Knocking the wind out of lung disease

The January unveiling of President Obama’s Precision Medicine Initiative—to fund research that better predicts which treatments will be most effective for which patients—highlights the increasing importance of personalized medicine today. But while physicians and scientists have made strides in tailoring treatments to patients with cancer and diseases caused by mutations in a single gene, similar advances in other diseases have lagged behind.

Members of the School of Medicine’s Section of Pulmonary, Critical Care and Sleep Medicine (PCCSM) are changing that paradigm. By applying high-throughput RNA sequencing technologies and genomic methods to the study and treatment of chronic lung diseases like pulmonary fibrosis and asthma, they are unraveling the underlying mechanisms of these illnesses and developing targeted approaches to help patients.

Pulmonary fibrosis is a respiratory disease in which uncontrolled scarring damages the lungs and impairs breathing. Patients typically survive three to five years after being diagnosed, but, as with many diseases, how well they do can vary widely. Until recently, doctors had nothing to offer in the way of treatment short of a lung transplant.

Research by Naftali Kaminski, M.D., the Boehringer Ingelheim Pharmaceuticals, Inc. Professor of Medicine and chief of PCCSM, has shed light on the disease, revealing that it is an active process of destruction and rebuilding with many pathways. Kaminski’s approach to developing personalized treatment has focused on analyzing gene expression in pulmonary fibrosis to help predict which patients progress more quickly. His lab identified a family of microRNAs—small RNA molecules which do not code for proteins but instead regulate which genes are turned on and off—that are changed in patients with pulmonary fibrosis. Last year he showed that supplementing mice with a molecule that mimics miR-29, a microRNA decreased in fibrosis, not only blocked fibrosis but could potentially reverse it.

With a new five-year, $7.1 million Centers for Advanced Diagnostics and Experimental Therapeutics (CADET) grant from the National Heart, Lung and Blood Institute (NHLBI), Kaminski’s team is taking its findings to the next level. Awarded last July, the grant is enabling the team to develop the evidence needed to support the use of miR-29 mimics as FDA-approved drugs. They will evaluate miR-29 as a therapeutic agent for pulmonary fibrosis in humans and identify biomarkers to show which patients will benefit from the treatment. “The aim in five years is to have both a molecule [for drug development] and a target population,” he said.

Kaminski’s passion for pursuing personalized medicine is shared across his section by colleagues both junior and senior. Working in the Kaminski lab, Jose Herazo-Maya, M.D., instructor in medicine, was able to identify a gene expression signature in the blood of patients with pulmonary fibrosis that indicated which patients’ disease would likely progress more quickly. Such information could be useful in light of two drugs recently approved by the U.S. Food and Drug Administration that can slow disease progression. “We think that the use of gene expression profiles in the blood of patients with pulmonary fibrosis may be helpful to actually get these patients on the drugs faster and to predict when lung transplants will be needed,” Herazo-Maya says.

Geoffrey L. Chupp, M.D., associate professor of medicine, uses an approach similar to Kaminski’s to treat asthma patients. He developed a system for collecting sputum that provides a window into the lung. After isolating cells from the airway and analyzing the gene expression of those cells, he has identified three sub-groups of patients whose genetic profiles correlate with the severity of their disease. He has also identified a gene expression signature in the blood that he has validated in both adult and pediatric asthma patients.

“In asthma there’s a revolution of [therapeutic] biologics coming down the pipeline,” says Chupp, also director of the Yale Center for Asthma and Airways Disease and the Pulmonary Function Laboratory at Yale-New Haven Hospital. He and his colleagues are conducting more than a dozen clinical trials to study these biologics—antibody-based therapies that bind to specific targets—and identify which therapies work best in which patients. Chupp is also the recipient of an NHLBI-funded CADET grant that he is using to develop a biologic that binds to and blocks YKL-40, a protein that is typically elevated in those with severe asthma.

Kaminski and Chupp are co-directors of the Center for Precision Pulmonary Medicine (P²MED), a new program that houses genomic technology and expertise within PCCSM. Technology alone cannot, of course, provide the kinds of insight required for precision medicine. “The idea is to create a skilled critical mass of pulmonary physician-scientists who are well versed in clinical medicine, as well as in genomics, bioinformatics and computational biology—the trade tools of precision medicine” Kaminski says.

Genetic analysis generates a massive amount of data—what scientists call “big data”—that require expertise to decipher, a process central to developing personalized treatments. “When you look at outcome data you can gain some insights, but you don’t know exactly why some patients are responding while others are not,” says Xiting Yan, Ph.D., assistant professor of medicine and director of the P²MED Data Analysis and Bioinformatics Hub. “Big data can provide hints about why and how patients respond to a drug.”

The location of P²MED within PCCSM affords scientists easy access to its resources and computational expertise. Meanwhile, Yale’s clinics and hospitals provide a wealth of clinical information for faculty members to harness in their quest to develop targeted therapies. Each year more than 8,000 patients visit PCCSM’s outpatient facility, the Winchester Chest Clinic, for example, and Chupp and Kaminski look forward to the day when each of them will benefit from the genomic discoveries now taking place. “We put in infrastructure very close to the clinical setting,” Kaminski says. “That’s the way you generate the next generation of physicians who will have the skills to understand genomic information and use it for the benefit of our patients.”