Targeted Approach to Lung Repair and Regeneration in Alveolar Type II Cell Disease

Topic Area: Acute Lung Injury and Lung Injury Problem: Over 14 percent of Veterans who have been in a combat zone eventually develop lung disease.[1] The lungs are very easy to damage by inhaling dangerous substances, and Soldiers are exposed to many during wartime: dust, sand, tiny bits of metal and soil released by explosions, unfamiliar allergens native to the countries they are stationed in, and more. Soldiers also smoke cigarettes more than Americans at home, and all of these factors may cause Veterans to suffer from higher rates of lung disease. Lung disease severely impacts Veterans and their families. The inability to breathe properly affects everything in their lives, limiting their ability to work, play with their children, or even just climb the stairs. And unfortunately ? although there are some ways to help with symptoms ? doctors have no way to actually repair lungs once they have been severely injured. Lung transplant is the only permanent treatment, and there are many fewer donor lungs available than patients in need. Innovation: Our project investigates a completely new, two-step therapy that aims to help damaged lungs to repair and regenerate themselves. If successful, this would be the very first lung therapy to work in this way and create for the first time ever a good alternative to transplant. To pursue this goal, we are focusing on one particular type of cell in the lung that is involved in many lung diseases that affect Veterans as well as civilians (including acute respiratory distress syndrome [ARDS] and chronic obstructive pulmonary disease [COPD]). Within the lungs are tiny air sacs called alveoli, which are the lungs? functional units ? where vital oxygen from the air gets into the bloodstream and carbon dioxide is removed. The cells we are focusing on are part of the alveoli and are called alveolar type II (ATII) cells. When these ATII cells are injured or diseased, the alveoli cannot function properly and therefore they cannot deliver sufficient oxygen to the bloodstream or remove carbon dioxide, causing respiratory symptoms. We have designed an innovative, inhalable drug that aims to kill these ?bad? ATII cells so they can be cleared out and make way for the implantation of new healthy ATII cells to repair the lung. The drug, called DT388-SPA, is a molecule that joins (1) a substance naturally produced by the lung (SPA), which ATII cells readily absorb, together with (2) a poison to kill the ?bad? cells (DT388). We predict that diseased ATII cells in the lung will absorb the part of the drug molecule they recognize. This will give the attached poison the chance to get into only these cells and kill them, while leaving all the rest of the lung intact. Then, using advanced cell technology, we will introduce new, healthy ATII cells into the lung. These cells will use the space created by our therapy to take hold and actually regrow lung tissue. Our project aims to: (1) find out how effective our DT388-SPA therapy is, by examining it in the ATII cells of genetically defective mice in which these cells do not work properly; (2) figure out the best way to deliver our therapy into the mice?s lungs by inhalation; and (3) deliver our therapy to living genetically defective mice through the airway, followed by implanting healthy ATII cells to repair and regrow the lung. Impact: If successful, this approach could be the first-ever way to repair and regrow injured lungs. This could potentially be used immediately after injury to help heal the lungs and prevent the development of disease ? as well as to treat chronic lung diseases that already exist. Our drug molecule could also be changed specifically to treat lung diseases caused by other types of cells in the lung. All of this could radically improve the lives of Soldiers, Veterans, and regular civilians who suffer from lung disease.