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、毁灭性肺部疾病，初次诊断后平均预期寿命为 3-5 年，每年有 40,000 名患者死于 IPF。 IPF肺的特点是由于肺泡膜增厚而导致广泛的氧交换缺陷。目前尚无治疗 IPF 的药物疗法。 IPF肺的特征是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、细胞外基质的积累以及散布着正常肺实质的异常重塑区域。从分子角度来看，IPF 肺表现出 mRNA 和 microRNA 表达模式以及 DNA 甲基化的显着改变，以及凝血、细胞凋亡、氧化应激、内质网应激的畸变。 和发育途径的激活。 MicroRNA 特别令人感兴趣，因为它们通过抑制目标 mRNA 的翻译或促进降解来充当基因表达的负调节因子。 由于单个 microRNA 通常调节多个具有相关功能的靶基因的表达，因此调节单个 microRNA 的表达原则上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 家族已证实的靶标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，例如 IGF1 和 CTGF。与 IPF 具有特定相关性，在人 IPF 肺以及肺纤维化动物模型中，mir-29 家族成员的表达降低，而 mir-29 靶标的表达增加。将 mir-29 引入肺部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部分布，被证明可以减弱博来霉素诱导的小鼠肺纤维化。 该提案的总体目标是在耶鲁大学医学院、miRagen Therapeutics 和 Lovelace 研究所的互补专业知识的基础上，促进 mir-29 拟态的发展，作为一种新型的长期、高效和个性化的抗纤维化疗法。 我们将通过执行成功的 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、吸收、代谢、分布途径，在大型动物中进行毒理学和生物利用度研究，扩大生产和制造以及生物标志物的需求和功效的开发和验证。 （摘要完）

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)