Mechanism of Action Characterization for a Galectin-3 Inhibitor as Treatment for Lung Injury
Abstract
Fiscal Year 2014 Peer Reviewed Medical Research Program Topic Area: Respiratory Health. Acute lung injury (ALI) is defined as an inflammatory process in the lungs that can result from multiple causes such as trauma, sepsis, inhalation injury, as well as a myriad of other medical conditions. The incidence of ALI in the United States is estimated at 64.2 cases per 10^5 person year. If not resolved, acute lung injury can develop into chronic lung disease, a condition that severely compromises the patient s respiratory health. Chronic lung disease is a progressive scarring of the lung which leads to the destruction of lung architecture and ultimately organ failure. Hundreds of millions of people worldwide suffer from chronic respiratory disease. According to the 2004 WHO (World Health Organization) estimates, around 64 million people have chronic obstructive pulmonary disease (COPD), while millions have allergic and other fibrotic respiratory diseases. In the United States, more than 23 million people have asthma, approximately 13.6 million adults have been diagnosed with COPD, and an approximately equal number with undiagnosed chronic lung disease. According to the National Heart, Lung and Blood Institute, the annual healthcare expenditures for respiratory illness is more than $80 billion. Deployed military personnel can be exposed to inhalational hazards (e.g., combustants, dusts, and toxic gasses) and trauma that increase their risk of developing respiratory illness. Respiratory illness was the second most common ailment reported in a sample of recently deployed Soldiers. Despite the huge healthcare burden, the current treatment options for ALI are very unsatisfactory, consisting of supportive care and antibiotic therapy. The therapeutic options for the treatment of fibrotic lung disease are poor. Two new drugs, pirfenidone and nintedanib, have only recently been granted Food and Drug Administration approval for the treatment of idiopathic pulmonary fibrosis (IPF) -- a specific form of chronic lung disease -- but their ability to ameliorate or reverse fibrosis due to other causes remains to be established. Transplantation currently remains the only option for end-stage disease. Applicability of the clinical research: Our research over the last 10 years has identified galectin-3 as an important inducer of inflammation in the lung. We propose TD139, a molecule that blocks galectin-3 functions, as a novel therapy for lung disease. In this proposed project, we wish to establish how TD139 works in ALI and how this may affect the subsequent development of chronic lung injury. We will look at the drug effect in three ways: (1) using isolated immune cells (human and mouse); (2) using various mouse lung injury models; and (3) examining blood and lung wash samples from patients with lung fibrosis who are participating in a TD139 clinical trial. If successful, our proposed project will lead to the clinical development of an inhaled local therapy that targets the site of injury with reduced side effects and with the potential to reverse established disease. Direct lung administration would also reduce the cost in comparison with an injectable or oral therapy. We believe this approach will be beneficial both in terms of patient well-being and compliance. With the only curative option being lung transplantation, with all its risks and complications, our proposed drug will provide an alternative means for restoring full lung function without the need for surgery. This would result in improved recovery time and would not require life-long immunosuppression. Timelines: We expect to complete the first TD139 clinical trial in patients in early 2016. With the insights gained from this present proposal, we will progress to further developing this compound for other causes of lung injury. We would expect to see TD139 available as a therapy for lung fibrosis within the next 5 years.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510499
Entities
People
- Alison Mackinnon
Organizations
- United States Army
- University of Edinburgh