When the gene for cystic fibrosis (CF) was discovered 25 years ago, hopes ran high that new treatments are just around the corner. But new drugs have proved difficult to design, and sometimes they do not work as expected. Now a pair of studies suggests why two advanced therapies may not help many patients as much as hoped.
CF is caused by mutations in the CFTR gene. Like many genetic diseases, a variety of different mutations may trigger the condition, and the average life expectancy for patients flat in the late 30s About 0% of patients with at least one mutation called F508 and it is one that is particularly difficult to repair. Mutation disables the CFTR protein in two different ways: It misfolds, and prevents it from reaching the cell surface, where it is believed to help control the balance of water and salt in the cells. When CFTR can not do its job, people develop a dangerous accumulation of mucus in the lungs and elsewhere.
One of the new CF drug, VX-770, was designed to address a much more rare mutation causing CF. Called G551D, he's behind about 4% of US cases; the protein reaches the cell surface as it is supposed to, but it is closed tight and can not work. VX-770, designed by Vertex Pharmaceuticals, opens the protein in the proper configuration so it can do its job. VX-770 was approved in 2012 for patients with this particular mutation, under the brand name Kalydeco.
Although this is great news for patients with G551D, the much larger pool, with AF508, does not benefit from VX -770 alone. Scientists had hoped that the combination of VX-770 with yet another experimental drug Vertex VX-809, which moves the CF protein on the cell surface, would do. Two groups have decided to explore this idea further in lung cells.
What they found was surprising. A team led by cell biologist Martina Gentzsch at the University of North Carolina, Chapel Hill, looked at a type of human lung cells that is often used in CF research, with the F508 mutation. They found that chronic exposure to VX-770, which is supposed to activate the mutated protein, made the other drug, VX-809, less effective, and this was particularly true with high doses of VX-770. "At high concentrations" of VX-770 when combined with VX-809, "there is a very strong inhibition" of how the functions of proteins, said Gentzsch. At lower doses, mutated protein was not always so touched. Labour disputes with previous studies of cells in which the VX-770 was given only briefly and showed the success. chronic exposure, it seemed, had a more complicated effect .
at McGill University in Montreal, Canada, cell biologist Gergely Lukacs and his team have seen something similar. They found that exposure of lung cells with the F508 mutation in the VX-770 long term mimicking what happens in patients who take the drug for long periods, often the function of the CFTR protein evil than the short-term exposure. the hypothesis is that Lukacs, although at VX-770 some respects could get CFTR into the right functional form, in other ways it is destabilizing. "He has that effect duality," he said.
What does this mean for patients? The documents, published today in Science Translational Medicine appear by accident a few weeks after Vertex announced results from a phase III trial in which patients with the mutation AF508 got both drugs for an extended period of time. Their lung function has improved, albeit modestly, to 2.6% to 4%.
"at first glance, this may seem at odds" with the cell studies, said Philip Thomas, a biochemist at the University of Texas Southwestern Medical Center in Dallas, CF studying and was not involved in the current research. and it is clear that in people with the most common mutation, the two drugs work better together than either does on its own. But he and others believe the work of the cell is to teach something important CF community: drugs can interfere with each other, packing a punch less powerful than doctors and patients would like to see. The combo can work some patients because the dose of VX-770 is probably lower than in laboratory work, he suspects, cushion the negative impact of the cellular studies report.
"It really makes me think there is room for improvement," said John Clancy, a pediatric pulmonologist at the Medical Center Hospital of Cincinnati Children in Ohio who was not involved in the research. back in his lab, Lukacs also worked with a similar experimental compound VX-770 which did not have the drawbacks of the drug. in the long term, it suggests, this compound may be a better option for some patients.
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