Repurposing of gamma interferon via inhalation delivery.

Pulmonary diseases frequently involve imbalances in immunity. The inability to control bacteria in tuberculosis is a failed response to a pathogen. Idiopathic pulmonary fibrosis (IPF), a progressive fibrotic lung disease, can lead to respiratory failure and death within 3 years of diagnosis. Chronic obstructive pulmonary disease (COPD) progresses until death and in recent years has been labeled an autoimmune disease. Proposed mechanistic pathways of pathophysiology involve uncontrolled healing governed by pro-fibrotic cytokines that are unresponsive to the standard anti-inflammatory agents (e.g., corticosteroids). Interferon-γ (IFN-γ), currently delivered as a subcutaneous injection for chronic granulomatous disease and osteopetrosis, is a cytokine that can stimulate macrophage function and inhibit fibrotic pathways. In recent studies, our group has repurposed IFN-γ as an inhaled aerosol, targeted directly to the lung to treat a host of diseases affected by dysregulated immunity. At present, we have studied its potential in treating tuberculosis and IPF. In a controlled clinical trial in tuberculosis, inhaled IFN-γ was effective while parenteral IFN-γ was not, indicating that macrophages can be effectively immune-stimulated by aerosol therapy. A similar approach has been taken in IPF. In a two-year safety study treating patients with IPF, the drug was safe and the pretreatment decline in pulmonary function was reversed. Furthermore, the same fibrotic pathways active in the lung parenchyma in IPF may be at fault in the airways of COPD patients. These experiences warrant the continued evaluation of inhaled IFN-γ in human clinical trials.