When Charlie Tolchin visited his old lungs in the laboratory at UNC’s Cystic Fibrosis Research Center, he was glad to know they were no longer inside him. “Like sponges dipped in honey” is how Tolchin described the organs in his book about his transplant experience, Blow the House Down.

That description is not far from the truth. Research by Richard Boucher at UNC’s center has shown that CF lungs are missing the extraordinarily thin layer of water – just a third of a teaspoon in volume – that rests on healthy lungs’ airway surfaces. Usually, that thin layer helps to clear out the mucus that traps outside allergens and particles that enter the body. Without it, CF patients can expect infections and decreased breathing capacity over time.

Essentially, the defect in the CFTR gene that causes cystic fibrosis prevents chloride from passing through the cells of the lungs, as well as the pancreas and sweat glands, in a normal manner. At the same time, sodium passes through the cells too quickly. Salt, which is a sodium and chloride compound, draws water to it like a magnet; when the balance of sodium and chloride is off, so is the level of salt in the cells, and thus, the layer of water that would normally line the airway surfaces.

The tiny cilia – microscopic brush-like hairs on airway surfaces – need that water to pressure-wash out the mucus that we all naturally create to catch foreign particles in our lungs. When the water isn’t present, as in CF lungs, the cells don’t realize that mucus isn’t being swept off the surface, and they continue to produce it until the cilia are simply crushed under the mucus’ weight. Meanwhile, bacteria in the body invade the mucus and set up camp there, thriving and multiplying and creating recurring infections.

The body’s innate mechanism for dealing with infection is to release neutrophils – white blood cells – to travel to the bacteria and fight them. But the bacteria is so imbedded in the mucus that it is impenetrable, and the neutrophils become frustrated and die, releasing their own stringy, thick strands of DNA on top of the mucus already present, making an even stickier mess.

The main line of defense thus far in CF treatment has been the use of antibiotics to combat the infections that neutrophils can’t. But two therapies being developed on the basis of knowledge out of UNC work to replace that missing third of a teaspoon of water before its absence causes damage.

The first, INS37217, came about as a result of CF studies in first-of-their-kind mice models at UNC that had been rigged to have CF symptoms. Although all of the mice died from gastrointestinal disease related to CF, none ever showed lung disease. Intrigued, Boucher’s lab discovered that the mice were not affected in the same way by the CFTR gene. More importantly, mice have a second chloride channel, regulated by an entirely different system, that helps move the element across airway cells.

They discovered that humans also had the alternative chloride channel, and that all they had to do was create a long-acting treatment that would turn the channel on, causing a secretion of salt and water that would get the cilia beating and the mucus moving. In CF Foundation literature, its impact is measured on the same breakthrough level as gene and protein therapies. INSPIRE pharmaceuticals has proved INS37217 to be well-tolerated in patients in clinical trials and is moving on to Phase II and III trials – the last step before FDA approval – in the coming months. In October, INS37217 won fast-track approval from the FDA, meaning that it may be considered for priority review or for accelerated approval and reach its market audience more quickly.

The second treatment, still in the infancy stages at CyFi Inc., doesn’t yet have a name or a number – but it has a history dating before INS37217. Experiments conducted in the early ’90s at UNC used the drug amiloride, a diuretic developed by Merck Sharp and Dohme that was used for a number of disorders, including hypertension. It seems counterintuitive – after all, what we need is more water in there, not less – but amiloride works by inhibiting sodium absorption by cells, and CF is caused partly by too much sodium absorption. Boucher tried giving an inhaled form of amiloride to his patients. But while the tablet amiloride served the purpose for which Merck created it, the inhaled form stayed on the surfaces of the lungs for only 30 minutes.

“So if you inhaled it three or four times a day,” said Boucher, “you’d only be protected for four to six hours a day. CF is a 24-hour-a-day disease.” CyFi is working on a longer-lasting amiloride compound that could be effective if inhaled only twice a day.

Both treatments – one on the cusp of the public’s embrace as far as research years are measured, and one with a long road yet ahead of it – could be revolutionary when, and if, they go live on the drug market. But both of them also show the painstakingly incremental routes that are required to cause a medical revolution and how a mistake can eventually turn into a miracle.

“The good thing is that when you fail,” says Boucher, “you have a pretty good idea of what the hurdles were – and what you have to do to surmount them.”

Copyright 2002 UNC General Alumni Association

Published in Carolina Alumni Review November/December 2002.

(Sidebar to Breathing Lessons“)