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2015 ; 147
(ä): 91-110
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Epigenetic targets for novel therapies of lung diseases
#MMPMID25448041
Comer BS
; Ba M
; Singer CA
; Gerthoffer WT
Pharmacol Ther
2015[Mar]; 147
(ä): 91-110
PMID25448041
show ga
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.
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