 Hi, everyone. My name is Dr. Daniel Beard and I'm a lecturer in physiology and a stroke researcher at the University of Newcastle. It's my great pleasure to be here today to give you an update on the latest treatments in stroke for brain awareness week. So first of all, what is stroke? So stroke occurs when there's a disruption of blood supply to the brain, resulting in neurological, neuro neural cell death and neurological dysfunction and even death in some patients. And it can be caused by two main things. So a blockage due to a clot, reducing downstream blood supply to areas of the brain, resulting in brain cell death. And this is known as an ischemic stroke. And this occurs in about 85% of stroke patients. The other type of stroke is known as a hemorrhagic stroke, which results from a rupture of a blood vessel in the brain, causing blood to leak out into the brain tissue and cause it damage and also reducing blood supply to downstream brain tissue, resulting in its subsequent damage and death. So the most common type of stroke is ischemic stroke. So this treatment update that I'm going to provide to you is to do with the treatment of ischemic stroke. So stroke is bad news. So it occurs in approximately 20 million people per year and causes about 5 million deaths per year worldwide. And it's the third leading cause of death in Australia was causing killing more men than prostate cancer and more women than breast cancer. Stroke leaves a lot of survivors disabled. So it's the leading cause of adult disability worldwide and leaves over 65% of stroke survivors with a disability. And a stroke will occur in one in six people alive today. So what's the current state of play in treatments for ischemic stroke? So currently, clot busting with the drug called Alta Plays is approved since 1995. And you can think of this as a sort of molecular pac-man that you inject into the blood and it goes and chops up the clot and restores blood supply to the brain. However, there's been a revolution in how we treat stroke in that there's a mechanical way of doing it called clot retrieval where you can think of this as almost like a skill test at an arcade where the surgeon goes in through the groin, puts a device called a stentriever up to the brain and pulls the clot out physically and restores blood supply to the brain. So both these treatments are approved. One, Alta Plays is approved as soon as possible or no later than four and a half hours. And the mechanical thrombectomy is as soon as possible or no later than six hours in most patients, but sometimes up to 24 hours in those patients that have lots of brain left to save that late. But as you can see from these treatments, they're very time sensitive. And this is you might have heard of the saying time is brain. That means that every minute that passes in a stroke, two million brain cells are dying. So getting to the hospital and getting these treatments as soon as possible is critical. So why is this? Because thrombolysis are one of the most effective treatments in all of medicine. However, they are more effective when administered early. And that's because there's usually more brain left to save. And as I mentioned, they're approved within four and a half hours or six hours on average for thrombectomy. But sometimes these time constraints may limit the access that some patients have to them. They may not arrive at hospital in time. And this is particularly relevant to patients that live in rural or remote areas where they need to travel long distances to get the hospital to receive these therapies such as thrombectomy. And this means that only about two to five percent of patients ultimately receive these therapies. So a lot of people miss out. So one such area of research and active research in the stroke field is how can we buy the patients more time? How can we slow down how fast the brain dies while the stroke is happening so that patients can get to hospital and receive these therapies to open the vessels back up and have a good outcome? So this is my area of research in that if we look at what happens during a stroke, there's a ischemic stroke here with a blockage of the middle cerebral artery. And downstream from that blockage, you get this area of blood flow deficit or drop in blood flow that's quite severe, results in rapid cell death. And this part of the brain tissue is beyond saving with therapy. However, further downstream from that blockage, you get this more gradual and smaller reduction in blood flow. And this keeps the brain tissue at risk, but it's still alive. So it's at risk of dying, but it's not dead yet. And this is known as the ischemic penumbra. And the reason that the ischemic penumbra exists is because there's this bypass blood flow network known as collateral blood flow that can redirect blood flow around the clot and keep the brain alive for a set amount of time. And so one way to try and slow down the rate of brain cell death is to try and boost the blood supply through this collateral network while the patient might be being transported to hospital. And this is because we've known from over 20 years of imaging studies that if you have, if a patient has good collateral, they have more of this penumbra available to save. They have better responses and better rates to these clot busting or clot retrieval therapies and ultimately have a better outcome. So if we can boost the blood flow through these vessels, we can keep the brain alive longer and transport patients and ultimately get patients to the hospital with brain left to save and have a positive response to the reperfusion or clot busting or clot retrieval therapies. So I was very fortunate to just attend and speak at the International Stroke Conference held in Dallas, which is the world premier meeting for clinicians and stroke scientists to share their latest groundbreaking research and clinical trials. And I was invited to give a talk and give an overview of the different therapies that were available to enhance collateral blood flow in a scheming stroke. And one such therapy that I spoke about is known as PP007. And this is a modified hemoglobin molecule that can relax and open up collateral vessels, but also an increased oxygen delivery to the ischemic or dying brain. And this had been previously shown to increase collateral blood flow and deliver more oxygen to the brain in preclinical models of stroke. But what was really exciting is at the International Stroke Conference, the clinicians and scientists from the USA just shared their latest results from a phase one says the earliest phase studies looking at the safety of a therapy in actual patients at first in human. And they found that in a small number of patients giving this potential collateral enhancing drug was safe and that it's now planned to progress to a larger phase two study where they can look for further safety signals and then start to look for signals of the effectiveness of boosting or enhancing collateral blood supply which may then lead to its testing in a phase three study that may lead to improvements in collateral perfusion in stroke patients. So let's just say in an ideal world we've boosted our collateral blood flow and the patients made it to hospital and they're going to receive the thrombolysis or thrombectomy therapies. There's some recent developments in our understanding of how these clot busting and clot retrieval therapies work. Although they're highly effective, there's evidence that they could be more effective and if we apply what we know about the science and mechanisms of opening up vessels and improving brain survival. So once again at the International Stroke Conference, there's some really interesting work being presented on thrombolysis or clot busting with the drug Alta Plays. So Alta Plays works by, as I mentioned, like a molecular pacman, it goes in and targets clots and it targets a part of the clot known as fibrin which was thought to be, which we can see in this picture of sort of tying up the center of the clot shown on the left here. It's tying up the red blood cells in it holding the clot together and if we give Alta Plays that will come and chop that up and the clot will fall apart. But what's been shown is that Alta Plays only works in about 50% of clots. Some clots are very resistant to Alta Plays treatment and what these scientists at the International Stroke Conference show is that there's evidence that there's more components to a clot. There's this outer fibro shell that also holds the clot together and this is made up of a thing called a protein known as von Willebrand Factor as well as these immune cells called neutrophils that get trapped in it and release DNA that actually holds the clot together. And so what they're investigating is, well, maybe we need to combine Alta Plays, the original clot busting therapy with some novel drugs that are going to not only chop up fibrin but also chop up this von Willebrand Factor or this DNA from immune cells. And so clinicians and scientists from the USA reported that there's this novel therapy that can break down von Willebrand Factor that had been shown in vitro, so in clots in a dish that could increase the effectiveness of Alta Plays and you can combine that with it to break down clots. And that this was safe in phase one studies and is also now ready to progress to clinical studies and potentially enhance the effectiveness of Alta Plays and opening up the vessel and fasting clots in more patients. So what about the areas of development in thrombectomy? So thrombectomy is revolutionised how we treat stroke and it shows it's highly effective in opening up the blocked artery. So 60 to 90 percent of clots are being removed. However, there's still a bit of a discord, a bit of lag between the number of vessels that are being opened and the number of patients that can look after themselves after treatment, so they're disability free. There's a number of theories behind this, but one such theory is that there is some brain damage that can also happen after the vessel's open, so-called reperfusion injury. And activation of the immune system, the body's defence system is thought to play a role in this. So during a stroke as shown in this figure here, the brain cells send out these help me molecules called damps. And these damps will activate a receptor known as TLR4, which is basically a message receiver on the immune cells to say, there's damage in the brain, we need to go and help clean it up. But what happens in stroke sometimes is that the immune system can become too active and it goes in and tries to clean up the damage, but you get this immune cell-friendly fire basically where immune cells come in and clean up the damage tissue but also cause collateral damage to otherwise healthy tissue that can continue the brain being damaged even after the vessel's been opened up. So what was really exciting from the International Stroke Conference was that these clinicians and scientists from Barcelona reported these exciting results in a early phase study, so phase 1B2A, so a study that looked at the safety but then also started to look at is there mechanisms of efficacy or effectiveness of the therapy in a small number of patients and what they found is if you give this drug called Aptol, which blocks the message receiver, the TLR4, on the immune cells, you can dampen down the immune response and when it's given with thrombectomy, so opening the vessel back up, it significantly reduced the amount of death and disability in this small number of stroke patients if when the drug is given with the thrombectomy, so opening the vessel back up again. So this is really exciting but it's only a phase 2 study, so it's a small number of patients, so it's exciting but it now needs to progress into a large phase 3 study that will then determine the ultimate effectiveness of this therapy in a large number of patients across multiple stroke trial sites around the world to see whether it actually does work but it's very exciting times in the stroke field and what we know now is we have these two very well established and approved therapies in thrombolysis and thrombectomy but our understanding of stroke pathophysiology, how it works, we can then now leverage and have these additional therapies, these adjunctive therapies to clot-busting or clot-lysis, clot-lysis or thrombectomy, so clot removal, to increase the number of patients that are going to benefit ultimately from these therapies and having more patients achieve a favourable outcome. And we look forward to seeing how these progress into the future and hopefully in future stroke updates, future brain awareness weeks, we can update you on how these therapies are progressing. So thank you so much and I hope you enjoy the talk.