Mir-29 mimicry as a therapy for pulmonary fibrosis

描述（由申请人提供）：特发性肺纤维化（Idiopathic Pulmonary Fibrosis， IPF）是一种病因不明的致死性和破坏性肺部疾病，自初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肺的特点是由于肺泡膜增厚导致广泛的氧交换缺陷。目前还没有治疗IPF的药物。IPF肺的特点是广泛的组织学改变，包括成纤维细胞/肌成纤维细胞灶的形成，细胞外基质的积累以及与正常肺实质穿插的异常重塑区域。从分子上看，IPF肺在凝血、细胞凋亡、氧化应激、内质网应激中表现出mRNA和microRNA表达模式的显著改变，以及DNA甲基化和畸变

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)