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.

摘要：特发性肺纤维化 (IPF) 是一种进行性纤维增殖性疾病，影响约 300 万人。全世界患有功能限制性进行性症状且中位生存时间为 2-3 年的人虽然 IPF 的病因尚不清楚，但遗传因素、环境暴露和微生物是影响 IPF 诊断的重要因素。吡非尼酮和尼达尼布目前已被确定为IPF危险因素。然而，这两种药物都伴随着广泛的不良反应，限制了其实用性。因此，根据一项发现，对可耐受且有效的治疗方案存在着高度未满足的需求。学术合作伙伴耶鲁大学实验室 TargetSite Therapeutics Corporation 正在开发一类新型药物选择性干扰“增强剂”结合相互作用的寡核苷酸治疗剂 microRNA”（e-miRNA）、miR466l-3p，到 mRNA 3'UTR 内的特定靶位点，这些“靶位点阻断”。 (TSB) 寡核苷酸有效且特异性地干扰个体促炎细胞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。据报道，IPF 患者的支气管肺泡灌洗 (BAL) 液中的浓度显着升高。针对 IL-17A mRNA 建议使用特定的 TSB 并评估其在已建立的博来霉素中的功效与 Matinas Biopharma 合作，将尝试封装诱导性肺纤维化 (IPF) 模型。我们将验证多层脂质纳米晶体中的 IL-17A TSB，该晶体针对口服给药进行了优化。这些 TSB-LNC 在体外对 Th17 细胞的功效，以及它们在减少 LPS 诱导的 IL- 将通过 LNC 封装和裸露 (PBS) IL-17A TSB 寡核苷酸在小鼠中测试 17A 的功效。在博来霉素诱导的小鼠 IPF 模型中进行腹膜内和口服（通过强饲）给药的初步评估。参数包括肺纤维化、组织病理学和生化，以及 BAL 液和血清 IL-17A 预计疾病严重程度会降低（通过可量化纤维化减少 50% 以上来确定）。该项目将成为可实现的里程碑和可定义的成功标准。确认 IL-17 mRNA 导向的寡核苷酸是否有益地改变疾病，从而提供一种新的治疗方法在 IPF 的治疗中。