[MUSIC] Today, we're going to talk about Marfan syndrome. An interesting, relatively rare condition that really illustrates the power of understanding mechanisms to go to therapy. So the problem in Marfan syndrome, I've already shown you this picture before, is this unusual body habitus. This is four members of a family from three different generations. You can see that they're all tall, skinny, and they have these very, very long arms with very long fingers. This is an autosomal dominant condition and its been recognized for decades and decades, in fact more than 100 years. So the inheritance is well understood, and we'll come back to genetics in a moment. The clinical features are kind of interesting. It's not just a skeletal problem, but you can see that there's tremendous problems with the bony structure and the hands, they're double jointed, so to speak. And there's curvature of the spine scoliosis, and they also characteristically have a problem with the lens of the eye, and ectopic lens placement, and difficulty with vision. But the biggest problem is in the aorta. You see the chest X-ray shows a pretty widened mediastinum. And the CT scan shows a dissection, that what you see there is FL, which is a false lumen, and a flap in the aorta. So what has happened is the aortic wall has ruptured, and the blood is actually in a false lumen, not in the true lumen. The photo micrograph shows the underlying pathology, and that is the aortic wall has been ruptured. So, this is the most feared complication of Marfan syndrome, because it can result in sudden death. Perhaps, the most recent, famous example was Flo Hyman, arguably the best volleyball player the United States has ever produced. A tall woman with long arms, but none of the other feature of Marfan syndrome and that's pretty typical, not everybody has all the features, and she died suddenly. The death was attributed initially to coronary disease, until the autopsy showed that she had died of a ruptured aneurism of her ascending aorta, which is the typical place. The other person who you will occasionally hear who had Marfan syndrome, was Abraham Lincoln. He was very tall, especially for his time, and had part of the body habitus of Marfan syndrome. So he may in fact have been a carrier of this condition. So if the problem is in the aortic root, then how do you treat it? Before the genetics were dissected, it was well know that certain brands of turkey get aortic aneurysms and will die. And it turns out that giving those turkeys beta blockers makes them live longer. The notion is that they have a, quote, weak, unquote, aortic wall, and by reducing not the pressure in the aorta so much, as the rate of change of pressure, the DPDT, they are less susceptible to aortic rupture. And of course, propranolol also is effective in severe hypertension and is used in the treatment of dissecting aneurysms of the usual kind. Again, partly to lower the blood pressure, but mostly to lower the DPDT. So people have looked at the effect of beta blockers in Marfan syndrome and here's a study from the New England Journal in the early 1990s, showing patients who ended up on propranolol had a slower rate of change in the aortic diameter compared to patients who did not end up on a beta blocker. This is not a randomized trial, but it still nevertheless suggests that the trajectory of patients with Marfan syndrome can be altered by the use of propranolol, these are all patients with Marfan syndrome of course. So the state of the art is propranolol treatment which slows the progression of the disease and that's the way people thought. So the disease gene in Marfan Syndrome, is a gene called fibrillin. It's a large gene, and you can tell by its name that has something to do with the way the cells interact with the extracellular matrix. And for a long time, the notion was that mutations in fibrillin would somehow disrupt the extracellular matrix, and therefore result in this so called weak aortic wall. This slide shows many, many mutations, there are now many more mutations that are shown here. Each of which has been associated with Marfan syndrome in a family, so like other diseases that we've talked about familial hypercholesterolemia or the Long QT syndrome. This disease also has a single disease gene with many, many, many mutations, each one of them causing the disease. Now the problem came when people started to think more critically about this weak wall idea, and one of the breakthrough studies was actually in mice that have Marfan syndrome. So people looked at the lungs, and the lungs are one of the affected organs in humans as well as the mice. Humans develop early emphysema as a manifestation of Marfan syndrome. So when people looked at the elastin staining in mice with Marfan syndrome, it was completely normal. So that really suggests that fibrilin, despite its name and despite the appeal that somehow it weakens the extracellular matrix. Fibrillin actually has some other function, so here is the idea. Inside the cell there is a protein called LTBP, Latent TGF- beta binding protein. And its job in life is to hang on to a protein called TGF beta, transforming growth factor beta. And so it's job in life is to hold onto to TGF beta inside the cell. LTBP also interacts with the extracellular matrix through the, and it's a long protein as you can see from the cartoon and it interacts with fibrillin. Fibrillin is located inside the cell. So the notion is, when you get a mutation in fibrillin, it disrupts this complex, and when it disrupts the complex, the complex releases TGF-beta. And it's unrestrained TGF-beta signalling that actually results in the diverse manifestations of Marfan syndrome, from the bony structures to the aortic wall, to the lungs, to the lens of the eye. So that's the idea and what was really interesting in this story, is that there are patients who have almost Morfan syndrome, who have many of the manifestations, particularly the aortic manifestation, and yet who don't have mutations in fibrillin. They seem to have a related disease and that related disease now called Loeys-Dietz disease, because those are the first and last author of the paper that first described it, have mutations in the TGF-beta receptors. So, that again implicates this TGF-beta signaling problem, and unrestrained TGF-beta activation inside cells across the body, as the mechanism underlying Marfans syndrome, through pathways that are being worked out still. So Dr. Dietz, who's a leader in this field made mice that have Marfans syndrome and this is a picture of a mouse heart with the aortic root shown by the arrows. So the aortic root is pretty small, especially in mice it's really small. But if you give mice, if you construct mice with a fibrilin mutation, of the type that he's shown here, you can see the aortic root is much, much dilated. So the question then becomes, what happens if you give a treatment? Now the treatment, the standard treatment is a beta blocker and so, if you give the beta blocker, that's shown in panel C, the aortic root is smaller. But what's really interesting is, if you treat these mice starting when the mothers are pregnant, with losartan, which is an angiotensin receptor blocker that acts by inhibiting TGF beta signaling in cells. You get absolute prevention of the phenotype. You can see the aortic roots in the three mice on the bottom panels look just like the wild type. They don't aortic root dilatation at all. Now, there's a problem in a sense that you can't give people losartin when they're pregnant, because it causes birth defects. But this is a very important proof of principle that inhibiting the TGF-beta signaling pathway, gets at the root of the problem and can actually prevent the manifestations of the problem. Here is a small study of a group of patients who were put on an angiotensin receptor blocker, Losartan usually, and you can see that this is the progress of the aortic-root over time and you can see that what happens is, before the medicine has started, the aortic root is dilating as a function of time and after the medicine has started that dilatation almost stops. That's a much more impressive effect at least in this very small study, than the propranolol effect I showed you earlier. There are now about a dozen randomized trials going on, comparing losartan and drugs of that type to beta-blockers or to placebo. It's hard to think about having Marfan syndrome and taking placebo, but taking a beta blocker or losartan and those results are just now coming out. The very first of those trials has been reported and interestingly, losartan seems to slow the rate of progression in adults with Marfan syndrome in terms of aortic-root dilatation. So there's great excitement, the trials are going on, and where in this awkward phase where there are Evangelists, who really feel we've stumbled across a new medicine and we ought to just go ahead and use it, and the Purists who say we really ought to prove it in randomized trials. I think we're going to get to an answer, the National Marfan Organization is a place to go and get more information about that, and they website is shown here. So, I think this is a really compelling story from a syndrome that you sort of describe by saying well they have long fingers and long arms, to understanding a therapy based on what you understand from turkeys. To understanding the molecular genetics, to looking in great detail at how those molecular genetics work to cause the disease, and then coming up with therapies that appear to be relatively specific. And it's a very exciting time for Marfan, and I think it illustrates the power of going from a gene to a new therapy. 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