experimental study fibrogenesis human subject impaired capacity improved in vitro testing in vivo mortality mouse model multiple sclerosis treatment nanoparticle nanoparticulate novel particle preclinical development preclinical safety residence response safety study targeted treatment three dimensional cell culture transcription factor uptake

项目摘要

Idiopathic pulmonary fibrosis (IPF) is a disease of aging, with a mean age of 66 years at the time of diagnosis. Despite this strong association, cellular/molecular mechanisms that account for the aging predilection to fibrotic disease have not been elucidated. Previous studies in our lab have demonstrated that myofibroblasts, key effector cells in fibrogenesis, demonstrate a diminished capacity to maintain redox homeostasis in aging; this was in part regulated by a deficient induction of the antioxidant response transcription factor, Nrf2. Human subjects with IPF exhibit decreased Nrf2 expression in myofibroblastic foci, supporting this cellular redox imbalance in a human fibrotic disease. Our preliminary data support this Nrf2 redox imbalance in a novel aging model of non-resolving fibrosis in mice. This represents, to our knowledge, the first aging model of fibrosis that recapitulates the non-resolving nature of human IPF. The Nrf2-activator, dimethyl fumarate (DMF), is an FDA- approved drug for the treatment of multiple sclerosis via the oral route of administration. We have developed a novel DMF microparticulate/nanoparticulate formulation using nanotechnology and FDA-approved excipients, which can be administered locally to the lungs as a Dry Powder Inhaler (DPI). We will utilize FDA-approved human inhaler devices, FDA-approved excipients, and an FDA-approved Nrf2 activator to deliver this novel Nrf2- activator formulation in vivo via an inhaled route. Experiments will be conducted under FDA/USP conditions using required in vitro tests specified by the FDA/USP, including in vitro 2D cell culture (i.e. liquid-covered culture and air-interface culture mimicking the air-liquid lung interface), in vitro 3D cell culture (i.e. air-interface culture), and in vivo pharmacokinetics/pharmacodynamics studies. These studies will evaluate mechanisms influencing cell viability as a function of drug dose, particle-cellular membrane interactions, particle cellular uptake, membrane permeability, drug cellular transport, and activation of cellular Nrf2. Finally, we will evaluate the efficacy of this novel Nrf2-activator formulation and delivery method in an aged mouse model of established fibrosis. The proposed studies in this application were designed to: (1) Determine the efficacy of DMF, an FDA- approved drug (multiple sclerosis), for a new indication (pulmonary fibrosis); (2) Test the efficacy of a novel DMF formulation, as a DPI; (3) Investigate oral versus inhaled (local) administration of an antioxidant strategy for IPF; and (4) evaluate safety and efficacy profiles of therapeutics that could lead directly to clinical trials for IPF.

特发性肺纤维化（IPF）是一种衰老疾病，诊断时平均年龄为66岁。尽管有这种牢固的关联，但细胞/分子机制却是偏爱纤维化的衰老的疾病尚未阐明。我们实验室的先前研究表明，肌纤维细胞，关键效应细胞在纤维发生中，表现出保持衰老中氧化还原稳态的能力降低。这部分受抗氧化反应转录因子NRF2的诱导不足的调节。人类 IPF受试者在肌纤维细胞灶中表现出降低的NRF2表达，支持该细胞氧化还原人类纤维化疾病的失衡。我们的初步数据支持这种新型衰老中的NRF2氧化还原不平衡小鼠非分辨纤维化的模型。据我们所知，这代表了纤维化的第一个老化模型概括了人类IPF的非解决性质。 NRF2激活剂，富马酸二甲基（DMF）是FDA- 批准通过口服给药治疗多发性硬化症的药物。我们已经开发了新型的DMF微观/纳米刻张配方，使用纳米技术和FDA批准的赋形剂，可以将其作为干粉吸入器（DPI）局部施用。我们将利用FDA批准人类吸入器设备，FDA批准的赋形剂和FDA批准的NRF2激活剂，以提供这种新型的NRF2- 通过吸入途径在体内配方。实验将在FDA/USP条件下进行使用FDA/USP指定的所需体外测试，包括体外2D细胞培养（即液体覆盖的培养物和空气接触培养模仿空气肺界面），体外3D细胞培养（即空气接触培养），和体内药代动力学/药效学研究。这些研究将评估影响的机制细胞活力与药物剂量，颗粒细胞膜相互作用，颗粒细胞摄取的函数，膜通透性，药物细胞转运和细胞NRF2的激活。最后，我们将评估这种新型NRF2激活器公式和递送方法在已建立的老鼠模型中的功效纤维化。该应用程序中提出的研究旨在：（1）确定DMF的功效，FDA- 批准的药物（多发性硬化症），用于新的适应症（肺纤维化）；（2）测试新型DMF的功效配方，作为DPI；（3）研究口服与吸入（局部）给药IPF的抗氧化剂策略；（4）评估可以直接导致IPF临床试验的治疗剂的安全性和功效概况。