Idiopathic pulmonary fibrosis (IPF) is a morbid fibroproliferative lung disease of older adults that causes progressive dyspnea and hypoxemia. Current treatments for IPF are only partly efficacious, and often have unacceptable side-effects. Development of a safe, effective IPF therapy would be a major advance. Reactive oxygen species (ROS) generated by NADPH oxidases (NOX) play an important role in the development of fibrosis. Investigations during Cycle 1 of this tPPG showed that inhibition of NOX4 with a small molecule pharmaceutical (GKT137831) decreased the severity of the pulmonary abnormality and improved survival in an animal model of persistent fibrosis. GKT137831 treatment also reduces ROS production and decreases ECM production in other animal models of liver, kidney, and cardiac fibrosis. Importantly, GKT137831 has a good safety profile in early phase human trials for other indications. Other studies conducted during Cycle I of this tPPG showed that o,o?-dytyrosine, which is a ROS-induced covalent modification of protein-tyrosine residues, was increased 18-fold in the plasma of IPF patients relative to healthy controls. ECM turnover is also a fundamental process in IPF pathogenesis, and increases in the circulating products of collagen digestions by matrix metalloproteinases, including the neoepitope C1M, were recently shown to predict lung disease progression in IPF patients. We hypothesize that treatment with the NOX1/4 inhibitor GKT137831 will reduce oxidative injury in IPF patients, and propose here a pilot study to test this hypothesis. The goal of Specific Aim 1 is to conduct a double-blinded Phase IIB clinical trial in 60 ambulatory IPF subjects at five major medical centers. Subjects will be randomized 1:1 to GKT137831 or placebo, and treated for six months. The primary endpoint of this trial will be treatment effects on o,o'-dityrosine plasma levels, measured pretreatment, and at six week intervals. We hypothesize GKT137831 therapy will reduce plasma levels of o,o'-tyrosine, reflecting a drug-induced reduction of ROS injury.
Specific Aim 2 will determine effects of GKT137831 compared to placebo, on a.) Collagen degradation product C1M concentrations in sera; b.) Forced vital capacities; c.) Six-minute walk distances; and d.) Adverse event (AE) rates. We hypothesize GKT137831 therapy will decrease C1M, and have an acceptable AE profile. The clinical measures will facilitate detection of an unprecedented benefit of this novel approach. This highly innovative clinical trial could provide evidence that selective NOX inhibition is safe and beneficial in IPF patients. Results of this study will help to confirm and establish methods, and provide the rationale that will facilitate and justify subsequent definitive trials to evaluate the clinical benefits of NOX inhibitors in IPF. This research has the potential to be paradigm-shifting, will fill several existing gaps, and could ultimately extend the lives of many future patients.
The placebo-controlled, double-blind Phase IIb trial proposed here will test GKT137831, an inhibitor of the NAPDH enzyme NOX4, in 60 patients with idiopathic pulmonary fibrosis at five major medical centers. The results of this trial could show therapy with GKT137831 safely decreases oxidative stress and other indicators of pulmonary fibrosis. This research has the potential to be a significant advance in the treatment of IPF, and could prolong the lives of patients who have this lung disorder.
|Hough, Kenneth P; Trevor, Jennifer L; Strenkowski, John G et al. (2018) Exosomal transfer of mitochondria from airway myeloid-derived regulatory cells to T cells. Redox Biol 18:54-64|
|Bernard, Karen; Logsdon, Naomi J; Benavides, Gloria A et al. (2018) Glutaminolysis is required for transforming growth factor-?1-induced myofibroblast differentiation and activation. J Biol Chem 293:1218-1228|
|Ge, Jing; Cui, Huachun; Xie, Na et al. (2018) Glutaminolysis Promotes Collagen Translation and Stability via ?-Ketoglutarate-mediated mTOR Activation and Proline Hydroxylation. Am J Respir Cell Mol Biol 58:378-390|
|Hough, Kenneth P; Wilson, Landon S; Trevor, Jennifer L et al. (2018) Unique Lipid Signatures of Extracellular Vesicles from the Airways of Asthmatics. Sci Rep 8:10340|
|Cui, Huachun; Banerjee, Sami; Guo, Sijia et al. (2018) IFN Regulatory Factor 2 Inhibits Expression of Glycolytic Genes and Lipopolysaccharide-Induced Proinflammatory Responses in Macrophages. J Immunol 200:3218-3230|
|Chanda, Diptiman; Otoupalova, Eva; Smith, Samuel R et al. (2018) Developmental pathways in the pathogenesis of lung fibrosis. Mol Aspects Med :|
|Qu, Jing; Zhu, Lanyan; Zhou, Zijing et al. (2018) Reversing Mechanoinductive DSP Expression by CRISPR/dCas9-mediated Epigenome Editing. Am J Respir Crit Care Med 198:599-609|
|Thannickal, Victor J; Antony, Veena B (2018) Is personalized medicine a realistic goal in idiopathic pulmonary fibrosis? Expert Rev Respir Med 12:441-443|
|Rangarajan, Sunad; Bone, Nathaniel B; Zmijewska, Anna A et al. (2018) Metformin reverses established lung fibrosis in a bleomycin model. Nat Med 24:1121-1127|
|Zhou, Yong; Horowitz, Jeffrey C; Naba, Alexandra et al. (2018) Extracellular matrix in lung development, homeostasis and disease. Matrix Biol 73:77-104|
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