title: Epigenetic targets for novel therapies of lung diseases.
abstract: In spite of substantial advances in defining the immunobiology and function of structural cells in lung diseases there is still insufficient knowledge to develop fundamentally new classes of drugs to treat many lung diseases. For example, there is a compelling need for new therapeutic approaches to address severe persistent asthma that is insensitive to inhaled corticosteroids. Although the prevalence of steroid-resistant asthma is 5-10%, severe asthmatics require a disproportionate level of health care spending and constitute a majority of fatal asthma episodes. None of the established drug therapies including long-acting beta agonists or inhaled corticosteroids reverse established airway remodeling. Obstructive airways remodeling in patients with chronic obstructive pulmonary disease (COPD), restrictive remodeling in idiopathic pulmonary fibrosis (IPF) and occlusive vascular remodeling in pulmonary hypertension are similarly unresponsive to current drug therapy. Therefore, drugs are needed to achieve long-acting suppression and reversal of pathological airway and vascular remodeling. Novel drug classes are emerging from advances in epigenetics. Novel mechanisms are emerging by which cells adapt to environmental cues, which include changes in DNA methylation, histone modifications and regulation of transcription and translation by noncoding RNAs. In this review we will summarize current epigenetic approaches being applied to preclinical drug development addressing important therapeutic challenges in lung diseases. These challenges are being addressed by advances in lung delivery of oligonucleotides and small molecules that modify the histone code, DNA methylation patterns and miRNA function.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of South Alabama, Mobile, AL, 36688, USA.
authors.forename: Brian S
authors.initials: BS
authors.lastname: Comer
authors.affiliation: Department of Pharmacology, University of Nevada School of Medicine, Reno, NV 89557, USA.
authors.forename: Mariam
authors.initials: M
authors.lastname: Ba
authors.affiliation: Department of Pharmacology, University of Nevada School of Medicine, Reno, NV 89557, USA.
authors.forename: Cherie A
authors.initials: CA
authors.lastname: Singer
authors.affiliation: Department of Biochemistry and Molecular Biology, University of South Alabama, Mobile, AL, 36688, USA. Electronic address: wgerthoffer@southalabama.edu.
authors.forename: William T
authors.initials: WT
authors.lastname: Gerthoffer
mesh_terms: D000818:Animals; D001993:Bronchodilator Agents / Q000008:administration & dosage; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics; D016503:Drug Delivery Systems / Q000379:methods / Q000639:trends*; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000235:genetics*; D018390:Gene Targeting / Q000379:methods / Q000639:trends*; D006801:Humans; D008171:Lung Diseases / Q000235:genetics* / Q000628:therapy*
chemical_list: D001993:Bronchodilator Agents
keywords: Asthma; COPD; DNA methylation; Fibrosis; Histone code; Noncoding RNA