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)

• 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
• 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' 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

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。特发性肺纤维化（IPF）是一种进行性纤维增生性疾病， 全世界有功能限制性进行性症状的患者， 诊断.虽然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。吡非尼酮和尼达尼布目前是两种口服 给予纤维化抑制剂。然而，两者都伴随着广泛的不良反应特征，限制了效用。 因此，对可耐受和有效的治疗方案存在高度未满足的需求。根据一项发现， 学术合作伙伴耶鲁大学实验室，TargetSite Therapeutics公司正在开发一种新型的 寡核苷酸治疗剂，其选择性地干扰“增强”寡核苷酸的结合相互作用， 微RNA”（e-miRNA），miR 4661 - 3 p，作用于mRNA的3 'UTR内的特定靶位点。这些“目标站点屏蔽” (TSB)寡核苷酸有效且特异性地干扰单个促炎因子的产生 细胞因子和生长因子，包括IL-17 A、IL-22、GM-CSF、IL-23 A、VEGF-A和IL-1β。IL-17 A已被 据报告，IPF患者的支气管肺泡灌洗液（BAL）中的TdR显著升高。因此我们 建议用特异性TSB靶向IL-17 A mRNA，并评估其在已建立的博来霉素中的疗效- 诱导的肺纤维化（IPF）模型。在与Matinas Bioburma的合作中，将尝试将 IL-17 A TSB在多层脂质纳米晶体中，其被优化用于口服递送。我们将验证 这些TSB-LNC在体外Th 17细胞中的功效，以及它们在降低LPS诱导的IL-12表达方面的生物活性。 17 A在老鼠身上将通过以下两种方法测试LNC包封的和裸（PBS）IL-17 A TSB寡核苷酸的功效： 在博来霉素诱导的鼠IPF模型中，腹膜内和口服（通过管饲）递送。主要评估 参数将是肺纤维化、组织病理学和生化学，以及BAL液和血清IL-17 A 程度.疾病严重程度的降低，如通过可量化的纤维化减少>50%所确定的，预期为 一个可实现的里程碑和一个可确定的成功标准。该项目的实验证据将 证实IL-17 mRNA指导的寡核苷酸是否有益地改变疾病，提供一种新的治疗方法， 治疗IPF。