An oxysterol drug candidate, Oxy210, for inhibition of pulmonary fibrosis through targeting hedgehog and TGFβ signaling

氧甾醇候选药物 Oxy210，通过靶向刺猬蛋白和 TGFβ 信号传导抑制肺纤维化

基本信息

批准号：
10545973
负责人：
FARHAD PARHAMI
金额：
$ 31.81万
依托单位：
MAX BIOPHARMA, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-10 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10545973
关键词：
Address Affect Anti-Inflammatory Agents Antiinflammatory Effect Biological Bleomycin California Cardiovascular Diseases Cell Line Cells Chemotherapy and/or radiation Chronic Collaborations Collagen Complement Factor B Cytochrome P450 Data Development Diagnosis Disease Disease Progression Dose Drug Kinetics Embryo Epithelial Erinaceidae Exposure to FDA approved Family Fibroblasts Fibronectins Fibrosis Gene Expression Growth Health Human In Vitro Injury Interstitial Lung Diseases Intervention Kidney Lead Life Ligands Lipids Liver Liver Fibrosis Lung Lung Neoplasms Medicine Modeling Molecular Morbidity - disease rate Mus Myofibroblast Ohio Oncology Oral Organ Orthopedics Pathologic Pathology Pathway interactions Patients Pharmaceutical Preparations Pharmacotherapy Phenotype Phosphorylation Pirfenidone Property Public Health Pulmonary Fibrosis Pulmonary Pathology Quality of life Radiation therapy Reporting Respiratory Failure Role Safety Series Signal Pathway Signal Transduction Structure-Activity Relationship TLR2 gene TLR4 gene Tissues Toll-like receptors Toxic effect Transcription Factor AP-1 Transforming Growth Factor beta Transforming Growth Factors Tyrosine Kinase Receptor Inhibition Universities Virus analog antagonist base cell type clinical development connective tissue growth factor drug candidate efficacy evaluation fibrotic lung humanized mouse idiopathic pulmonary fibrosis improved in vivo in vivo Model indium-bleomycin inhibitor kinase inhibitor liver inflammation macrophage migration mortality mouse model neoplastic cell neutralizing antibody nintedanib nonalcoholic steatohepatitis novel pancreatic cancer cells patient population pulmonary function decline response scale up screening smoothened signaling pathway therapeutic development transcriptome sequencing vascular inflammation wound healing

项目摘要

ABSTRACT Idiopathic Pulmonary Fibrosis (IPF) is a chronic interstitial lung disease, characterized by progressive, irreversible scarring of lung tissue and declining lung function, terminating in respiratory failure. Median patient survival is limited to 3-5 years post diagnosis. Two currently available therapies, Pirfenidone and Nintedanib, only slow the progression of the disease and have not greatly reduced IPF mortality or significantly improved quality of life in IPF patients since they were approved in 2014. Hence, new and improved IPF drug candidates are urgently needed. IPF disease progression is driven in significant part through inappropriate reactivation of embryonic cellular signaling pathways, such as the Transforming Growth Factor beta (TGFβ) and Hedgehog (Hh) signaling pathways. In fact, Pirfenidone and Nintedanib act in part through modestly blocking these signaling pathways. At MAX BioPharma, we are developing novel, proprietary, oxysterol-based antagonists of aberrant cellular signaling that may have disease modifying properties in human IPF and other fibrotic diseases. This application covers an oxysterol-based drug candidate, Oxy210, a dual inhibitor of Hh and TGFβ signaling that ameliorates hepatic fibrosis and inflammation in a humanized mouse model of non-steatohepatitis (NASH). In this application, we present encouraging preliminary data from in vitro studies with Oxy210, demonstrating its inhibitory effects on proliferation and pro-fibrotic gene expression in a normal pulmonary fibroblast cell line (IMR- 90) and an IPF patient-derived cell line (LL97A). Oxy210 has anti-inflammatory effects in LPS-treated macrophages through direct inhibition of Toll-Like Receptor (TLR4), TLR2, and AP-1, and does not interfere with the anti-inflammatory effects of TGFβ. Preliminary findings show the promising potential of Oxy210 to inhibit bleomycin-induced pulmonary pathology in vivo in mice. We propose to further characterize Oxy210 in relevant in vitro and in vivo models of IPF. Specifically, we propose to address the following specific aims: Aim 1. Elucidation of the effects of Oxy210 on myofibroblast differentiation and activation of primary pulmonary fibroblasts from normal lungs and from IPF patients in vitro. Aim 2. Identification of the effects of Oxy210 on lung fibrosis, fibroblast activation, and macrophage phenotypes at different stages of disease progression using RNA sequencing in bleomycin-treated mice. Aim3. Examination of Oxy210 safety using in vitro Ames, Cytochrome P450 inhibition, and off-target activity studies. We anticipate that data from the proposed studies will evaluate the potential of Oxy210 as a drug candidate for further development and targeting of IPF. Compared to existing therapies, Oxy210 may be more effective and safer as a standalone therapy or when used in combination with existing therapies for treating IPF.

抽象的特发性肺纤维化（IPF）是一种慢性间质性肺疾病，其特征是进行性、肺组织不可逆转的疤痕和肺功能下降，最终导致呼吸衰竭。目前可用的两种疗法：吡非尼酮和尼达尼布，生存期仅限于诊断后 3-5 年。只能减缓疾病的进展，并没有大幅降低IPF死亡率或显着改善自 2014 年获批以来，IPF 患者的生活质量不断提高。因此，新的和改进的 IPF 候选药物 IPF 疾病进展在很大程度上是由不适当的重新激活引起的。胚胎细胞信号传导途径，例如转化生长因子β (TGFβ) 和 Hedgehog (Hh) 信号通路事实上，吡非尼酮和尼达尼布在一定程度上通过适度阻断这些信号通路发挥作用。在 MAX BioPharma，我们正在开发新型、专有的、基于氧甾醇的异常拮抗剂。细胞信号传导可能对人类 IPF 和其他纤维化疾病具有疾病修饰特性。申请涵盖了一种基于氧甾醇的候选药物 Oxy210，它是一种 Hh 和 TGFβ 信号传导的双重抑制剂，改善非脂肪性肝炎 (NASH) 人源化小鼠模型中的肝纤维化和炎症。在此应用中，我们提供了来自 Oxy210 体外研究的令人鼓舞的初步数据，证明了其对正常肺成纤维细胞系（IMR- 90) 和 IPF 患者来源的细胞系 (LL97A) 在 LPS 处理中具有抗炎作用。巨噬细胞通过直接抑制 Toll 样受体 (TLR4)、TLR2 和 AP-1，并且不干扰 TGFβ 的抗炎作用的初步研究结果表明 Oxy210 具有抑制炎症的潜力。我们建议进一步表征 Oxy210 在小鼠体内诱导的肺部病理学。具体而言，我们建议实现以下具体目标：目标 1。阐明 Oxy210 对原发性肺肌成纤维细胞分化和活化的影响目的 2. 鉴定 Oxy210 对正常肺和 IPF 患者的成纤维细胞的影响。使用以下方法研究疾病进展不同阶段的肺纤维化、成纤维细胞活化和巨噬细胞表型使用博来霉素处理的小鼠进行 RNA 测序 Aim3。我们预计来自拟议研究的数据。将评估 Oxy210 作为进一步开发和靶向 IPF 的候选药物的潜力。与现有疗法相比，Oxy210 作为独立疗法或用于治疗时可能更有效、更安全。与治疗 IPF 的现有疗法相结合。