权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

摘要特发性肺纤维化（IPF）是一种慢性间质性肺病，其特征在于进行性，肺组织不可逆转的瘢痕形成和肺功能下降，最终导致呼吸衰竭。中位患者生存期限于诊断后3-5年。两种目前可用的治疗方法，吡非尼酮和尼莫地平，仅减缓疾病的进展，并没有大大降低IPF死亡率或显著改善自2014年获批以来，IPF患者的生活质量。因此，新的和改进的IPF候选药物是迫切需要的。IPF疾病进展在很大程度上是由以下因素的不适当再激活驱动的：胚胎细胞信号通路，如转化生长因子β（TGFβ）和Hedgehog (Hh)信号通路事实上，吡非尼酮和尼莫地平的作用部分是通过适度阻断这些信号传导。路径。在MAX BioPharma，我们正在开发新的，专有的，基于氧固醇的异常拮抗剂。在人类IPF和其他纤维化疾病中可能具有疾病修饰特性的细胞信号传导。这申请涵盖了一种基于氧固醇的候选药物Oxy 210，这是一种Hh和TGFβ信号传导的双重抑制剂，在非脂肪性肝炎（NASH）的人源化小鼠模型中改善肝纤维化和炎症。在本申请中，我们提出了令人鼓舞的初步数据，从体外研究与氧210，证明其对正常肺成纤维细胞系（IMR-1）增殖和促纤维化基因表达的抑制作用。 90)和IPF患者来源的细胞系（LL 97 A）。Oxy 210在LPS治疗的小鼠中具有抗炎作用通过直接抑制Toll样受体（TLR 4）、TLR 2和AP-1， TGFβ的抗炎作用。初步研究结果显示，Oxy 210具有抑制博来霉素诱导的小鼠体内肺病理学。我们建议进一步表征Oxy 210在相关 IPF的体外和体内模型。具体而言，我们建议实现以下具体目标：目标1。阐明Oxy 210对肌成纤维细胞分化和原代肺成纤维细胞活化的影响体外来自正常肺和IPF患者的成纤维细胞。目标二。确定Oxy 210对肺纤维化、成纤维细胞活化和巨噬细胞表型在疾病进展的不同阶段，博来霉素处理的小鼠中的RNA测序。目标3。使用体外艾姆斯检查Oxy 210的安全性，细胞色素P450抑制和脱靶活性研究。我们预计，拟议研究的数据将评估Oxy 210作为进一步开发和靶向治疗IPF的候选药物的潜力。相比与现有疗法相比，Oxy 210作为独立疗法或用于与现有疗法联合治疗IPF。