Washington: Scientists, including one of Indian-origin, have taken a critical step in making possible the discovery in the relatively near future of a drug to control cystic fibrosis (CF).
CF is 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 and his colleagues at Massachusetts General Hospital (MGH) 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.
Hongmei Mou, first author of the paper, 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,” Mou 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,” she said.
The epithelial tissue created 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.
“We`re not talking about a cure for CF; we`re talking about a drug that hits the major problem in the disease. This is the enabling technology that will allow that to happen in a matter of years,” Rajagopal said.
“When we talk about research and advances, donors and patients ask: `When? How soon?`` And we usually hesitate to answer. But we now have every single piece we need for the final push. So I have every hope that we`ll have a therapy in a matter of years,” he said.
Cystic fibrosis, which used to claim its victims in infancy or early childhood, has evolved into a killer of those in their 30s because treatments of the infections that characterize the disease have improved.
But despite those advances, there has been little progress in treating the underlying condition that affects the vast majority of patients: a defect in a single gene that interferes with the fluid balance in the surface layers of the airways and leads to a thickening of mucus, difficulty breathing and repeated infections and hospitalizations.
The discovery and recent FDA approval of the drug Ivacaftor, which corrects the G551D defect seen in about 2 percent of CF patients, has served as a proof of concept to demonstrate that the disease can be attacked with a conventional molecular treatment.
In fact, Ivacaftor was found by screening thousands of drugs on a far less than ideal cell line. In the end, many drugs that functioned well on this cell line proved ineffective when used on genuine human airway tissue.
The study has been published in Cell Stem Cell journal.