By Brita Belli
A month ago, Yale launched the Interstitial Lung Diseases (ILD) Center of Excellence at the section of Pulmonary, Critical Care and Sleep Medicine, which will engage in translational and basic research while also providing compassionate clinical care, support and education for patients suffering from one of many complex lung diseases. It is the only center of its kind in Connecticut and part of a growing effort at Yale to bring together expertise in identifying, studying and treating lung diseases including idiopathic pulmonary fibrosis (IPF). IPF is a progressive lung disease in which scar tissue builds up over time, making it more and more difficult to breathe. It affects about 200,000 people in the U.S. The mean life expectancy for a person with IPF is two to three years.
Dr. Erica Herzog, Associate Professor of Medicine, Director of the Translational Lung Research Program at Yale and Co-director of the Yale Fibrosis Program, is leading the ILD Center of Excellence which had its roots in 2007 with a pilot grant from the Yale Center for Clinical Investigation. That $25,000 grant allowed Herzog to begin to identify biomarkers for IPF progression from patient specimens and launched translational research at Yale that later drew funding from the National Institutes of Health, industry partners and several private donors.
The center is one of just nine centers in the U.S., and the only one in the Northeast, designated as a Pulmonary Fibrosis Foundation Care Center, indicating that it has the specialized staff and resources to engage in everything from accurate diagnosis to continuing care to collaborative research. “Until recently, care for fibrosis was not standardized,” says Dr. Danielle Antin-Ozerkis, the Medical Director of the center and Associate Professor at Yale. “It takes multidisciplinary review for accurate diagnosis and care.” The Yale team for each patient includes four pulmonologists, two radiologists, an occupational medicine specialist, a pathologist and a rheumatologist.
Dr. Naftali Kaminski, the Boehringer-Ingelheim Professor of Internal Medicine and Chief of Pulmonary, Critical Care and Sleep Medicine at Yale School of Medicine, says IPF was once thought of as a “boring disease,” but that’s all changed dramatically as understanding of IPF has improved. The early days of pulmonary fibrosis research focused on inflammation as a root cause of the disease. Fibrosis is now understood to be the result of progressive, abnormal wound-healing. “It’s the result of a milder type of injury that causes ongoing micro-injury to lung tissue,” Kaminski says. That change in understanding has brought a change in therapeutic targets—from immunosuppressant drugs to novel drugs now in clinical trials. “We became a ‘fibrosis family’ which includes liver, kidney, heart and lungs. Now there are separate drug targets,” he says.
New Drugs for Lung Fibrosis
This past May, the New England Journal of Medicine published the results of three Phase III studies for two new drugs—InterMune’s pirfenidone and Boehringer Ingelheim’s nintedanib—that experts call game changing. Both drugs slowed the progression of IPF in patients, the first time any drug has yielded such positive results. Nintedanib has FDA approval for use as a lung cancer treatment; pirfenidone has been approved for the treatment of IPF in Europe, Japan and India, but not yet in the U.S.
Yale participated in the clinical trials and hopes to offer both agents soon. “It’s the first time we’ve had any drugs available to treat IPF,” says Herzog.
Herzog’s research has focused on identifying mechanistic biomarkers for IPF, work that has zeroed in on the role of the protein Semaphorin 7a (Sema 7a), which may be able not only to predict the rate of progression of the disease, but also serve as a target for drug treatment. She holds a patent related to Sema 7a with the Yale Office of Cooperative Research (OCR). She is also the senior author on a paper just published in Science Translational Medicine which defines the role of the protein Chitinase-3 Like 1 (Chi3L1) in the development and progression of fibrotic lung disease. Yale holds the patent on this target with Herzog and Dr. Jack Elias, Dean of the Medical School at Brown University and former Chair of Medicine at Yale.
“Basic research being conducted at Yale today may yield the next generation of drugs to treat fibrotic lung disease,” says John Puziss, Ph.D., the Director of Technology Licensing at OCR. “We are pursuing this intellectual property and are actively seeking industry partners to further develop some of these early advances.”
Kaminski, who was recruited to Yale last year from the University of Pittsburgh, where he directed the Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease, one of the largest such centers in the U.S., has also devoted much of his research to blood biomarkers. These biomarkers can help identify which patients are most at risk for rapid disease progression and in need of treatment. Dr. Kaminski has also identified microRNAs—non-coding RNAs that regulate gene expression—that inhibit genes important in lung fibrosis and could be targets for drug therapy. “I’m excited about microRNAs,” Kaminski says. “They are ideal drug targets that would have less troublesome effects than other such targets.” Kaminski is working with a series of industry partners on developing this research, including Biogen-Idec, Boehringer Ingelheim, InterMune, Gilead and MiRagen.
He and Herzog are working closely with doctors in the YALE-ILD Center of Excellence to advance understanding of IPF and discover new therapeutic pathways, including Antin-Ozerkis; Dr. Mridu Gulati, Associate Director of the ILD Center; Dr. Jonathan Siner, Assistant Professor of Medicine (Pulmonary); Dr. Robert Homer, Professor of Pathology and Medicine and Ami Rubinowitz, Associate Professor and Co-Chief of Thoracic Radiology.
There remains just one path yet unexplored: a lung transplant program. “We’re behind the curve of the need,” Kaminski says, noting that there are more lung transplantations performed in Pennsylvania in a year than in New York, New Jersey, Connecticut, Massachusetts and Rhode Island combined. “We are working with Yale-New Haven Hospital to have a program here,” Kaminski adds. “It would be incredibly beneficial for our patients.”