Although a variety of treatment options are available for patients with lung diseases such as asthma and chronic obstructive pulmonary disease (COPD), some patients do not respond to existing medications or experience side effects that limit the patients’ ability to use the drugs. In addition, for rare lung diseases, there are often no therapeutic options. To address these treatment shortcomings for lung diseases and sleep-disordered breathing, the NHLBI created the Centers for Advanced Diagnostics and Experimental Therapeutics in Lung Diseases (CADET) program to stimulate the development of new drugs and diagnostics for pulmonary diseases and sleep-disordered breathing.
The first stage of CADET, which began in 2011 and concluded in 2013, funded centers to examine the pathways that lead to lung diseases and sleep disorders and to identify particular steps within those pathways that researchers could arrest or interfere with and thereby prevent disease development or progression. The second stage of CADET (known as CADET II) is now underway with 10 different research teams trying to develop new therapeutic products by providing the evidence needed to support a New Drug Application to the FDA. Below we present the work of three teams whose research relates to pulmonary fibrosis.
In idiopathic pulmonary fibrosis (IPF), scar tissue develops in the lungs, impairing patients’ ability to breathe. Although scientists have not been able to determine what causes IPF, research has revealed that the scarring of the lungs results from fibroblast cells excessively producing and depositing outside the cell collagen and other proteins that make up scar tissue. Many patients diagnosed with IPF die within five years of being diagnosed, and no medicines are proven to slow the disease’s progression. In October 2014, the FDA approved two medications to treat IPF, but it is too soon to know how many patients will respond to these medications or whether they will increase patients’ lifespan.
Inhibiting Signaling Pathway that Promotes Lung Thickening
University of California, San Francisco
Researchers at the University of California, San Francisco (UCSF) are targeting integrin proteins that lie on the surface of lung fibroblasts and play a role in activating the fibroblasts to produce collagen and other proteins that form scar tissue. The investigators are developing compounds that in animal tests inhibit these integrins and lung tissue scarring.
Dr. Dean Sheppard, who is leading the UCSF researchers, is hopeful his team will develop a drug that does more than merely stop fibrosis. “It’s even possible that drugs like this could reverse pulmonary fibrosis because there are normal homeostatic mechanisms in the lung to repair and resorb excess scar, but when the fibroblasts are just going full bore, those homeostatic mechanisms are overwhelmed. My real hope for the future is that we’ll be able to slow the production of scar tissue by fibroblasts, thereby allowing the normal homeostatic mechanisms to take over and achieve significant improvement and repair.”
Silencing RNAs to Treat Pulmonary Fibrosis
In recent years, the potential use of microRNAs as therapeutics has attracted considerable research interest. Naturally found in cells, microRNAs can reduce protein production by binding to messenger RNA (mRNA) molecules, which the cell “reads” to produce proteins, and degrading them. Because specific microRNAs bind to specific mRNA segments, scientists can design synthetic microRNAs that match and destroy the specific mRNAs that produce proteins that lead to disease. Scientists at Yale University are using this approach with a synthetic microRNA that may decrease the production of proteins that are involved in fibrosis.
The center’s investigators are testing a synthetic microRNA that would mimic the mir-29 family of microRNAs. In a healthy person, mir-29 controls the production of collagen and other extracellular matrix proteins so that excessive amounts do not accumulate in lung tissue. In the lungs of some IPF patients, on the other hand, researchers have found that mir-29 levels are lower, so the collagen production is unopposed, leading to lung tissue scarring.
The Yale researchers envision identifying these patients through a blood test that they are developing and then treating them with the mir-29 mimic that they are refining along with miRagen Therapeutics, Inc., and the Lovelace Respiratory Research Institute. Their preliminary research shows that the mimic is capable of reversing lung fibrosis in animal models of the disease, and the team is now testing how best to deliver the mimic to lung cells.
Dr. Naftali Kaminski, the lead researcher for the Yale team, commended NHLBI for creating the CADET program and enabling researchers to translate discoveries into potential treatments. “I’ve been in the business of discovery science for years now, but now the NHLBI has given me the opportunity to develop something actually for our patients, and for me this is very exciting.”
A Genetic Risk Factor for Pulmonary Fibrosis—and a Target for Treatment
University of Colorado Denver
Although doctors and researchers do not understand how idiopathic pulmonary fibrosis starts in the lungs, scientists at the University of Colorado Denver have identified a key genetic risk factor that is important in some patients with pulmonary fibrosis. In fact, about 40% of patients with idiopathic pulmonary fibrosis have this genetic variation. Based on this discovery, researchers at this center are planning to develop a diagnostic test that could predict who would develop this form of IPF. At the same time, the researchers are working on a drug to blunt the adverse effects of the genetic variation.
Individuals who have the genetic variant produce excess mucus that the researchers believe may promote fibrosis. “Mucus may decrease the ability of the lung to defend itself against air pollutants or bacteria that are inhaled into the lung,” explained Dr. Schwartz, the lead investigator for the team. “As a result, those air pollutant particles or the bacteria are likely causing damage to sensitive areas of the lung that go on to develop fibrosis.”
Reflecting on the three CADET projects to address IPF, Dr. Jerry Eu, a program officer in the NHLBI Division of Lung Diseases, expressed his hope that “CADET researchers will add to the arsenal of drugs available to fight this fast-progressing and deadly lung disease, which can be devastating to patients.”