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.
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, and 40,000 patients die each year from IPF. The microRNA mir-29, a small non-coding RNAs that regulates the expression of many fibrosis related molecules, is decreased in expression in patients with IPF. The objective of this proposal is to develop microRNA replacement (mimicry) as a viable and novel therapy for this devastating disease and an objective that will have significant impact on the morbidity and mortality of many patients with IPF.
|Yu, Guoying; Tzouvelekis, Argyris; Wang, Rong et al. (2018) Thyroid hormone inhibits lung fibrosis in mice by improving epithelial mitochondrial function. Nat Med 24:39-49|
|Tzouvelekis, Argyris; Herazo-Maya, Jose D; Slade, Martin et al. (2017) Validation of the prognostic value of MMP-7 in idiopathic pulmonary fibrosis. Respirology 22:486-493|
|Kass, Daniel J; Kaminski, Naftali (2017) Time to share: lessons from post hoc analyses of IPF trials. Thorax 72:101-102|
|Herazo-Maya, Jose D; Sun, Jiehuan; Molyneaux, Philip L et al. (2017) Validation of a 52-gene risk profile for outcome prediction in patients with idiopathic pulmonary fibrosis: an international, multicentre, cohort study. Lancet Respir Med 5:857-868|
|Brownell, Robert; Kaminski, Naftali; Woodruff, Prescott G et al. (2016) Precision Medicine: The New Frontier in Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med 193:1213-8|