Issam A. Awad, MD discusses risks and innovations with regards to Intracerebral Hemorrhage
ISSAM AWAD: Hello. My name is Issam Awad. I am a professor of neurosurgery and neurology at the University of Chicago Medicine. And I'm the director of the neurovascular surgery program. Today I want us to talk about the innovations and impact related to neurovascular disease. We have the opportunity to extract very important advances from the biology of blood vessels and apply them to the care of patients. The next slide will show you the extensive amount of blood vessels within the human brain. It is a phenomenal collection of vessels that ensure the delivery of blood to various parts of the brain, that are needed for the brain function. The only problem is that some of these vessels can weaken over time. And if they weaken and bleed it can cause a devastating stroke. The study of the biology of blood vessels gives us an opportunity to try to look at the genetics and the structure of the blood vessels. And understand what makes them weaken so that we can prevent this weakening and ultimately prevent the hemorrhage from ever occurring. The next slide introduces a concept that we all may remember from high school biology. What phenotype is, is what actual structure of the blood vessel or any other area of the body is. The genotype are the individual genes that result in that structure. We all have many cells and genes in our body, And the way these genes function, they ensure that our blood vessels form correctly, they form healthy tubes that are elastic, that do not leak. And that can be resilient even as we move and as we age. However, some of us are born with groups of genes that make our vessels weaker than others, more vulnerable to aging, and to high blood pressure. If we understood how those particular genes result in this vulnerability, we can make a difference in this process and develop ways of preventing the blood vessel from tiring, from leaking, and ultimately, the patient from having the stroke. So many, many pathologies of the human brain have been associated with specific genes that cause these pathologies. However, to date, the therapies have not developed very effectively based on this knowledge. I think we are starting to make a breakthrough in this with relation to the weakening of the blood vessels that happen in the human brain. And I want to share with you a little bit about the story and how it is already starting to help patients. Next slide will show you-- this is a complicated slide-- but it talks a little bit about how we go about gene discovery. What gene discovery means is we take the families of patients that have this predisposition, and try to look at how their genes are different from the families that do not have that problem. And in fact, we have been able to discover a group of genes that result in lesions where the blood vessel is very thin, ballooned, and vulnerable to leakage. This is in fact the disease that these families have. But the genes of those diseases are teaching us the mysteries of the weakening blood vessel and how it leaks. How do we go about that? We can take cells in the dish and inhibit those genes that cause the disease in those families. And then ask our self the question, how do those cells behave different in the dish. And in fact, we know in this particular disease that those cells will no longer form tubes, but instead will stay separated from each other. And we also learn, still in the dish, that we can alter this process. And we can restore the ability of these cells to form tubes by inhibiting certain signaling of the bad genes. So this sounds very complicated, but in fact it can be taken to living structures. At the beginning we have studied this in earthworms. And earthworms have only one blood vessel, which is also their esophagus. They only have one tube that serves for eating and for circulation. And sure enough, when we knock the genes that cause this familial disease in the worm, instead of forming a long tube, they form beads instead of a tube. And we are now able to test the therapies from the dish in the worm, and make the worm start to form a long tube again. And if that therapy works in the worm, the next step is to take it to the mouse, where we can also knock the same genes and look at there alteration. The beautiful thing about the mouse is that it is a mammal. A mammal, like the human being. All mammals share more than 90 percent of the same genes. So we and the mouse share 90 percent of the same genes, including all of the genes about the blood vessels. So what we can alter in the mouse, can be translated directly to patients. The next slide shows how we have taken the species to the mouse, and we have created the lesions in the tiny mouse brain you see on the left side. The whole mouse brain is only one centimeter. And yet within it, they have these lesions that are bleeding. And we can measure how much iron is leaking as a result of this bleeding. And if we feed the mice the right drug, we are now able to show in groups of mice that we are able to prevent the leak from that blood vessel abnormality. Our group, three years ago, reported the first evidence of a drug that prevents leakage of blood from weakened blood vessels in the mice. This has led us now to pursuing the same drug, potentially in patients, and it will probably come to clinical trials in the next five years. Next slide shows the work that we have to do in humans to prepare for these types of trials. We have to be able to develop techniques in patients where we can measure the vascular leak in the brain with the patient alive. Because we will not have their brain like in the mouse. So we have actually brought engineers together that are developing a technique to measure the leakage in the brain in the human patients. We have more than 100 patients with this disease, that come from all over the world to the University of Chicago, to get special imaging where we can tell them how much iron has leaked in their brain. And based on those numbers, that group of patients will form the core of the first clinical trials for this disease. Where we can measure the effect of the drug on the leak of iron in the human brain. We have also learned that this disease that happens, we call it familial CCM, or Cerebral Cavernous Malformation, not only will allow us to help patients with this problem, but it informs us about the much more common problem of leaky blood vessels as we age, and as we develop high blood pressure. In fact, the very same signaling aberrations and abnormalities we found in CCM disease, we are finding that they occur in the aging brain. So when we treat these very special families that come to Chicago with this rare disease, we are also opening the book on the opportunity to prevent the aging blood vessel from tiring and leaking. We do not want brain blood vessels to leak blood while the patient is alive. The next slide will tell you how our team uses this, and other types of innovations, for the benefit of every patient with a blood vessel problem that comes to our care. We actually will look at the problem from a multi-disciplinary perspective. And we have scientists weigh in on what kind of technology and opportunities we have, to deploy and leverage, to try to give the patient the best absolute solution for their problem. We believe that are common things that are treated very easily with common approaches. But we can do better, and there are many things for which medicine today does not have the answers. And we will need to inch our way very slowly, so that the care of neurovascular disease with take advantage of the wonderful knowledge available to us in modern biology. Thank you very much.