[MUSIC] So in this module, what I want to talk about is the way in which genetics has informed the drug development process, a phenomenon that I have alluded to before. But in one particular disease to develop genotype specific drug therapy. And the problem is the problem of Cystic Fibrosis. The case that I'm going to use to illustrate this is a 22 year old woman who has frequent respiratory infections as most patients with symptomatic Cystic Fibrosis do. Diagnosis of Cystic Fibrosis was made at age two. The FEV1 in the last year, or the last two years, has fallen from 45% of predicted to 27% of predicted. That's a pretty drastic decrease in the standard index that people use to gauge the extent of pulmonary disease and she's now being considered for the ultimate therapy in Cystic Fibrosis, a lung transplant. A lung transplant, of course, is not curative for Cystic Fibrosis. It trades in one disease for another disease, the other disease being management of the transplant. So recall that Cystic Fibrosis is an autosomal recessive disease. One person, one Caucasian, in 30 or 35 carries a mutant Cystic Fibrosis disease gene. I'll come back to what the disease gene is in a moment. And if they encounter a person who also is a carrier, that mating occurs one time in 900. One in 30 times one in 30. And then one in four of those children will develop Cystic Fibrosis, because they will inherit two genes. This is the autosomal recessive pattern that we see in Cystic Fibrosis. We'd see in Sickle Cell disease and we see in Mendel's peas where three normal peas and one recessive pea were the result of the matings that I described earlier on. Cystic Fibrosis affects multiple organ systems, but the main organ system that it affects is the lungs. Patients with symptomatic Cystic Fibrosis have to be very, very careful with nutrition, and spend a lot of time dealing with pancreatic enzymes and that sort of thing. There are many other manifestations that are shown on this slide, but the real life threatening event, or the real life ending event, is almost always pulmonary infections and pulmonary damage. The prognosis for patients with Cystic Fibrosis has improved quite strikingly over the last several decades, mainly because of increased attention to pulmonary toilet. People are very, very aggressive about physiotherapy and home physiotherapy to make sure the lungs are clear and stay clear. Despite a very aggressive physiotherapy, the average life expectancy is still less than 40 years of age. So the fundamental problem in Cystic Fibrosis are mutations in a gene called CFTR, the Cystic Fibrosis Transport Regulator. And that is actually a plasma membrane protein whose mission in life is to transport chloride from the inside of a cell to the outside of a cell. That happens normally, and chloride, when it's transported, drags water and sodium with it. Patients with Cystic Fibrosis do not have that chloride transport ability. They develop concentration of, their sweat becomes quite concentrated, for example, with chloride ions in one of the typical symptoms that we learn about in medical school is that a child with Cystic Fibrosis the mother will report that the sweat tastes quite salty, and that's because of this defect. Interestingly, CF mutations that cause Cystic Fibrosis were among the first that were discovered using modern genomic techniques, and the disease gene was actually isolated in the late 1980s. There was great hope at the time that we would just use gene therapy to correct the defect. In fact that hasn't happened, but the story I'm going to tell is how understanding the fundamental basis of disease actually informs the drug development process to the good of some patients. So this is the problem in Cystic Fibrosis, most patients the problem is, in fact, a misfolded protein that never gets to the cell surface. There's one common mutation that results in deletion of a phenylalanine in position 508 in the protein, the so called delta F508 mutation that results in a misfolded protein that is recognized as misfolded and never actually gets to to the cell surface. Other mutations, that's the class two mutation shown on this slide, the class one mutations are defects in protein processing, and then the class three and four mutations are defects in the way in which the channel behaves once it gets to the cell surface. So there are some channels that traffic normally to the cell surface, but once they get there, they actually don't conduct chloride, or they don't open it appropriately to conduct chloride under similatory conditions like increased intracellular AMP. So the idea here is to develop a drug that will fix the gating defect, that's the defect of the channels that get to the cell surface, but don't actually open and close properly once they get to the cell surface. So this is a cartoon of a channel that's like that, and the drug that was developed is a drug called Ivacaftor. And the cartoon shows that the idea behind Ivacaftor is it will interact with the cystic fibrosis regulate protein and that protein is the ion channel plus those little balls underneath, that's part of the protein, and allow chloride to exit the cell normally. So the way in which this drug was developed was really very, very interesting. It turns out that most mutations don't have a gating defect. So the first challenge was to identify a set of patients who have a genetic defect that results in an abnormality of gating. The defect that was targeted initially is a defect that results in a change in the amino acid that's called G551D. And that's a channel that gets to the cell surface, but doesn't gate properly. Only a small number of patients carry G551D, and this is the result of an initial trial of the drug, which didn't have a name at the time, in a small number of patients, and remember Cystic Fibrosis is a rare disease. G551D is a rare form of a rare disease, so how are you going to study a drug that is targeted to that rare form of the rare disease? You engage the Cystic Fibrosis community, and the Cystic Fibrosis community brought together investigators from all around the country, each one of whom might contribute one or two patients to a particular trial like this one. And what this slide shows is that within three days of starting Ivacaftor, the increase in chloride concentration in the sweat is normalized. That's the panel on the left. There was also a small increase in the FEV1, but remember that happens within three days of starting therapy as well. Although interestingly, there's a big placebo effect here as well, and you'd be hard pressed to say by the end of this particular trial that there was a major change in FEV1 compared to placebo. But these results were sufficiently encouraging, particularly the sweat chloride result, was sufficiently encouraging that people decided to go ahead and mount a trial that would last 48 weeks. The 48 week trial is shown here, and there's not much doubt that the drug does something enormous. So there is a huge increase in FEV1, that's the upper left panel. That is almost immediate and persistent over 48 weeks. There's a striking decrease in the number of events, hospitalizations, pulmonary exacerbations, that's the panel on the upper right. And what's really interesting is that there's pretty impressive weight gain. And that really suggests that many of the fundamental defects around this disease are being corrected by this particular drug. And that's so, these are results that were really outstanding and when you can read testimonials on the Web for example of patients who were parts of these trials, and they could tell, although these were randomized possible controlled double blind trials, they could tell within days whether they were on placebo or on the real thing. There are these very compelling stories of sisters, both of whom have the mutation, one of whom gets the drug and one of whom gets placebo and they know within a of couple of days, which one's on drugs. So it really has the potential to be life altering. Now the problem is that G551D is 5% of all mutations. And the real problem is that delta F508 is the biggie. And that's about 70% of all patients with Cystic Fibrosis carry that single variant. Of course they have two variant alleles. And so there's a hope that drugs that drag these abnormal channels to the cell surface, may be effective in some forms of Cystic Fibrosis, and it's possible that sometimes just dragging the channel to the cell surface will be enough to correct the defect. Sometimes you'll be able to drag the channel to the cell surface, and then you'll have to use another drug, perhaps Ivacaftor, or perhaps something else to actually change the gating of the channel. But there is this hope, that by understanding the fundamental mechanisms and developing drugs that specifically attack the defect conferred by a specific mutation, you'll actually get to the bottom of mechanism guided therapy. So there's been a huge amount of buzz around this. This is an FDA approved drug, and the big issue is cost. This drug costs $300,000 a year. And is that something that society can bear? There's a huge debate, as you can see, and the arguments go something like this. As you see at the bottom hot off the breath instead of hot off the press. Instead of Ivacaftor, I've a cost for. The $64,000,000 question. Now one side says, well we just can't afford that. The other side says, well you know, add up with the cost of taking care of a patient with Cystic Fibrosis are. How many times do they get admitted to the hospital? How many antibiotics do they chew up? How many enzymes do their intestines require in order to be able to digest foods? And when you add up the costs of taking care of these patients, compared to the cost of Ivacaftor, there are arguments to be made on both sides. Clearly a very, very expensive undertaking. There's a lot of concern that the community, the Cystic Fibrosis community, was responsible for the development of this drug and yet is being charged or overcharged for the cost of the drug. The pharmaceutical manufacturer, of course, takes a big risk by developing something like this. So these are unknowns, but this example is the first, I think, of many, many examples that we're going to face, because as we get better at defining the molecular basis, of not only common diseases, but rare diseases, we're going to have targeted, precise, highly effective therapies that will come at a price. [SOUND] [APPLAUSE]
