One of the central features of bronchiexis is chronic neutrophilic inflammation and the hypersecretion of neutrophil serum proteases like neutrophil elastase. These proteases are normally uh present at only very low levels in the airways, and they're balanced by antiproteinases like alpha1 antitrypsin and secretory leucoprotease inhibitor, so you don't have uncontrolled protease activity in the lungs. In people with. Bronchiectis, that system goes out of control, you have too much neutrophil elastase, there's not enough antiproteinase to block that, and so you have protease activity in the lung that's damaging the airways, driving too much mucus, impairing the response to infection, and causing disease progression. Uh, and unless something is done about that, the disease is gonna get worse over time, patients are going to experience pulmonary exacerbations. So the question is, what can we do about it? Uh, until recently, the answer to that question was not a great deal. Targeting the neutrophil was considered to be very, very difficult from a drug development point of view because neutrophils themselves. are important to fighting infection, and so the concern always has been if you target the neutrophil too robustly, you may increase the risk of infection. So the ideal therapy for bronchiexis just conceptually, would be something that reduces neutrophil proteases and neutrophilic inflammation, but doesn't increase the risk of infection. So enter the dippeeptoidal peptidase one inhibitors, what is dipeptidy peptidase one? So, DPP one is an enzyme that switches on, activates the neutrophil serum proteases as the neutrophils are developing in the bone marrow. So when neutrophils are made in the bone marrow, they have these very harmful chemicals that need to be packaged in there. If they were already active, they would damage your bone marrow, so they need to be packaged in there and activated just at the point that they're being loaded inside the neutrophils. I sometimes use the analogy of loading bullets inside a gun. Uh, and so DPP1 does that, it activates these proteases. If you block DPP1, those proteases don't get activated. You have a fully functional neutrophil, but it lacks these damaging chemicals that are central to the pathophysiology of bronchiectasis. So it sounds like a pretty good target to develop a bronchiectis, uh uh uh targeting drug. The other really reassuring thing is there's a very rare human condition called Papillon LeFevre syndrome. Uh, it's very, very rare, 1 in a million people, um, so OK if you've never heard of it, cause, uh, it's very unlikely you'll ever see a case. Um, but these are people who lack the gene for DPP1, uh, and what's important is although they have low levels of neutrophil serine proteases, just as you'd expect from the biology. These people do not suffer from recurrent severe infections, unlike many other conditions that affect the neutrophil. Why is that important? Because it predicts that if you have an effective drug that blocks DPP1, you'll have an effect on the neutrophil, but there's no reason to believe it would have an effect on increasing. Infections, and remember I told you that the dream scenario for a drug was one that reduces neutrophilic inflammation, but doesn't increase the risk of severe infections. So DPP one seems to tick those boxes, uh, and as you'll, uh, you'll hear as I tell you about the clinical trials, it does appear indeed that it ticks those boxes.
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