Targeting Epigenetic Mechanisms for Novel Therapies of Chronic Lung Vascular Diseases
Abstract
Despite recent advances in diagnosis and treatment, pulmonary hypertension (PH) remains a devastating disease with high mortality affecting both adult and pediatric patients. While it can arise for unknown (idiopathic) or genetic reasons, it is frequently associated with chronic lung disorders, such as chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, obesity, and viral infections, which are all extremely prevalent among Veterans. A lack of understanding of the factors that cause PH in patients with chronic lung disease has limited the therapeutic options for these patients. Notable is the fact that though some progress has been made in the treatment of patients with idiopathic pulmonary arterial hypertension (PAH), none of the drugs shown to be useful for these patients have shown any benefit in patients with chronic hypoxic lung diseases, such as COPD, or lung fibrosis, and in fact some patients given these drugs have had adverse side effects. PH, in the aforementioned chronic lung diseases, is generally believed to be hypoxic in origin. However, PH in these patients is often irreversible or minimally reversible with supplemental oxygen. This may be due to the structural changes in the lung blood vessels of these patients. These vessels exhibit thickening and fibrotic changes due to excessive proliferation and resistance to normal death of resident pulmonary vascular wall cells. Recent studies suggest that an inflammatory mechanism plays a significant role in the pathogenesis of these forms of PH. Interestingly, cells in the hypertensive lung blood vessels (including the ones we are proposing to study, smooth muscle cells and fibroblasts) have recently been shown to exhibit many of the same features as cancer cells including excessive proliferation, resistance to death, and a hyperinflammatory phenotype. While cancer is driven by genetic mutation in genes, it has recently been shown by our group and others that the changes in cell function in cells in chronic lung vascular disease are not due to genetic changes but rather to acquired changes in gene expression, referred to as epigenetic changes. In fact, we have data to show that pharmacologic agents targeting these epigenetic changes can reverse the abnormal characteristics of the cells from hypertensive patients and can reverse established PH in animal models. In this proposal, which is driven by exciting data produced in our currently funded Department of Defense grant, we test the idea that the persistence of functional abnormalities in cells from patients with chronic lung vascular disease can be effectively and safely normalized by treatment with drugs aimed at the epigenetic modifiers, which keep the cells in an abnormal state. The classes of drugs we propose to study have been used to treat various forms of cancer, but can have significant side effects, especially on the heart, which would make them potentially dangerous in patients with chronic lung vascular disease. Our proposed experiments are directly aimed at correcting this problem given we have identified a drug that is more specific than current drugs for targeting epigenetic changes and can potentially be used at a much lower dose with far fewer potential side effects. Further, we have preliminary data showing that this drug, when given in combination with another epigenetic-modifying drug, a near complete reversal of abnormal gene expression can be achieved using very low doses of both drugs. Our proposal will directly test whether this idea is correct. In this proposal, we will test the hypothesis that metabolic abnormalities, similar to those observed in cancer cells, exist in cells of the pulmonary vasculature and that they control the proliferative and inflammatory behavior of cells. Importantly, we also propose that these metabolic abnormalities can be targeted with specific pharmacologic therapies to reverse the cell abnormalities and mitigate pulmonary hyperten
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910259
Entities
People
- Kurt R Stenmark
Organizations
- United States Army
- University of Colorado Denver