actually for three to five years before the gene was identified, there had been seminal work in understanding that it was a defect in ion transport, or salt transport, in epithelial lining cells. There had been articles in the New England Journal in terms of what caused the salty sweat in patients. That was because of this abnormal salt transport patients had.
Then when the gene was identified in 1989, they were able to move forward at exponential speed and identify what the faulty protein was, where it was located, and how the protein functions normally, and what was wrong with the dysfunctional protein.
X: Despite all this fundamental, underlying biology that we now know, it hasn’t really added up…
BR: It hasn’t had any impact on treatment. That’s right. We now clearly understand what the cystic fibrosis protein does, and what goes wrong. We also know there are these different classes of mutations. There’s a type 1 mutation, where the protein isn’t transcribed. Those are called premature stop mutations. That’s the type of mutation that [South Plainfield, NJ-based] PTC Therapeutics is working on. Then there are other mutations, the most common type is the Delta F508. That’s one where the nascent protein is made, but doesn’t get properly trafficked up to the surface of the cell. Then there’s the type 3, the G551D, which is what the Vertex product is working on. That’s where the protein gets to the surface, but it’s not properly activated. So it gets up there to the surface of the cell, but it can’t properly transport the salt. Then there’s actually types 4 and 5, in which there are abnormalities in the channel itself.
But I think what’s really key now is that for the first time we’re really looking at therapies that could correct the protein. So, you ask, why has lifespan doubled when we haven’t been treating the underlying defect?
I think it’s because we started looking very systematically at the management of the illness and asked, “How can we improve the management and the secondary consequences of an abnormal protein?” The secondary consequences are where you get this dry, thickened mucus that blocks multiple organs, like the pancreas, the lung, the liver, the testes. You try to figure out better ways to hydrate and mobilize secretions. We know in the lungs that this mucus leads to secondary infections, and so we asked, ‘How do you better treat those infections?’
Over those 20 years, we’ve been much more aggressive in general treatment. It used to be you didn’t treat kids at all until they were almost school-age. I’m talking about the lung disease. They started coughing up sputum. We realized by that point, a lot of lung damage had already occurred. I think it’s an approach very similar to what happened in pediatric oncology, where they started getting very aggressive upfront, rather than waiting until they relapsed, and were already too sick. Now we’re very aggressive about starting nutritional supplements and enzyme therapy in the newborn period, because we now have newborn screening that’s nationwide. Children are never allowed to get malnourished
