Good morning, everyone. Good morning. This, uh, this morning, I have the honor of introducing Doctor John Kerr. Doctor Kerr is an associate professor of pediatrics at the Harvard Medical School and he's a staff physician in the cardiac intensive care unit here at Boston Children's. His academic journey began with uh at the University of Virginia, where he did his undergraduate in medical school, and then he did his pediatrics residency and chief residency in Cincinnati. And then completed his uh multiple fellowships here in pediatric critical care and cardiac critical care, and he's been with us on faculty ever since. Doctor Care is internationally recognized for his really impressive groundbreaking translational research, uh, as, as well as device, uh, and medical technology development. His work focuses on a number of different areas within critical care, including the development of IV oxygen microparticles, novel method, novel methods for monitoring oxygen and tissue oxygenation in the, in the ICU setting. As well as uh the hydrogen FAST trial, which is using hydrogen gas for organ protection and cardiac arrest. His work has garnered a lot of attention and support from numerous funding agencies, including the NIH and the Department of Defense. Beyond his innovations in science, Doctor Kerr is a passionate mentor who's who has guided countless fellows. Uh, it occupies many pages of his CV, all the people that he's mentored, both fellow students and junior faculty, many of whom have now gone on to get their own funding and grow their own careers in academia. His, uh, dedication to both the science and training and his progressing clinical care is the reason that we've invited him here today to speak with us. So please, uh, uh, welcome, join me in welcoming Doctor Kerr as he shares his insights about his research for us today. Thanks very much, Brian. I appreciate that. I assure you I'm not internationally known. I don't think anybody knows me. Um, but, uh, it's really great to be here. This is particularly meaningful for me because, uh, many of the people in the room were here, uh, when my research career started, and, um, are very meaningful mentors and people that I look up to. Uh, so, it's a great pleasure to be here. Um, I don't have any, let me see if I can get PowerPoint to work. I don't have any important disclosures, but I'm grateful for, um, funding sources, um, as mentioned. OK. So today, we're gonna talk about two things, and I don't really like talking about two things in one talk, uh, but they're hopefully related in some way, and I'll try to be clear in how we delineate them. One of them is injectable oxygen, and one of them is inhaled hydrogen. So two different gasses. Um, I'll share a little bit of my path in translational medicine, and hopefully, we'll have some fun. So we're gonna hone in today on the workhorse of the cell, which in addition to being uh responsible for energy production, is also a primary determinant of the health of the cell, and determines when the cell is viable and when it's not viable. So, of course, it's central to organ injury, um, and tissue damage and death. And the primary way that it does that is through the um energy production, through oxygen consumption, and just to refresh everybody, oxygen's job here is actually quite simple but important. It's the terminal electron acceptor in the electron transport chain. So, when uh oxygen flux is insufficient to meet electron flux, which is oxygen demand, Um, oxygen becomes supercharged with these electrons, and then does direct damage to tissue membranes, lipids, DNA, etc. which is really the stimulus for all the cascades downstream for cell death. OK. So we're gonna first, oh sorry, so go back, going back, we're gonna focus on two therapies. One of them's job is to sort of restore oxygen flux when it is deficient, and the other one's job is to sort of cover up these supercharged um oxygen ions, uh, when they occur. So we'll talk about them. The first one's injectable oxygen. So, this is kind of a crazy idea, but I'm not the first crazy person in the world. Back in World War One, they actually, this is from The Lancet in 1916, they actually injected oxygen gas directly. They attached a flow meter to an IV and they had a little bubble chamber, so they did 10 mL per 10 mLs per minute, 600 mLs per hour. of oxygen into uh soldiers who were hypoxic, presumably from pneumonia. Uh, and they, you know, said one of them was asking for more. Um, we all know that that was not a therapy that took off, um, for reasons that are obvious, bubble coalescence, pulmonary embolism, etc. But it was described in the literature. This was an end of 3 published in The Lancet. So, you can't do that anymore. OK. So, we, um, trying to get my thing fixed up here. OK. So, we've taken a meandering path towards injectable oxygen. I'm going to try, I'm not gonna cover up our failures, but I'm going to breeze past them, although they're a distant memory, um, even though some of them took 3 to 5 years. Um, OK, so we went through, have gone through 3 generations. I'll step through them quickly to create a way to actually inject oxygen without, uh, doing damage. OK. So I started this project, um, in 2006. I was taking care of a patient of HB Kim's, uh, who experienced an ECPR episode from a pulmonary hemorrhage. And um I was a brand new fellow and was very bothered by the fact that we were in a very heavily resourced environment, uh, and had no way to essentially recover a patient who had refractory hypoxemia. And that even just that 10 to 15-minute period of cannulation, Doctor Liliha, I believe, cannulated this patient. Um, even though it was very expeditious, that that brief period of hypoxemia created such severe organ damage that the patient ended up dying from it. Uh, so I set out on this project. I knew nothing about research, and I'm glad that I didn't because ignorance is bliss. So, we first started out with lipid microbubbles, OK? So you can think of these as like soap bubbles that are very easy to make, just like in, you know, uh, when you're washing your hands, uh, in the, in the scrub, in the scrub room, you know, you can make bubbles just by agitating your hands with a surfactant. So that's what we did. We created a, a homogenizer. Actually, back then, we were using a sonicator um at the air fluid interface that created bubbles. We would then centrifuge them, concentrate them, and create a syringe like this, that was full of bubbles. The problem with that, although they were very easy to manufacture for a novice like me, um, is that The bubbles were bubbles, and so they would go away within, you know, hours, certainly of manufacture. So we would manufacture them kind of the night before, and we would inject them into an animal, and they actually worked kind of OK. Uh, before I show you the animal results, I'll show you this. This is my like iPhone 3, and this is just a beaker of desaturated human blood. I think back then I was still probably using my own blood. Um, which I no longer recommend, but basically this is to show you the kinetics. So look how quickly you inject oxygen into the blood, and it transfers almost instantaneously and creates beautiful, uh, red oxygenated blood. We then um injected these into a rabbit. So, another rookie mistake, highly do not recommend working with rabbits if you're doing uh large animal research. I don't even know why we have them in arch, but nonetheless, we, um, chose this as our first animal, I think probably because they were cheaper, um, than swine. So, um, the, uh, model here was basically to anesthetize the Rabbit and occlude the breathing tube, uh, in a paralyzed and anesthetized rabbit. And then immediately upon, um, clamping the tube, the onset of asphyxia, we would infuse at a constant low rate, this foam, this oxygen foam. And what we found is that we could, if we matched exactly the rate of hypoxemia and maintained pretty severe hypoxemia, that the animal was OK. Uh, but But as soon as the oxygen saturation went higher, like higher than 70% on the arterial side, then things went badly and the animal became hypotensive. And what was happening is that we were creating a very severe oxygen diffusion sink. So that when we were infusing the bubbles at this constant rate, they would, they would basically dissipate and oxygen would get taken up very quickly by severe hypo severely hypoxemic blood. But when that was not the case, um, when it was not titrated perfectly, the bubbles would coalesce and create a gas embolism. So while this was cute and got us a nice paper, um, etc. it was never going to be, um, a translational therapy. So, um, that's basically the paradox of bubbles. They're easy to make. They have a thin shell. They're nice gas carriers, but they're really not very good for creating a drug like this. So, um, we spent 2 or 3 years trying to stabilize the bubbles, doing different, uh, types of modifications. We tried to freeze and thaw them to make them store better, etc. before being smart enough to move on. This was a little bit of a bad memory. So then we shifted completely to the other direction. We said, OK, bubbles are like, they're too fickle. So, let's make a solid shell. So, we spent 2 or 3 years trying to figure out how to take a PLGA, which is basically a polymer. Um, you guys probably know them cause many implants are made of PLGA and We figured out a way to make them hollow core using an oil and water emulsion. Um, and this should have been obvious in retrospect to us, but, uh, we learned that even though we could do this, and we created an oxygen permeable particle, um, they delivered a very diminutive amount of gas because the shell needs to go away immediately upon injection, otherwise, you're gonna be very dose limited, which is in fact what we found. So, I'm not even gonna show you the rat study that we did. Um, it got into like a nice journal, but it was a very silly set of experiments. So then we decided on these key design features. Um, the particle, of course, needs to be manufacturable at scale, it needs to be stable on the shelf. Yes, bubbles were microbubbles were not that. Um, but critically, the shell needs to dissolve immediately upon injection, and the shell needs to revert into something that's pretty benign, so that it can be excreted, and we can inject hundreds of mLs of a gas. OK, so then, um, I was very fortunate to meet and have now as a co-leader of our lab, a very talented scientist named Yi Feng Ping. And in addition to being um brilliant, he's so humble that he's not even here this morning, but this is all his work. So, his idea was, OK, what we need is a trigger. So, the shell in, in storage needs to be a solid, but then once it's injected into the bloodstream, it needs to become fluid. So he came up with this in like a matter of a month. He said, OK, let's take a polymer and let's modify it so that it's PKA just to remind everybody, PKA is basically like the threshold. Above the PKA if you're more acidic than that, there's a there's a hydrogen, if there's not, there's an ion, right? So everybody sort of probably remembers that from chemistry. So he modified dextrian. Um, to have the proper PKA properties, so that when it is, um, being homogenized, so we do the same process, we're homogenizing, look over here, um, to the beaker on the left, we're homogenizing, we're creating bubbles, and it's surrounded by the shell, which is basically lots of nanoparticles that are, um, soluble in water. And then we add acid, and when we add the acid, they all become hydrogenated, and they stick together through hydrogen bonding. OK? So we now have a solid shell particle, which is in the, the solid green core there, that's stable on the shell for months and probably years. We're testing that now. And then when you inject it into the bloodstream, They, uh, the pH of the venous bloodstream, even if it's a pH of, you know, 5.5 or something terrible, um, causes the shell to revert back, uh, into its excretable components, and that basically makes the shell dissolve immediately. And this works amazingly. Uh, and the components, we had to modify them somewhat so that now that they're very rapidly excretable, um, primarily through renal excretion and a little bit through, um, hepatic excretion. OK, so this is what they look like under SEM. Uh, their size is very well controlled, in the less than 5 to 10 micron range, red blood cells are about 8 microns, so they circulate nicely, but they really don't need to, because by the time they get to the pulmonary artery, they're already in the nanometer size. So over to the right, you're seeing essentially what happens after they dissolve in water, and they're very, very small, they're in the nanometer size. So just to put a little bit of color on that, if I show you here, this is basically the, uh, this is the pH that is normal, neutral pH, and you can see once things get mixed, how quickly they dissolve. OK, so, and the same thing is true under a microscope. So we're talking in a in a matter of seconds, and that was really, really critical to the safety and efficacy of this drug. OK. So this is just showing things in another way. Um, this is an echo in a rat in which, uh, we infuse particles or bubbles of different types into the tail vein. So what you can see here on the upper right quadrant, um, facing you is that, um, the left ventricle is fully opacified here. So the bubbles are crossing the pulmonary vasculature and showing up in the left ventricle, which is great if you want a contrast agent for an adult with a posterior LV but not great if you want to inject a gas. So then what you're seeing here is that no matter whether the particles. are filled with oxygen or air, that they are not visible in the left ventricle, uh, meaning that they're all fully dissolved and the gas is fully absorbed by the time they get to the left ventricle. So then we created a dramatic model of asphyxia cardiac arrest. So, um, unlike the first model that I described, in which we had a constant infusion of a drug that began with the Onset of asphyxia, that's really clinically not that relevant. We now knew that we had a drug or we thought we had a drug that we could inject as a bolus drug in an emergency. And so we really wanted to test that. So we created a pig model that was very challenging, um, and I'm very proud of our institution for doing this, um, this model because it was technically very challenging. So, essentially, it was a, a swine model. They were around 10 to 12 kg, um, and we would, uh, anesthetize them and then occlude the endotracheal tube in the same way, creating severe hypoxemia. But instead of treating right at the onset, we said, OK, let's simulate a clinical environment in which there's upper airway obstruction, for example, and then severe hypoxemia, and then at minutes 68, and 10, let's just pre predefine the time. Of, uh, administration of the drug, we'll randomize to either placebo or injectable oxygen at those time points. And then we'll say like, you know, Doctor Shamberer showed up at 12 minutes and the airway was restored, and then see what the outcome of the animal was. So this is, you know, it's a model, but it had, you know, some clinical relevance to it. Then we survived the animals out in a An intensive care environment for up to 54 days. So, the, the experiments were done on a Tuesday, and then we would um do a brain MRI. We would package up the swine, um, bring them over to the clinical side, and do a brain MRI on a Friday night. I don't know what you were doing, but that's where I was, um, and then, uh, do some terminal histopathology. It's a terrible way to start a weekend. Um, OK. So, the groups were similar. We had 8 and 10 between, you know, the two groups, and their, all of their metrics were similar. That's important because we were unable to blind, um, we were a small team, and the, the drug actually has pretty dramatic effects. So it was obvious which group the, um, which group the treatment, the treatment group was. OK. So, the changes in arterial oxygenation were actually um not that impressive. They were small. Uh, so what you're gonna see here, and I'll zoom in on this for you, is that you're seeing hypoxemia. The saturation by 3 minutes is undetectable, extremely, extremely low. And then, following injection, now, you need to remember this is a blood gas that we're drawing from. arterial side, the oxygen that goes into the vein equilibrates with the lung. So, there's a large FRC that entire volume of distribution becomes oxygenated. There's no, there's not a filter on the alveolus. So, oxygen can diffuse from the PA into the alveolus just as easily as it can from the alveolus into the PA, which is annoying when you're trying to inject the arterial side. Uh, but it's a fact of life. So, what you can see here is that we were able to raise the arterial oxygen saturation into the teens. Um, and low 20s, which was fine, and actually was enough, because what happened was most of these animals, by the time we injected, um, and started to inject at 6 minutes were in cardiac arrest, and otherwise, they entered cardiac arrest by 9 minutes, 100% of them in the control group. And what we found was that when we would inject the drug, we would have started CPR because the animal is very hypoxic. When we would inject the drug, the circulation would be restored. And so, um, that was a probably a manifestation of delivering a small amount of substrate to the myocardium, to the endothelium, etc. to restore the native circulation. And even though the blood was very hypoxic, having your own native circulation, um, is of immense benefit. So, we then um unclamped the breathing tube and what you can see here is that only 3 out of the 8 or so, maybe 3 out of 10 in the control group were able to get their circulation back, and they all had their circulation back, actually, almost none, probably none of them were getting CPR at the end of the asphyxia period um in the experimental group. Um, OK. And then, basically, what we're showing here is that the drug significantly decreased the burden of cardiac arrest and decreased the number of epinephrine doses, and the differences in outcome were dramatic. So, um, swine neuro neurologic deficit score is a 500 point score where 500 is basically brain death, 0 is normal, walking and talking and normal cranial nerve exam, etc. And essentially, the groups could not have been more different. So, this is a selection by So, we did not really score the patient, the animals who died, uh, but even the ones who survived, um, were dramatically injured. They all had refractory status epilepticus. Um, none of them were able to successfully extubate, um, and they had severe brain injury by brain MRI. Um, and I'm not gonna show you the seizing pig, but over here is the, um, treated pig, which was just wonderful to see, um, this juxtaposition of outcomes, uh, when it had been sort of modeled after a patient that, um, I had cared for, who turned out a lot like the swine on the left. OK, so then we did brain MRIs. This is the median brain injury, and the 3 surviving swine was essentially the entire brain and brain stem, and in comparison, the group that we treated was much better off over on the right. Um, and that's kind of gross, but you can see the gross histopathology needs no explanation. Um, we also saw attenuation of kidney injury, um, in the treated group. Presumably this was related to ischemia. Um, and this was very, uh, reassuring to us because, you know, in the setting of giving a drug that is renally excreted, um, in a patient who is at risk for kidney injury, one might be very concerned about creating further kidney injury, but what this showed to, to me at least, was that, um, preventing or decreasing the burden of ischemia outweighed the, you know, the, the side effects, any side effects of the drug. Uh, we also looked at other, other, um, markers. Uh, we had previously in prior generations had seen problems with thrombocytopenia, and we are grateful that we didn't see any of that, um, in the treatment group. So, we concluded that in a clinically realistic model of hypoxemia, injectable oxygen decreases the time in cardiac arrest and leads to improvements in survival. OK. So where are we going from here? Uh, so now we're thankful for funding from HMS and also another grant from the NIH to work on, um, manufacturing. So we're now in, in the hard part of translational research. So, we published a nice paper, but now we need to create a drug. So, um, we are still manufacturing these in a biosafety cabinet, um, in our lab. Uh, and so we're gonna be, we are moving now to, um, a place called Landmark Bio, which is a great incubator that you guys probably know about because Childers invested some money into it. It's in Watertown. Um, and it's a beautiful facility. So we're gonna start off basically in this clean development room, uh, and we've developed a closed loop homogen like a closed loop manufacturing process. So, we're taking everything that we would do out in the open and putting it into a closed space. Um, so this is a continuous, you know, everything in here is enclosed and sterilizable in one continuous loop. Um, and we're going to, um, move to that space, and then once that's all validated and we do all of these, um, hard things like IQOQ and PQ, which are, um, basically qualifications of the manufacturing process, um, we will do, um, some. Other additional testing that's required and then get ready to submit um our data to the FDA. We're also gonna be working on uh establishing a packaging system. My favorite is the Bristajet from my days as a paramedic, but we may think about just prepackaging it into an injectable syringe. Um, etc. So, um, our goals here in, in the near term are to work on, uh, what's called GMP or good manufacturing Practice manufacturing. Um, CMC is chemistry, manufacturing and control. So those are all basically aspects of development that are required by the FDA, um, and for any good practice of injecting a drug. Uh, we will then apply for what's called an IND or an investigational new drug, um, and do our first in human trial. We will probably do that here at Boston Children's, um, in healthy adults. And then, we're still sort of figuring this out, but probably what we will do next is, um, do an efficacy trial, um, in healthy people because we wanna be able to do very good informed consent. Um, and We really are not, we're not gonna try to show long-term outcomes. Really, what we need to show is that we have reversed hypoxemia. So we'll probably just create iatrogenic hypoxemia in um healthy consenting adults and show that injectable oxygen reverses that, uh, and then we'll move on towards a new drug application and hopefully one day, there will be a drug that you can inject along with epinephrine that Instead of fixing blood pressure, or in addition to fixing blood pressure, fixes oxygen saturation. OK, so, I'm going to pause there, and we're gonna pivot now to talk about hydrogen. Uh, we can do questions at the end, I guess, but if anyone has a burning question, I'm, I guess we can pause. All right, I'll keep going. Um, OK. So now we're gonna talk about hydrogen gas. So this is not injectable, not yet, but I will confess that, um, the reason I started working in this space was that, um, usually investors were, would meet with us regularly and they would say, John, what are you gonna do about, you know, ischemia reperfusion injury and isn't oxygen bad for you and all that stuff. And it's true, and I was always frustrated that they were like misunderstanding the point that we're trying to decrease the area under the hypoxia time burden. Um, but they were right in some regards that, um, when the mitochondrion is dystoxic, that it uses hydro it uses oxygen in a pathologic way. So then I started investigating other gasses that could, um, you know, work, uh, against that, and, uh, did a very deep dive, uh, into, um, hydrogen gas, uh, and started researching with it. OK. So, uh, I'll tell you about the trial that we're doing now. So, what is hydrogen gas? It is a very abundant molecule. Um, it's how all the water in the universe is made by reacting with oxygen. Um, hydrogen, the, the name hydrogen, very cool, um, it's hydro and gen, meaning water generating. It's my favorite factoid about hydrogen. Um, and so the person who named the proton electron combination knew that it was present in water. Those guys were so smart back then, and gals. I don't know how they figured that out, but they did. OK, so, in the cell, Um, we talked about tissue dysoxia when there's tissue hypoxia, essentially, um, oxygen molecules become supercharged, um, and hyperreactive. And there was a brilliant paper that I'll reference in one second here that showed this mechanism, um, in nature medicine in 2007. It was a group in Japan who has really led this research effort. But essentially what they showed was that um administration of hydrogen to a cell line or to a mouse significantly attenuated the concentration of hydroxyl and other reactive oxygen species in the setting of ischemia. Essentially, like a sponge to all the bad humors that develop in a cell, um, when oxygen supply is deficient. Uh, so this is the paper that I read that really captured my attention. A picture or a figure is worth 1000 words or more. Um, so just a word to all the scientists and writers out there, make good figures. So this figure to the, your far right here is essentially a mouse model of a middle cerebral artery occlusion. So they would essentially go in, ligate, uh, functionally like the carotid artery, create ischemia, and then during the early reperfusion period, they would treat with hydrogen. So, the column to the right shows the hydrogen-reed brain, which has much less um infarct size in the same injury that was present on the left without hydrogen, and that was enough for me. So, they, um, they essentially showed, um, significant reduction. There are many, many papers like this, um, in both focal ischemic models like myocardial infarction, um, and stroke, and then other animal models like sepsis, transplant, people have done all sorts of things with hydrogen, mostly in, um, in the Asia, in Asia. So, we wanted to bring this here. So this was in the early 2010s, um, while we were meandering through the polymer phase of our oxygen development. I was getting bored waiting for the chemists to figure things out. So, I did a large animal model of hydrogen. So, we went back to the animal lab, we created a model of Warm ischemia. So I'm not gonna get into the details of why we did the model this way. I'm still trying to figure out exactly what I was going to do with hydrogen, and maybe we would use it in circulatory arrest on bypass. So that's actually how we created um this model. Um, one of the first things that we did that was really important, um, some areas of translational research are really not glamorous. This is one of them. So, all prior research with hydrogen had, um, well, take a step back. So, above 4% hydrogen is explosive and flammable, so we don't want that. Um, but you can mix hydrogen with other gasses below 4%. It's just hard to make. So, um, I had to make about 4000 phone calls to convince Praxair, and then eventually other gas companies to create this mixture, um, which is 2 or 2.5% hydrogen. With balance or the remainder of the gas being oxygen. So, this gas is non-flammable once it's made, but you have to pass through a dangerous zone while it's being manufactured. So, um, it takes a lot of regulation, um, around the manufacturer. The reason this was important to me is that On bypass and in any critically ill patient, we don't wanna mandate hypoxemia. So you don't really wanna say, oh, you can only use 30 or 40% oxygen, which is what most of the other trials have done because they mix hydrogen with nitrogen. So you could only give 50%, you know, 4% hydrogen with 96% nitrogen. If you wire that in to, you know, a 50/50 mixture with 100%, then you're only giving 50% um oxygen and 2% hydrogen. So this mixture was very important for us to be able to make, because then we can say, OK, you can put the FIO2 at whatever you want, you can just bleed this directly into the ventilator or anesthesia machine, and you, the anesthesia person, uh, anesthesiologist won't even notice that if you put the animal on 100% or the person on 100%, and they're getting 98% oxygen. So it essentially made the administration of this gas, um, much more feasible. So that was really the most important thing that we showed in the study. OK. So then we created this model of uh warm ischemia, so it was circulatory arrest at 25 degrees for 75 minutes. For those who don't know, deep hypothermic circulatory arrest, which is Protective. Protective is a hardcore in quotes, um, is 18 degrees. So 25 degrees is not very protective, it's sort of called warm circulatory arrest. Um, and so we created this global warm ischemia, and then we would administer hydrogen at the end of the ischemia, and then throughout, um, the next 24 hours, and then we would again survive for a 3-day, uh, period. Same thing as before that you're now used to. A high score on the swine neurologic deficit score is bad. So we showed that um swine experiencing circulatory arrest like this had a lot of injury. Again, they had seizures, etc. Um, and the hydrogen was protective. Those Animals had better neurologic outcomes. Um, we showed less brain injury by MRI, uh, and we also showed a lower serum creatinine in the hydrogen-treated group. So we were encouraged by this. Uh, GFAP is basically like a troponin for the brain, which was also improved, um, with hydrogen. OK. So then I, um, this was in 2019, uh, decided to interface with the FDA for the first time, which was actually wonderful. Um, they were very receptive to the study. I said, basically, what I'd like to do, is I'd like to treat healthy adults who are signing informed consent with 2% hydrogen, um, at Boston Children's Hospital. And basically, that was fine. That was, that part was easy. So, um, we brought in patients. This was terrifying the first time that I did it because doing anything to a healthy person is very scary. I, I've never heard someone say that before, but it's really true. Kinda gave me a little bit of a feeling about how surgeons feel every day, but at least you're treating a disease. It's like, even harder when you're doing something that you're, you know, is research. Um, so anyways, um, it all went well, thankfully. Uh, and we found nothing. We found that hydrogen is completely benign. Um, there were no changes in vital signs. There were no complaints. The people weren't dizzy or having neuropsychiatric symptoms. There was no change in their spirometry, EKG, or any of their labs. Um, we were a little bit worried about coagulation. I don't know why because that's never been reported, but it didn't do anything with coagulation. So, then, um, I was a little further down the pathway, but this trial came out called the Hybrid 2 trial, which was again out of Japan, uh, 15 different centers. This never actually got federally funded, um, in Japan. So, this was a 15-center randomized control trial on the backs of some very, very dedicated colleagues. Um, who are just wonderful people, uh, who really believe in hydrogen. So they, uh, they took survivors, adult survivors of out of hospital cardiac arrest, um, who achieved return of spontaneous circulation but were in a coma, randomized them to treatment with or without hydrogen. Um, and, uh, they were able to enroll 39 patients in the hydrogen group and I think 32 or 33 in the control group. They described no adverse events related to hydrogen. And this, these were both secondary outcomes, but they did show an improvement in um survival, 90-day survival in the hydrogen-treated group, and a leftward shift in the modified rank and score. So, for those who don't remember, modified rank and score is basically a score of activities of daily living. Uh, 0 is great, a 6 is really bad. And so you can see here that hydrogen shifted a few patients from a 6 to a 0. So, that was encouraging. OK. So, all of this is being planned. I was sort of baking into uh the plan to try to translate hydrogen from healthy adults to really sick children. And the choice of population to use was a challenging one. And my logic was basically, if we're going to try to translate hydrogen to the clinical side and get a label from the FDA then we need to have some sort of injury signal. Uh, first of all, we don't really use circulatory arrest very much, and when we do, their outcomes essentially become normal. We know this from the Boston Circrest Study. Their outcomes. Basically normalized by 6 years of age. And so, you know, you could do a therapy and sure, maybe they're like, have a better Bailey score at 1 year, but like, who really cares? Um, I thought that that was like a, that was not a great goal for a for a treatment, um, effect. Um, and so, we instead chose to use um the ECPR population, and I think I left the slide out. But Basically, um, ECPR in the cardiac population, um, has very challenging outcomes. About 50% of patients die. It is a severe, dramatic, clear ischemic event, meaning the cardiac arrest, followed by a very clear reperfusion event, meaning, you know, starting ECMO. So that seemed like a good, um, good population for us to study. Uh, this was challenging for the FDA, um, um, in many respects, uh, they have a very strange way of regulating ECMO. Um, but at any rate, they view ECMO and bypass as exactly the same thing. So, their first question was, you can't treat patients on ECMO for longer than 6 hours. And so that was kind of weird. So I had to explain to them that that happens all the time. Uh, and then, uh, so they wanted us to do, OK, so you're gonna expose these membranes to hydrogen. What does the hydrogen do to the membrane? Which was a little bit funny because these are like polymers and hydrogens and inert gas. And so, Yi Feng and I had a good laugh about that. And then We did this experiment, um, in which we exposed, um, eCO membranes to hydrogen for 6 days and showed that everything was benign. That's what the inside of an eCO membrane looks like. Very cool. So, like, there's these fibers, and that's basically the transmembrane, uh, gradient. So the gas goes inside here, and if you do a cross section of that, that's what the membrane itself looks like. I thought that was cool. Then we also looked at um the ventilator to make sure that 2% hydrogen did not negatively affect the spirometry and the way that gas flows through it, and sent all of this to the FDA as part of the package, and they said, OK, that's fine, you can do this clinical trial, which was a great day. Um, OK. So, what are we doing? The Hydrogen FAST trial, this is an IND investigation new drug trial that is taking place at Boston Children's and soon to be 2 or 3 other sites. Um, we've enrolled 4 patients, so I'll tell you a little bit about that. So, uh, the trial design is cardiac arrest in the cardiac ICU. There's a decision made to cannulate, so there's ischemia happening right now. And we want to enroll patients right at that moment. So, we're gonna ask a question, what happens with informed consent? So we're gonna talk about that. Um, the process for enrolling patients in an emergency, there is a sanctioned way to do that called EFIC, which is exemption from informed consent. And I have a couple of slides about it, cause I assume that some of you will be curious, but just Put that on pause for one second in your mind. Um, we're using a process, um, by which there's essentially an opt-out program. So, people hear about the study, there's a website, there's flyers around, and if they say, oh, I don't wanna be part of that, then they send an email or a phone call or whatever, and we put them on an opt-out list, OK? And so there's an opt-out, there's a do not enroll. List. So, any patient who's admitted, who meets exclusion criteria, which is very rare, cause there's basically no exclusion criteria except if you're pregnant or you're a prisoner, or you had a prior ECPR episode. So all of those are very rare, as are the opt-outs. So, we have a list, and if the patient is not on the list, then they are going to be enrolled in the trial at the time of cardiac arrest. Um, and then patients are randomized, so I'll show you how that's done, manual, no fancy computers, and then we start treatment. And the goal is to start treatment within 2 hours of the onset of ischemia. This is really important. Um, and it's really the entire point of the EFIC mechanism of enrolling patients is that you can get a treatment or test a treatment in a population with very little latency in treatment time. So, treatments are started, then we talk to the family. If they object to participation, then we can remove the treatment from them, etc. Um, and then we look at adverse events for 30 days, and then we look at functional status score at 6 months. So here's the path to EFIC, just to sort of level set everybody. I'm gonna tell you just a little bit about the Process since it's a little different from the usual. So, the first thing is that the, there's a community consultation. And so, that means we talk to faculty, we talk to staff, and we talk to family members. In this case, we talked to family members of patients who have um congenital heart disease, including a couple of patients, actually. Um, and told them about the trial, we told them about cardiac arrest, told them about ischemia, told them about hydrogen, uh, and they were very receptive. They basically all said, don't do informed consent, don't talk to me about the trial beforehand. When my child's getting CPR, I don't wanna talk to you about a trial, just do the trial. Um, which is what we sort of thought, um, and this is This was very reassuring to hear. So, we do these community consultations, we report back, um, all of these, uh, uh, you know, comments to the IRB. They weigh all of these things and they say yay or nay. And then, um, there's a process of public disclosure, which basically means we talk about the trial, um, in public. So there's a, like I said, there's a website, there's a video, um, on the website. There's signage throughout the hospital, etc. And then, once a period of time passes, then we begin enrollment. And um if there's an eligible patient, I'll show you the sort of the process by which we um can uh check the opt-out list, etc. Uh, and then there's an opportunity, like I said, for patients to object to ongoing, um, enrollment after they're enrolled. OK, so these, these were some of the outcomes, um, of our community consultations. So we talked to 28 patients and families, um, and, you know, most of them had had either surgery or cath. Some of them had experience with developmental delay, um, and clinical trials. And then the staff, we did an extensive community consultation with, including all the people you see there. Um, the staff, uh, so these are basically the percent of respondents who responded favorably or in green. Um, and we, our target was 80%. And the one that's, there that's in red is, could you check the orders for an opt-out. So we went through several different iterations for how to identify patients who did not want to participate. And we finally ended up on the simplest is always the best, a list that you could check, and then a bracelet around the patient's wrist that said, don't give me hydrogen. Um, and so we had other things like, can you check the orders and critical contingencies and stuff like that. The families, like I said, were basically universally in favor of the trial. So here's the website. We have a little flyer in all the bed spaces in the heart center. Um, the flyer is here. I'm not gonna go through it, but basically, it talks about, it was a, it was a balance. We had to balance talking about ECPR and cardiac arrest with, you know, people don't really wanna hear about that, but we wanna inform them about the trial. So, um, this took some back and forth to get this right. Um, here's the bracelet and the stickers on the nameplate. All right, so this is what it looks like in action. So, the hydrogen tanks, this is, uh, uh, basically a rapid response cart. So this has hydrogen and air, this has hydrogen and oxygen. On the back of the cart here is a manifold. So the manifold is basically, you can attach the ventilator, you can attach the sweep gas for the eCO membrane, um, down here, we have CO2 for the spectrum membrane. Um, and, uh, it works very well. It's been fun. Here's the do not enroll list. There are the, um, randomization envelopes. And then basically, this is the first patient that we enrolled um in the back, uh, this on the left of the simulation, but the patient um on the right here, this is the first one. So we have a backup set of tanks, um, so that if when one of the, when the, one of them runs out, the backup just takes over automatically. It makes it a lot easier. So our endpoints are really related to feasibility and safety. Um, we're looking at the fraction of the 1st 72 hours that we can administer this treatment. Um, and then we're looking at a safety endpoint that's really a composite endpoint that I won't really get into, but a lot of bad things happen on ECMO, and so we had to design, um, an endpoint that accounted for that. Basically, things that were out of, out of pocket for the clinical situation, um, is that endpoint. Uh, and then we're looking at lots of efficacy endpoints secondarily. So, participation to date, there have been two families that have, um, enrolled in the opt-out program, um, that's since March, so that's a long time, uh, which made me happy because it means people are reading about it and thinking about it. Um, 4 patients have been enrolled to date, all within 2 hours. I'm very proud of that cause that's not that easy to do in an ECPR situation. Uh, no families have opted out following enrollment. Um, I, yesterday got a thank you card from one of them, which is really cool. Um, and all patients have treated 72 hours of hydrogen treatment. And I'm not supposed to talk about this, but none of the patients that we've treated so far have had evidence of brain injury by, um, any imaging, which is exciting, but it's very early. Um, OK. So, now we're working on some other trials. Um, now that we've done some of the hard stuff of interfacing with the FDA and getting through a lot of the CMC work, we're going to try to launch a birth asphyxia trial, um, with Brian Kalish here at a A bunch of birthing centers, um, are in the greater Boston area. We're, um, launching an out of hospital cardiac arrest trial in adults, um, um, out of a center, a great center in Pittsburgh. Uh, and then we're going to try to get an adult stroke trial off the ground as well. Um, and if anybody here is interested in A clinical trial of, I don't know, I figured HB would come up and say, why don't we give this to liver transplants. But we can certainly talk about using hydrogen for other ischemic um injuries. Anyways, um, it's an amazing team. This is an incredible institution that we work at. Um, I wanna give a special credit and shout out, not only to Yi Feng and um all of my lab mates and colleagues, the hydrogen clinical trial team down here, but also to, um, some of the institutional leads. Susan Kornetsky leads an incredible IRB and I wanna really state how important that is to be able to do hard research like this at an institution like this. She's really one of the defining people, um, of our institution, I believe. Um, our Aya Cook is great, um, as well as the Translational Research Program has been very encouraging in some of the dark days. So, if anybody wants to talk about any of these things, I'm happy to, but, um, it's a real honor to be here with you today. Take any questions. Mhm Well, just incredible, um. You know, this epitomizes the concept of translational research and what can be done in a place like this with persistence by somebody like yourself. I've had the great sort of joy of watching your story and sometimes in the parking lot or on the bridge to hear little updates and excited to hear the details and see, and, and see the actual data. But you're one of Actually a growing number of um people who at this institution can take an idea. That at the beginning. Of their quest already know the answer to the so what question, right? So in discovery science. People are studying Phenomena. For the joy and for understanding, knowing that it may in a lifetime or in the future make a difference. Translational research. Starts with uh If I can do this, then the impact will be to, to people. But you described your path so beautifully, and yeah, we had this great idea, and then we realized like, like, you have to be able to come to the point. Yeah, where you say, OK, great idea, not gonna work. What's next, right, recognizing the investors are asking a question like, yeah, but isn't that gonna be a problem? Yeah, OK, they have a point. They might not understand the whole thing when they have a point, right? And you epitomize in your description, um, uh, a, a, a very famous folkmanism. There's a fine line between persistence and obstinence, right? In order to get to the, you're treating human beings with your concept because you persisted, but you weren't obstinate, uh, and, and, uh, um, just kudos for overcoming all these barriers and not being afraid to take advantage of the other brilliant people around. Here and elsewhere giving them credit, taking advantage of the resources, the large animal facilities, the IRB, and like it wasn't always so easy to do the kind of things that you described. Getting these kind of trials to the FDA through IRB used to be almost just so discouraging that people would give up. Um, we've had people in this room who have struggled with, uh, good manufacture, just DMP, it's just impossible. Boston Children's isn't there, right? Being able to translate to investors, companies, right? You are, um, partly the beneficiary of predecessors who fought that battle, but also driving it forward, and, and I think we all understand enough of the physiology and see these patients to understand the potential benefit in the. In your career, uh, could become routine reality, um, so, um, I, I'm sure there's lots of, um, excitement and, and questions, and, um, I don't know if we're gonna do this for, for livers. Thanks, Steve. John, it's amazing, uh, work, really, congratulations. Um, uh, I'm curious about the IV oxygen delivery, almost just like in terms of logistics. Um, how, how is it maintained? Is it kept under pressure? Is it gonna be on the code cart just as a shelf stable thing? How do you envision that happening? Maybe it's not clear yet. No, um, that is, that should be pretty clear. So, um, plastic is gas permeable. Um, to, to slow leaching, but it's gas permeable, so it probably will need to be a glass container. Um, and it could need to be vacuum sealed. Uh, but yes, that I envision it, uh, on a code cart, um, as a drug, uh, an injectable drug, basically for hypoxia in the same way that we would treat, um, hypotension with epinephrine. Yeah. Thank you. That's, um, it's all mind-blowing. Uh, and, you know, as, as you do too, we all like in the ICU we're dealing with patients who are hypoxic for, for days and we're on 100% FIO2 and barrel trauma and um I'm sure you've thought about this already, but like, do you foresee a day where either of these therapies could be used sort of as maintenance or as a way to bring down the ventt settings, bring down the FIO2, you know, as a maintenance thing in your hypoxic patient who's not coding from, from like a scientific standpoint, do you think it's possible with these? Yeah, it's a great question. I definitely think that hydrogen can be, um, if it's effective, um, in doing what we think it will do, I definitely think it could be used for long-term treatment. Um, and I could easily foresee, you know, a device to make it a lot more easy to administer, etc. There are a lot of easy ways to make and administer hydrogen. Um, I think the oxygen question, the volume of administration, the final product only contains about 60 volume to 70 volume%, otherwise, it becomes very viscous. Um, and so I don't think that that will be like a long-term replacement for a ventilator. Um, and so, I don't think ACMO is going anywhere for those patients, um, but it's possible that one day, uh, we got a grant that never really went anywhere to try to nano-spray the gas directly into the bloodstream, like, basically make the tiny bubbles. Maybe there's a way to do that, um, but that's, it was a little bit of a distraction at that point, and so I, I sort of stopped working on it. But I could see somebody creating maybe like a needle that goes in, that's spraying oxygen at just the right rate. But what's nice about what we've done is that you can bolus it. And I think that's a really important clinical um factor that sort of what Steve was talking about, these are things that an engineer in a room would not focus on, you know, cause they don't understand the clinical realities. But for us, I know, I know what the ICU is like, I know what the pressure on the syringe is gonna be like, and, you know, the drug needs to be able to withstand that. So John, this is incredibly intriguing, uh, work, uh, perhaps a bit of a naive question, but, but trying to understand sort of a, uh, with the injectable oxygen, a dose response curve, or how much can you give and when do you get in trouble and too much oxygen, obviously a bad thing. Yeah, it's a really good question. I think we have the benefit of pulse oximetry. Which is, which is great, and also sort of the, um, the FRC of the lungs. So I, I think it's gonna be very hard to make a patient hyperoxic with this, with this drug. Um, I think the best we will be able to do is maintain normoxia or a non-lethal degree of hypoxia. Um, I, but it, it is, I tried to find a video last night actually, cause it's very cool. Essentially, you, when you inject in an animal, you see the pulse oximeter go from, like, 0 to 100, like that, like in one heartbeat. And then, you know, it sort of decrements down slowly, as, so basically, what happens is that the lung backfills with oxygen, and then normal oxygenation occurs uh over a period of time. So, um, it creates basically like a reservoir. Um, and so, yeah, the dose responses. Essentially one of a bowl, if you just give an injection, it goes up and then it decrements over, it depends on what your VO2 is. So if you're not consuming oxygen, then it will stay up. If you are consuming oxygen, it kind of comes down in um proportion to your oxygen consumption rate of oxygen consumption. Uh, I want to say excellent work. I remember when you first started doing this and came into my office and with this idea because you were discouraged and you showed the rabid a rest and completely recovered when you injected the, the bubbles that that was earlier on. I just want to say I'm proud of you for Doing so well and moving this forward against all those obstacles. People are asking me if you're brilliant or crazy, and I said, probably both. So congratulations. Yeah. Thank you. I'll take that. I'll take that any day. We're all a little bit crazy. Hey, fantastic, amazing, John. Um, quick question, some of the people who code, particularly as you're thinking about what other avenues outside the hospital setting can this be applied to, don't have an IV and Can this be like the injectable oxygen? Can this be like intramuscular? Can it be intraosseous, like, particularly for that sort of pre-hospital arrest situation? Yeah, we did a little bit of work early on with IO and I think it will work well. Um, it's something that we'll probably work on after we do manufacturing, that'll be an easy add-on experiment, but I suspect that IO will work. I am probably a little bit more challenging. We've published a couple of papers about injecting it into tumors. Which works very well. Actually, it'll probably be a really nice uh ancillary treatment for solid tumors, but I don't know if IM administration will work. Thanks. Sure. Well, we're, we're at time. Um, I think it should be obvious to you from the response, and I'm sure you get this in all forms that you talk enthusiasm, um, uh, and appreciation for your work and your persistence and your, and your. Your brilliance and craziness, um, and, uh, I, I'm, I'm sure you'll have people here, uh, with creative minds who will come to you, and I know that you're open to, uh, help them develop their thoughts, potentially have collaborative ideas, but even if they have ideas that are completely unrelated to your work that you actually have no expertise in, um, I would encourage people. To reach out to John about his experience, about his path, about trying to do something, an idea that you have, and like, how do I get through that pathway to if I see the, so what at the end of my question, but I see all these barriers, and like, really? You can do a trial on people without getting consent, right? We can't get people like in the operating room for a hernia, uh if, you know, somebody thinks that you haven't signed on the right line at the right time. And, and here we're doing experimental phase one trials on, on people without consent. It's astounding what's possible if you can find a way you sort of get over those actual and and and mental and emotional barriers. So um I think what you're seeing here is is is a mentor for when you have those ideas about how to do that, and I, and I'm. I trust that you would be receptive and enthusiastic to help in that regard, of course. Thank you so much. I think it is important to say, like, it's not all sunshine and roses. There have been like so many dark days, uh, in the process of research. People, like, no, it's not always congratulations. There's a lot of people who, uh, for various reasons, oppose progress like this, and you know this as a chairman and probably anybody who's lived older, more than 30 years knows this, but Um, it's hard. Life is hard and, and innovating is hard, and translational research, when you're trying to drive towards a specific goal is also very hard. So, I would love to commiserate, talk, uh, to anybody. Um, uh, this is a great place to be, so. Hear, hear. Thank, thank you so much. Congratulations.
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