IL-17A mRNA-targeted oligonucleotide therapeutics in Idiopathic Pulmonary Fibrosis (IPF)

IL-17A mRNA 靶向寡核苷酸治疗特发性肺纤维化 (IPF)

基本信息

批准号：
10761365
负责人：
JEFFREY R. BENDER
金额：
$ 24.5万
依托单位：
TARGETSITE THERAPEUTICS CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-18 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10761365
关键词：
3&apos Untranslated Regions Acute Adverse effects Affect Analysis of Variance Antibodies Attention Autoimmune Binding Binding Sites Biochemical Biological Biological Assay Biology Bleomycin Bronchoalveolar Lavage Fluid CD4 Positive T Lymphocytes Cardiology Cell Line Cells Chemicals Clinical Clinical Pathology Deterioration Development Diagnosis Disease Disease Management Disease Progression Dose Dyspnea Encapsulated Environmental Exposure Enzyme-Linked Immunosorbent Assay Etiology Experimental Autoimmune Encephalomyelitis Fibroblasts Fibrosis Formulation Future Gene Deletion Generations Genetic Goals Granulocyte-Macrophage Colony-Stimulating Factor Growth Factor IL17 gene Immune Immunobiology Immunologist In Vitro Individual Inflammatory Interferon Type II Interleukin-1 beta Interleukin-6 Laboratories Legal patent Lipids Medicine Messenger RNA MicroRNAs Modeling Modification Molecular Immunology Mus Oligonucleotides Oral Pathogenesis Pathology Pathway interactions Patients Persons Phase Physicians Pirfenidone Production Proteins Pulmonary Fibrosis Quantitative Reverse Transcriptase PCR RNA RNA Interference Rattus Reporting Research Research Personnel Risk Factors Role Route Scientist Serum Severity of illness Site Small Business Innovation Research Grant Small RNA Specificity Structure Symptoms T cell differentiation Technology Testing Therapeutic Therapeutic Agents Time Toxic effect Treatment Efficacy Universities VEGFA gene Work autoimmune uveitis clinically relevant comparison control cytokine detection assay disabling symptom effective therapy efficacy evaluation efficacy study efficacy validation experience experimental study idiopathic pulmonary fibrosis immune activation improved in vivo indium-bleomycin inhibitor interleukin-22 intraperitoneal mouse model nanocrystal nintedanib novel novel therapeutics pathogenic microbe pharmacokinetics and pharmacodynamics preclinical study prevent professor pulmonary function response secondary lymphoid organ success therapeutic development therapeutically effective timeline translational immunology

项目摘要

Abstract. Idiopathic pulmonary fibrosis (IPF) is a progressive fibroproliferative disorder affecting ∼3 million people worldwide with function-limiting progressive symptoms and a 2-3 year median survival time from diagnosis. While the etiology of IPF is not clear, genetic factors, environmental exposures and microbial pathogens have been identified as IPF risk factors. Pirfenidone and nintedanib currently are two orally administrated fibrosis inhibitors. However, both are accompanied by a wide adverse effect profile, limiting utility. Thus, a high unmet need exists for tolerable and effective treatment options. Based on a discovery in the academic partner Yale university laboratory, TargetSite Therapeutics Corporation is developing a novel class of oligonucleotide therapeutic agents that selectively interfere with the binding interaction of an “enhancing microRNA” (e-miRNA), miR466l-3p, to specific target sites within an mRNA’s 3’UTR. These “target site blocking” (TSB) oligonucleotides effectively and specifically interfere with the production of individual pro-inflammatory cytokines and growth factors including IL-17A, IL-22, GM-CSF, IL-23A, VEGF-A and IL-1β. IL-17A has been reported to be significantly elevated in the bronchoalveolar lavage (BAL) fluid of IPF patients. We therefore propose targeting the IL-17A mRNA with a specific TSB and assess its efficacy in the established bleomycin- induced lung fibrosis (IPF) model. In partnership with Matinas Biopharma, attempts will be made to encapsulate the IL-17A TSB in multilayered lipid nanocrystals, which are optimized for oral delivery. We will validate the efficacy of these TSB-LNC in Th17 cells in vitro, and for their biological activity in reduction of LPS-induced IL- 17A in mice. The efficacy of LNC-encapsulated and naked (PBS) IL-17A TSB oligos will be tested, both by intraperitoneal and oral (via gavage) delivery, in the bleomycin-induced murine IPF model. Primary assessment parameters will be lung fibrosis, histopathological and biochemically, as well as BAL fluid and serum IL-17A levels. A reduction in disease severity, as determined by >50% reduction in quantifiable fibrosis, is expected as an achievable milestone and a definable criterion for success. Experimental evidence from this project will confirm whether the IL-17 mRNA-directed oligos beneficially modify the disease, providing a novel therapeutic in the treatment of IPF.

抽象的。特发性肺纤维化（IPF）是一种进行性纤维增生性疾病，影响约300万全球范围内具有限制功能性渐进症状的人和2 - 3年的中位生存时间诊断。尽管IPF的病因尚不清楚，但遗传因素，环境暴露和微生物病原体已被确定为IPF风险因素。 Pirfenidone和Nyntedanib目前是两个口头管理员纤维化抑制剂。但是，两者都伴随着广泛的不良效应概况，并限制了实用程序。这是对可耐受和有效的治疗选择的高未满足需求。基于发现耶鲁大学学术合作伙伴耶鲁大学实验室，Target Sote Therapeutics Corporation正在开发一种新颖的类别寡核苷酸的治疗剂有选择地干扰“增强”的结合相互作用 microRNA”（E-MIRNA），miR466L-3P，在mRNA的3'UTR中。（TSB）寡核苷酸有效，有效地干扰了单个促炎的产生细胞因子和生长因子，包括IL-17A，IL-22，GM-CSF，IL-23A，VEGF-A和IL-1β。 IL-17A已经过去了据报道，IPF患者的支气管肺泡灌洗（BAL）流体显着升高。因此，我们针对IL-17A mRNA的提案，具有特定的TSB，并评估其在已建立的博来霉素中有效诱导肺纤维化（IPF）模型。与Matinas Biopharma合作，将尝试封装多层脂质纳米晶体中的IL-17A TSB，可针对口服递送进行优化。我们将验证这些TSB-LNC在TH17细胞体外的功效，以及它们在减少LPS诱导的IL-的生物学活性中 17a在老鼠中。 LNC封装和裸（PBS）IL-17A TSB寡核体的效率将通过博来霉素诱导的鼠IPF模型中的腹膜内和口服（通过饲料）递送。主要评估参数将是肺纤维化，组织病理学和生化，以及BAL流体和血清IL-17A 水平。疾病严重程度的降低，可预期可量化纤维化的50％降低确定为50％一个可实现的里程碑和成功的定义标准。这个项目的实验证据将确认IL-17 mRNA指导的寡核酸寡核苷是否良好地修饰该疾病，提供一种新的疗法在IPF的治疗中。