Mir-29 mimicry as a therapy for pulmonary fibrosis

描述（由申请人提供）：特发性肺纤维化（IPF）是一种病因不明的致命性和破坏性肺部疾病，从首次诊断起平均预期寿命为3-5年，每年有40，000例患者死于IPF。 IPF肺的特征在于由于肺泡膜增厚导致的广泛的氧交换缺陷。目前，IPF尚无治愈性药物疗法。 IPF肺的特征在于组织学变化的广泛变化，包括成纤维细胞/肌纤维母细胞病灶的形成、细胞外基质的积聚和散布在正常肺实质中的异常重塑区域。在分子水平上，IPF肺表现出显著改变的mRNA和microRNA表达模式以及凝血、凋亡、氧化应激、内质网应激中的DNA甲基化和畸变 和发育途径的激活。 microRNA是特别令人感兴趣的，因为它们通过抑制靶mRNA的翻译或促进靶mRNA的降解而充当基因表达的负调节剂。 由于单个microRNA通常调节具有相关功能的多个靶基因的表达，因此原则上，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。 mir-29家族的靶点包括多种细胞外基质分子，包括纤连蛋白、胶原蛋白1和3以及促纤维化分子如IGF 1和CTGF。与IPF特别相关的是，mir-29家族成员的表达在人IPF肺以及肺纤维化动物模型中降低，而mir-29靶标的表达增加。将mir-29引入肺可减弱疾病动物模型中的纤维化反应。最近，一种miR-29模拟物（由miRagen开发）在全身给药时表现出优先的肺分布，显示出在小鼠中钝化博来霉素诱导的肺纤维化。 该提案的总体目标是促进mir-29模拟作为一种新型长期、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 Therapeutics和Lovelace研究所的互补专业知识基础上。 我们将通过执行成功IND申请所需的步骤来实现这一目标，包括确定mir-29模拟物的最佳递送途径、吸收、代谢、分布，在较大动物中的性能毒理学和生物利用度研究，扩大生物标志物的生产和制造规模，并开发和验证其需求和功效。 (End摘要）

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)