Mir-29 mimicry as a therapy for pulmonary fibrosis

描述(申请人提供)：特发性肺纤维化(IPF)是一种致命性和破坏性的肺部疾病，病因不明，从最初诊断起平均预期寿命为3-5年，每年有40,000名患者死于IPF。IPF肺的特点是肺广泛，由于肺泡膜增厚导致氧交换障碍。目前还没有针对IPF的根治性药物疗法。IPF肺以广泛的组织学改变为特征，包括纤维母细胞/肌纤维母细胞灶的形成，细胞外基质的积聚，以及穿插在正常肺实质中的异常重塑区域。在分子水平上，IPF大鼠肺组织中的mRNAs和microrna表达模式、dna甲基化以及凝血、细胞凋亡、氧化应激、内质网应激等过程中的异常发生了显著变化。 和发育途径的激活。MicroRNAs特别受关注，因为它们通过抑制靶mRNAs的翻译或促进其降解来作为基因表达的负调控因子。由于单个microRNA经常调节具有相关功能的多个靶基因的表达，因此，从原理上讲，调节单个microRNA的表达可以影响整个基因网络，从而改变复杂的疾病表型。Mir-29家族是与肝、肾、心脏和肺纤维化有关的关键microRNA家族之一。已证实的mir-29家族的靶点包括多种细胞外基质分子，包括纤维连接蛋白、胶原蛋白1和3以及纤维蛋白原分子，如IGF1和CTGF。与IPF特别相关的是，mir-29家族成员在人IPF肺组织和肺纤维化动物模型中的表达减少，而mir-29靶点的表达增加。在疾病动物模型中，将mir-29引入肺可钝化纤维化反应。最近，一种由miRagen开发的miR-29模拟物(由miRagen开发)在全身给药时显示出优先的肺分布，显示出钝化博莱霉素诱导的小鼠肺纤维化。这项建议的总体目标是促进mir-29模拟疗法作为一种新型的长期、有效和个性化的抗纤维化疗法的开发，该疗法建立在耶鲁医学院、miRagen治疗公司和洛夫莱斯研究所的互补专业知识的基础上。我们将通过执行成功应用IND所需的步骤来实现这一目标，包括确定最佳给药途径、吸收、新陈代谢、分布、MIR-29模拟物、在较大动物中的性能毒理学和生物利用度研究、扩大生产和制造，以及开发和验证需求和疗效的生物标记物。 (摘要结束)

DESCRIPTION (provided by applicant): Idiopathic Pulmonary Fibrosis (IPF) is a fatal and devastating lung disease of unknown etiology with an average life expectancy of 3-5 years from initial diagnosis, 40,000 patients die each year from IPF. The IPF lung is characterized by extensive leading to defective oxygen exchange due to thickening of the alveolar membrane. Currently there are no curative drug therapies for IPF. The IPF lung is characterized by extensive changes in histological changes that include formation of fibroblastic/myofibroblastic foci, accumulation of extracellular matrix and areas of aberrant remodeling interspersed with normal lung parenchyma. Molecularly, the IPF lung exhibits significantly altered patterns of mRNA and microRNA expression and DNA methylation and aberrations in coagulation, apoptosis, oxidative stress, endoplasmic reticulum stress and activation of developmental pathways. MicroRNAs are of particular interest because they act as negative regulators of gene expression by inhibiting the translation or promoting the degradation of target mRNAs. Because individual microRNAs often regulate the expression of multiple target genes with related functions, modulating the expression of a single microRNA can, in principle, influence an entire gene network and thereby modify complex disease phenotypes. The mir-29 family is among the key microRNA families implicated in liver, kidney, heart and lung fibrosis. Proven targets of the mir-29 family include mutiple extracellular matrix molecules, including fibronectin, collagens 1 and 3 as well as profibroti molecules such as IGF1 and CTGF. With specific relevance to IPF, expression of members of the mir-29 family is decreased in the human IPF lung as well as in animal models of lung fibrosis and expression of mir-29 targets is increased. Introduction of mir-29 to the lung blunts the fibrotic response in animal models of disease. More recently, a miR-29 mimic (developed by miRagen) that exhibits preferential lung distribution when administered systemically, was shown to blunt bleomycin-induced pulmonary fibrosis in mouse. The overall objective of this proposal is to facilitate the development of mir-29 mimicry as a novel long- term, efficient and personalized anti-fibrotic therapy building on the complementary expertise of Yale School of Medicine, miRagen Therapeutics and the Lovelace Institute. We will achieve this objective by performing the steps required for a successful IND application, including the determination of best route of delivery, absorption, metabolism, distribution, of the mir-29 mimic, performance toxicology and bioavailability studies in larger animals, Scaling up production and manufacturing and development and validation of biomarkers for need and efficacy. (End of Abstract)