Big advance against cystic fibrosis

Harvard stem cell researchers at Massachusetts General Hospital (MGH) have taken a critical step in making possible the discovery in the relatively near future of a drug to control cystic fibrosis (CF), a fatal lung disease that claims about 500 lives each year, with 1,000 new cases diagnosed annually.

Beginning with the skin cells of patients with CF, Jayaraj Rajagopal, MD, and colleagues first created induced pluripotent stem (iPS) cells, and then used those cells to create human disease-specific functioning lung epithelium, the tissue that lines the airways and is the site of the most lethal aspect of CF, where the genes cause irreversible lung disease and inexorable respiratory failure.

That tissue, which researchers now can grow in unlimited quantities in the laboratory, contains the delta-508 mutation, the gene responsible for about 70 percent of all CF cases and 90 percent of the ones in the United States. The tissue also contains the G551D mutation, a gene that is involved in about 2 percent of CF cases and the one cause of the disease for which there is now a drug.

The work is featured on the cover of this month's Cell Stem Cell journal, which appeared online today. Postdoctoral fellow Hongmei Mou, PhD, is first author on the paper, and Rajagopal is the senior author.

Mou credits learning the underlying developmental biology in mice as the key to making tremendous progress in only two years. "I was able to apply these lessons to the iPS cell systems," she said. "I was pleasantly surprised the research went so fast, and it makes me excited to think important things are within reach. It opens up the door to identifying new small molecules [drugs] to treat lung disease."

Doug Melton, PhD, co-director of the Harvard Stem Cell Institute, said, "This work makes it possible to produce millions of cells for drug screening, and for the first time human patients' cells can be used as the target." Melton, who is also co-chair of Harvard's inter-School Department of Stem Cell and Regenerative Biology and is the Xander University Professor, added, "I would expect to see rapid progress in this area now that human cells, the very cells that are defective in the disease, can be used for screening."

Rajagopal said, "The key to our success was the ecosystem of the Harvard Stem Cell Institute and MGH. HSCI investigators pioneered the strategies we used, helped us at the bench, and gave us advice on how to combine our knowledge of lung development with their exciting new platforms. Indeed, we also enjoyed a wonderful collaboration with Darrell Kotton's lab at Boston University that was able to convert mouse cells into lung tissue. These interactions really helped fuel us ahead."

The epithelial tissue created by Rajagopal and his colleagues at the MGH Center for Regenerative Medicine (http://www.massgeneral.org/regenmed/) also provides researchers with the same cells that are involved in a number of common lung conditions, including asthma, lung cancer, and chronic bronchitis, and may hasten the development of new insights and treatments into those conditions as well.