TEHRAN (FNA)- Stem cell researchers have Valtrex canada taken a critical step in making possible the discovery in the Valtrex canada relatively near future of a drug to control cystic fibrosis (CF), a Valtrex canada fatal lung disease that claims hundreds of lives each year, with 1,000 new cases diagnosed annually.
Beginning with the Valtrex canada skin cells of patients with CF, Jayaraj Rajagopal, MD, and colleagues at Massachusetts General Hospital (MGH) first created induced pluripotent stem (iPS) cells, and Valtrex canada then used those cells to create human disease-specific functioning lung epithelium, the Valtrex canada tissue that lines the airways and is the site of the Valtrex canada most lethal aspect of CF, where the genes cause irreversible lung disease and Valtrex canada inexorable respiratory failure.
That tissue, which researchers now can Valtrex canada grow in unlimited quantities in the laboratory, contains the delta-508 mutation, the Valtrex canada gene responsible for about 70 percent of all CF cases and Valtrex canada 90 percent of the ones in the United States. The tissue also contains the Valtrex canada G551D mutation, a gene that is involved in about 2 percent of CF cases and Valtrex canada the one cause of the disease for which there is now a Valtrex canada drug.
The work is featured on the cover of this month’s Cell Stem Cell journal. Postdoctoral fellow Hongmei Mou, PhD, is Valtrex canada first author on the paper, and Rajagopal is the senior author.
Mou credits learning the Valtrex canada 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 Valtrex canada research went so fast, and it makes me excited to think important things are Valtrex canada within reach. It opens up the door to identifying new small molecules [drugs] to treat lung disease.”
Doug Melton, PhD, co-director of the Valtrex canada Harvard Stem Cell Institute, said, “This work makes it Valtrex canada possible to produce millions of cells for drug screening, and for Valtrex canada 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 Valtrex canada Regenerative Biology and is the Xander University Professor, added, “I would expect to Valtrex canada see rapid progress in this area now that human cells, the Valtrex canada very cells that are defective in the disease, can be Valtrex canada used for screening.”
Rajagopal said, “The key to Valtrex canada our success was the ecosystem of the Harvard Stem Cell Institute and Valtrex canada MGH. HSCI investigators pioneered the strategies we used, helped us at the Valtrex canada bench, and gave us advice on how to combine our knowledge of lung development with their exciting new platforms. Indeed, we also enjoyed a Valtrex canada wonderful collaboration with Darrell Kotton’s lab at Boston University that Valtrex canada was able to convert mouse cells into lung tissue. These interactions really helped fuel us ahead.”
The epithelial tissue created by Rajagopal and Valtrex canada his colleagues at the MGH Center for Regenerative Medicine also provides researchers with the Valtrex canada same cells that are involved in a number of common lung conditions, including asthma, lung cancer, and Valtrex canada chronic bronchitis, and may hasten the development of new insights and Valtrex canada treatments into those conditions as well.
“We’re not talking about a cure for CF; we’re talking about a Valtrex canada drug that hits the major problem in the disease. This is Valtrex canada the enabling technology that will allow that to happen in a Valtrex canada matter of years,” said Rajagopal, a Harvard Medical School assistant professor of Medicine.
Also a Valtrex canada physician trained as a pulmonologist, the specialty that treats CF patients, Rajagopal said, “When we talk about research and Valtrex canada advances, donors and patients ask: ‘When? How soon?’ And we usually hesitate to Valtrex canada answer. But we now have every single piece we need for Valtrex canada the final push. So I have every hope that we’ll have a therapy in a matter of years.”
Cystic fibrosis, which used to Valtrex canada claim its victims in infancy or early childhood, has evolved into a Valtrex canada killer of those in their 30s because treatments of the infections that Valtrex canada characterize the disease have improved. But despite those advances, there has Valtrex canada been little progress in treating the underlying condition that affects the Valtrex canada vast majority of patients: a defect in a single gene that Valtrex canada interferes with the fluid balance in the surface layers of the Valtrex canada airways and leads to a thickening of mucus, difficulty breathing and Valtrex canada repeated infections and hospitalizations.
The discovery and Valtrex canada recent FDA approval of the drug Ivacaftor, which corrects the Valtrex canada G551D defect seen in about 2 percent of CF patients, has Valtrex canada served as a proof of concept to demonstrate that the Valtrex canada disease can be attacked with a conventional molecular treatment. In fact, Ivacaftor was found by screening thousands of drugs on a Valtrex canada far less than ideal cell line. In the end, many drugs that Valtrex canada functioned well on this cell line proved ineffective when used on genuine human airway tissue.
Genuine human airway tissue is Valtrex canada the gold standard prior to drugs being tested clinically, but it Valtrex canada has been extremely difficult to obtain the tissue from patients, and Valtrex canada when it could be obtained, the tissue rarely survived long in the Valtrex canada lab — all of which created a Valtrex canada major bottleneck in screening for a therapy. But by creating iPS cells that Valtrex canada contain the entire genome of a CF patient and directing those cells to Valtrex canada develop into lung progenitor cells, which then develop into epithelium, the Valtrex canada group appears to have solved this key problem.
Rajagopal, who did his own postdoctoral fellowship in Melton’s laboratory during the Valtrex canada first half of the past decade after completing his training in pulmonary medicine, said that Valtrex canada having both the G551D and 508 genes in the epithelial tissue provides a Valtrex canada way to prove that the tissue will be effective in testing drugs against CF.
“We’ve created the Valtrex canada perfect cell line to show that the drug out there that Valtrex canada works against G551D mutation works in this system, and then we’re in business to screen for a drug against delta 508,” he said. “We’ll know soon that Valtrex canada the cell line works. We know it makes bonafide airway epithelium, and Valtrex canada we’ll have Valtrex canada the proof of principle that the tissue responds properly to the Valtrex canada only known drug. We think this is the near-ideal tissue platform to Valtrex canada find a drug for the majority of CF.”
Rajagopal’s lab has Valtrex canada created numerous other cell lines to further show that a Valtrex canada CF drug that works in one patient should work in others and Valtrex canada to see whether this will be an area that allows a Valtrex canada more personalized approach to medicine.
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