Clinical Trials & Senolytics Q&A | Dr. James Kirkland, Mayo Clinic
7:15AM Apr 1, 2021
Speakers:
Allison Duettmann
Joe
Creon
Karl
James
Jim
Keywords:
senescence
trial
cells
senescent cells
senescence cells
drugs
people
question
aging
analytics
senescent
animal models
cancers
agents
conditions
target
subjects
decreased
early
accumulation
welcome everyone to foresight biotech and health extension strategy group sponsored by 100 plus capital i will post in this chat three links one is to all videos and summaries of our previous meetings bullock has written fantastic summaries for other people to to read up for those who can't join us here then the second thing i'm going to share is an application to our accelerator we had last at our last meeting original about on brain cell replacement so if you're interested in the accelerator please take a look at that meeting at that keynote program and reach out to me if you have any questions and then lastly i'll share our calibration spreadsheet and so this is just a reminder for yourself in in the map member registry i do get a lot of folks always telling me how they actually do find people via that spreadsheet so i think it's quite useful okay great so today we're going to be discussing clinical trials and analytics with dr kirkland from the mayo clinic and i'm really really happy he's joining us again at the previous meeting that we had last year where we had our first q&a with him and the video got a comment there where someone called you the most intelligent man he's ever seen so no pressure for this for this video and for this meeting thank you so much for having joined us back then it was a really really fantastic talk i tentatively named the session clinical trials and selling senators q&a just because those are the two topics that unsurprisingly people thought were most engaging at our previous meeting but feel free to discuss anything you'd like and likewise for everyone else and as we started to collect questions feel free to collect questions on other things that you may find inspiring from dr kirklands very extensive bio which i'm going to share here in the chat and yeah i mean you've not only really published your lab hasn't only really published like one of the first papers on analytics but really since then you've paved the way and and in terms of overcoming regulatory hurdles for a variety of different interventions so thank you so much for joining us again i know the group really really appreciates your advice and without further ado i think i'll just let you present for i think about 30 minutes in the meantime we'll be collecting questions and then we'll start into a q&a so i'll be in the chat in case anyone has questions and for my end again just thank you so so much for joining us and it's much appreciated by the group all right
well thank you very much for the kind introduction and we're just groping our way along and this what i'm talking about is the work of a lot of people it's not just me and i'm not particularly smart i just happen to be in have an office with a lot of smart people around me so i'll try to share my screen i did talk fairly recently on this program so i'm just going to try to briefly recap what we discussed before and then hopefully give a few updates so we'll talk again about analytic agents and as we discussed last time and i think as many of your other speakers have pointed out aging chronologic age is by far the largest predictor for most of the chronic diseases that account for the bulk of morbidity mortality and health expenditures and is also related in advanced chronological ages to the geriatric syndromes that things like frailty and age related muscle impairment and mild cognitive impairment as well as phenotypes that we see in older individuals that is how they look and their characteristics and decreased physical resilience or decreased ability to recover say after surgery or an infection so these aging processes of course begin at the time of conception fundamental aging mechanisms can develop at site to age related diseases anywhere from early development on through later life the process that we're interested in is cellular senescence first describe back to 1961 by hayflick and morehead and senescence cells are cells that have lost replicative potential and are essentially replicated li arrested but they're viable some senescence cells are very metabolically active and have increased protein production and they're hard to kill they're resistant to a ptosis to program cell death and they're normally only removed by the immune system there are no completely sensitive and specific markers for senescent cells they accumulate at sites of age related diseases they end chronic diseases they accumulate and healthier older individuals across multiple tissues in later life, but they can appear at any point in any vertebrate from conception on. senescence cells, for example, in the placenta, are responsible for producing factors that drive the baby through the birth canal. senescence cells clear up tissue damage after wounding. They're important during fetal development, and they act as a defense against cancer. So senescent cells will form in response to to stimulate that drive a cell into cancer. So some of our genes are repeated replication or DNA damage can make a cell become senescent. And if they appear in in the middle of a cancer, they slow down the rate of growth of the cancer but also some senescent cells 30 to 70%, have a senescence associated secretory phenotype where they produce factors that kill cells around them. So you don't want to interfere with the ability to generate senescent cells. But once they're there, many if not most, senescent cells harbor cancerous mutations, and if you make them start dividing again, or if they escaped the replicative arrest, they can come back as cancers. So and once they asked a good question, please.
So this is a lot of different functions and properties and benefits that are associated with these senescence cells, at least in some cases that you just went over is senescent. Really the right word for them. And how is it defined? Is it just to find that they've stopped replicating and then and then beyond that there's all these different possibilities for what they're doing good or
bad. It's a sulfate like replication, differentiation, apoptosis or necrosis is the fifth sulfate. So any cell can become senescent. They can become senescent in response to damage signals repeated replication problems with macromolecules problems with intracellular organelles in response to infectious antigens, and in response to drugs or radiation or other kinds of damaging insults. So any kind of cell can become senescent. senescence is basically defined as essentially irreversible loss of capacity to divide takes 10 days to six weeks for a cell to become fully senescence, so it's slower than other sulfates. And some but not all senescence cells can have a secretary phenotype where they damage the cells around them spreads in essence, interfere with STEM and progenitor cell function, damaged tissues and can produce a range of signals that attract, activate and anchor immune cells. So this is a sulfate it's a necessary process. You don't want to interfere with the ability of a cell to become senescent. But if they become senescent and they persist and they're not cleared by the immune system, and they achieve a threshold, above which they spread faster than they can be removed, they spread through their secretions faster than they can be removed by the immune system, then they start to take off and systemic problems can develop. There are probably two types of senescence cell at least. And the kind the nature of senescence cells depends on the starting cell type. What induced senescence are 40 or 50 things that can do it and how long the cell has been senescent but 30 to 70% produce damaging factors we call those deleterious senescence cells and other senescence cells don't produce those damaging factors, we call them helper senescence cells. So those cells are important in wound healing and so forth. So they're the definition of senescence is basically entry of a cell into essentially, cell cycle arrest, that that's irreversible, unless there are further mutations or things that happen to that cell. So senescent cells have been found at their found at etiologic. sites of multiple chronic diseases like in fat, tissue and diabetes are the pancreas and diabetes, the brain and Alzheimers disease, they accumulate with advancing age, their rate of accumulation is slowed by interventions such as caloric restriction that are associated with an increase in health span. That was published in 2004 by Ned Sharpless is now Director of the National Cancer Institute and that prompted us in 2004 to ask whether accumulation of senescence cells that have a size and are damaging, whether whether that is causal with respect to age related phenotypes of geriatric syndromes and chronic diseases or stress associated. So we tried to we began trying to develop ways to clear senescent cells to ask if this was more Cause but really, if this is more than than association was, in fact causal relation. We eventually after trying multiple ways to kill senescent cells, like using fusion proteins and high throughput library screens and so forth, came on, you know, remembered that senescent cells survive despite the fact that the senescence cells and the deleterious ones with a secretary phenotype kill cells around them. So that led us to hypothesize that they must have survival pathways that defend them against the things they're using to kill cells around them. So we use bioinformatics approaches to look at proteomic and transcriptomic databases, we found indeed, they have upregulated prosurvival pathways in a network. That depends on the senescence cell type. And in some respects, the other hypothesis that we use to develop analytic drugs is that, in some respects, senescence cells are like cancer cells that don't divide, in fact, many of them are cancer cells, before they've become dividing cancer cells. And those two hypotheses allowed us to use bioinformatics approaches, and then other approaches to develop us analytic drugs. So
we found there are indeed prosurvival networks, we found that disabling some or combinations of those networks would transiently just for a few hours would allow senescent cells that have a secretary phenotype, to kill themselves instead of the cells around them to basically commit suicide. And that's how us analytics act. So because it takes 10 days to six weeks for new senescent cells to form, these agents can be given in a hit and run manner. Once, you know once or twice, if there's an insult, like radiation that's not repeated, that is caused in essence, or in say, a situation like high fat feeding and obesity and diabetes periodically as new senescent cells form. So in those situations, in experimental animals, the drugs can be given once every two weeks or once a month, and that is the same effect as giving these agents continuously. We're not trying to occupy a receptor or inhibit an enzyme, we're trying to get rid of a cell type, we're trying to allow these cells to call themselves a two to three hour exposure to these drugs is enough to do so. And then it takes 18 hours for the cells to call themselves so they can be given in a hit and run manner. So we moved away in developing these agents from the old fashioned single drug single target single disease approach to using combinations of agents in some cases or agents that act through multiple mechanisms. To transiently disable these networks, we're not going after a single target, we're going after a network of pro survival pathways that sometimes are redundant. And the view is that if the geroscience hypothesis is true, we might affect multiple age related disorders, chronic diseases, and so forth that are associated with with aging. So the strategy for developing these agents was much closer to developing antibiotics and drugs with a single micro target or for a single disease. And there, there are multiple I won't go through it all I went through it the last time animal models of various diseases and conditions in which intermittent cephalic administration appears to alleviate some of those conditions or delay or prevent them. So one of the things that we have is something called the translational geroscience network. It's a consortium of the nine organizations that I've listed there. It's funded by the National Institutes on National Institute on Aging. And this network is there in order to help take drugs from the bench, to the bedside, in early phase clinical trials. And one of the things that we have through this network is what we call a facility for geroscience analysis where we can study samples, say blood, or urine or cheek swabs that contain cells from across these clinical trials. The clinical trials are not just about analytics, but they're also other agents that target fundamental aging processes. And eventually what we'd like to do is combine some of these interventions to see if there are less than additive, additive or synergistic. And we also want to begin doing trials where we combine these interventions with lifestyle interventions, and also with disease specific drugs. Given the situation that fundamental aging processes may be root cause contributors to serious diseases, but in some cases, there are some disease specific drugs. And the question would be does combining these approaches result In a synergistic, greatly improved response over using just a drug that targets a fundamental aging process alone versus targets a disease alone.
So in that network, and there are other clinical trials underway of sunlux. In that network, there are currently 15 clinical trials of analytics. As I mentioned, the network is not only studying analytics, there are clinical trials of other kinds of agents, including drugs related to rap Of Mice and Metformin, and a list of others that target the pillars of aging. And so I'll I'll go through a few of these trials, none of them. There are only a couple of early results from a couple of the trials. So we've got a long way to go before we know that these drugs are safe and effective in humans. The earliest drugs we chose to bring to trials are deciding which has been on the market since 2006. It's used as any physician can prescribe it in the US, at least, for treating various kinds of cancers like lymphomas and chronic lymphocytic leukemia. It's also used off label to treat a number of skin conditions like scleroderma. It's a tyrosine kinase inhibitor but it's not like others tyrosine kinase inhibitors that it inhibits a particular tyrosine kinase that some kinds but not all kinds of senescence cells depend on dependence receptor tyrosine kinases, which are Sark kinases, another agent we've been looking at his car set and it's in Apple peels at what it's what makes them taste better, it will target other kinds of senescence cells deciding that may not target very well and the common combination seems to be synergistic. And furthermore, care setting reduces the side effects potential side effects of design. The other agent that we're looking at in early trials is as admin and some of the trials were comparing to set of incarcerating on the one hand to fuzz that and on the other is that in is also it's very closely related to care setting that's one hydroxyl group different. It's one of the three naturally occurring flavonoids that appears to be so analytic it's present in strawberries, for example. But we have to give very, very high doses, you'd have to eat 15 pounds of strawberries and five minutes to get the kind of dose we're giving to act as cellulosic and a hit run manner. We chose these agents because their side effect profiles are relatively well known. And they've got short elimination half lives because we're trying to use agents where we can briefly expose to the drugs and then we want them out of the system. Because what we're trying to do is kill senescent cells, as I mentioned, they take 10 days to six weeks to come back, we're not trying to continuously occupy a receptor inhibit an enzyme. So we're not looking for steady state levels of these drugs in the blood, we're trying to use them in a hit and run manner. So a couple of the trials are in frail, elderly subjects, the affirmed trials, these are have forgotten their placebo control there. They're both about halfway through now. One of them is for elderly women with extreme frailty with a gait speed of less than point six meters per second that incidentally carries about a two year 50% survival, so having a slow gait speed and frailty, if you're elderly below point six meters per second is probably a worse prognostic indicator than most cancers. There are several trials just beginning and there was a pilot, a couple of pilot trials done before these trials began for Alzheimers disease. One of them is Alton light that just is beginning to recruit now. And that is to look at targeting what we call target engagement. Are we actually killing senescent cells in these subjects? I'll explain that trial a bit more in a moment. There are there's a multicenter, double blind placebo controlled trial that's about to begin called stomp ad.
There are
trials for chronic kidney disease. There's a trial looking at inflammation and stem cells in diabetes and preliminary results from that were published, which I'll show in a moment, but it's continuing their trials in bone marrow transplant recipients this trial is almost finished. So people who get a bone marrow transplant get a high dose of chemotherapy and radiation that can induce unfortunately senescence as a side effect before they get their bone marrow transplant because you have to not not you have to destroy basically their own immune system before they can get a bone marrow transplant, for example for various cancers. Turns out that a number of people who've had bone marrow try Plans, not all of them. But some of them after three to five years get an accelerated aging like state. And so that led us to test whether clearing senescent cells would alleviate that accelerated aging like state where these people get cognitive impairment, diabetes, second, unrelated cancers, and arthrosclerosis with heart attacks and strokes. So they, some of them sort of look like they're aging very rapidly. There is a trial based on that same kind of logic at St. Jude, that's been funded by the National Cancer Institute. And that trial is comparing that into deciding of incarcerating to placebo. It's an open label trial, though, but it's randomized. That trial should be beginning in June, it's funded approved. And what it's to do is to look at the accelerated aging like state that can develop and people when they're in their 30s and 40s, who've been treated for cancers as children. So people who have been treated for leukemia or lymphoma as children have chemotherapy and radiation that can induce cellular senescence, and I'll, I'll show you the data confirming that and I'll discuss that trial in a bit more detail. There, there's a trial about to begin double blind trial. In idiopathic pulmonary fibrosis, preliminary results from an open label arm of that were published. And there's another safety trial which is about to be published. But these were a lead up to a larger double blind placebo controlled trial. And I'll come back to that in a moment. There is a trial which I'll explain in a bit more detail to look at age related osteoporosis, which is about halfway through now. It's recruited about slightly more than half the subjects that's an NIH funded trial. There's a trial funded by the Office of Naval Research to look at osteoarthritis, which is a disorder linked to senescent cell accumulation in and around the knee joints. There's several trials that are underway or beginning for Coronavirus and its complications. There's an outpatient trial, a hospital trial and a large nursing home trial that's funded by the NIH that is just beginning now. So the idiopathic pulmonary fibrosis trial I mentioned idiopathic pulmonary fibrosis is an usually fatal lung disease that occurs in older subjects. It's associated with senescence, cell accumulation in the lungs. In animal models of this particular condition, where a chemotherapy agent is inhaled by mice, these drugs appeared to alleviate the condition. So a clinical trial. An open labeled, non placebo controlled clinical trial was done where nine doses of deceptive incarcerating were given over a three week period. And then five days after the last dose, a number of frailty measures were made, because we know in experimental animals, and people with idiopathic pulmonary fibrosis like states that frailty is a key parameter that you see. And in the animal models, this is alleviated faster than the pulmonary fibrosis, which takes quite a bit of time to alleviate with analytics animal models. So the decision was made to look at frailty in these subjects. And there appeared to be come in within subjects before versus after treatment and improvement in six minute walk distance,
gait speed, ability to stand from a chair and the short physical performance battery. But I'd strongly caution that there are learning effects for all these tests. We don't this was not placebo controlled, it was not blinded. It's very early and all it was all the entire reason for doing this was only to know if there was some degree of justification in going on to a double blind, placebo controlled phase two kind of trial. So that's the only reason this trial was done. There was a trial done, as I mentioned before, an early phase of the diet of the study and obesity and diabetes and obesity and diabetes, a lot of senescence cells accumulate in adipose tissue in fat tissue. So in these subjects, a biopsy was done of their subcutaneous fat at day zero, and another biopsy at day 14. On days, one, two and three. They got doses of deciding of incarcerating by mouth Then they didn't get any more drug after that these drugs are cleared from the body within 36 hours because the elimination half life of deciding three or four hours and of course setting is about 11 hours. So the drugs are long gone by day 14. So in comparing the day 14 to the day zero biopsy, there was a decrease in some markers of senescence. There are no perfect, completely sensitive and specific markers of cellular senescence, so we normally have to measure several different markers to convince ourselves there may be an effect on senescence, it's, you know, a question was asked about how do you define a senescence cell and it is very difficult to define them at the level of markers. Also immune cell infiltration. What happens in these people is with obesity and diabetes as they get inflammation of their adipose tissue with infiltration of things like macrophages, immune cells that cause inflammation, cd 68 cells, the abundance of the cells decreased in their adipose tissue. We know from other studies, that analytics Do not kill the cells what they do is attract and activate an anchor these kinds of immune cells. So we know from experimental animal studies that what that that says analytics don't directly call the cells but they reduce their abundance in things like fat tissue and animal models of obesity by reducing the senescence cell. The assassin cells there within the adipose tissue that are attracting, activating and anchoring themselves. So in these human subjects, we found decreased activated macrophages at day 14 compared to day zero, and also less fibrous tissue in their in their fat tissue or crown like structures. And there was a decrease in blood markers of senescence. Again, we can't follow any single marker. Through the facility for geroscience analysis, we measure over 100 parameters in the blood to look at the pillars of aging. And many of those are to give us an idea of whether senescence cell burden is being affected or not. Here, a composite score is being looked at of several factors that can be produced by those senescence cells that cause harm through their Secretary phenotype. And, again, a three day course of treatment with these agents resulted in a decrease in these factors. So that gave us confidence to go on to the larger double blind placebo controlled trial. So I mentioned that there are no completely sensitive and specific markers of senescence, a facility for geroscience analysis of the network, we measure well over 100 parameters, as I mentioned, some of them are proteins that are in the blood. Some of them are things related to DNA and RNA that are in the blood or in cerebral spinal fluid, or other body fluids. We measure a range of markers within cells. So we look for senescence cells in in the blood, but we also look at epigenetic clocks and all kinds of other things. And we also look at other fundamental aging processes, it seems they're all interlinked. So if we target senescence cells, we tend to affect all of the other pillars of aging as far as we know. And conversely, if we use agents that target other fundamental pillars of aging, we tend to affect senescent cells with their burden.
So the old timers trial, as I mentioned, that's mainly a safety and feasibility trial. It's open label, it's looking at subjects for a few months before versus after starting intermittence analytics, and this is in subjects with early but established Alzheimers disease. And the purpose of this particular phase of the Alzheimer studies is to know how big placebo controlled trials going to have to be. So this involves subjects who are over 65, it's just beginning to enroll. They've got intermediate Alzheimers disease as evidenced by cognitive function testing and looking at various markers, including pet imaging. It's going to be a small trial. It's mainly looking at Target engagement, as I mentioned, and it's going to be of intermittent deciding of incarcerating and this is based on studies in animal models where there appeared to be some alleviation of the of the Alzheimers like state that some most models have. Where we find that there are senescent cells in the parts of the brain that control memory and executive function. And that subtle effects in those animal models improve new nerve production, reduce inflammation in the brain, improve blood flow in the brain and decreased or even partially reverse brain surgery. shrinkage so we're seeing if that's true in patients with alzheimer's in patients with alzheimer's we know they have senescent cells in the hippocampus of the brain and the frontal lobes that control respectively memory and cognitive function so in that trial the main thing we're looking for is safety and tolerability we don't know if these drugs are safe so these drugs are being given intermittently over a 90 day period there are a lot of target engagement parameters being measured in their blood their cerebral spinal fluid and also looking at mri and other kinds of imaging as well as cognitive and functional status there's a trial that i mentioned before is over halfway through looking at analytics for age related osteoporosis they appear to be effective there in animal models where animal models have hormone deficiency related osteoporosis these drugs are not so effective that seems to be hormone deficiency related osteoporosis seems to be more independent of fundamental aging processes and age related osteoporosis so in this trial this deciding of incarcerating are being compared to the zetten it's a placebo controlled trial and it'll be it's it's it's just over halfway through and they're the subjects are getting two days of analytics 13 days off two days of analytics 13 days off over a number of cycles out to 140 days so they're they're they're getting sub seven cycles of these drugs and again this is based on preclinical animal model studies and in addition to looking at bone mass they're all the blood parameters that are being done and all the other trials are being done here as well as well as looking at bone turnover markers in the blood and imaging of bone i mentioned before about the childhood cancer survivors these people in their 30s and 40s the development accelerated aging like stayed at st jude they follow all of their patients for life as much as they can they've got over 800 of the subjects and carrying us and greg armstrong there found that senescent cells in the blood in these people who had received treatment for cancers as children are now in their 30s and 40s and are developing frailty heart attack stroke second cancers alzheimer's disease and look like they're much older than they are they found that the people with a slow gait speed and frailty had accumulation of senescent cells in their blood so that led to the trial that the national cancer institute is funded in these childhood cancer survivors with difficulty with gait speed and other criteria frailty and it is like some of the other trials comparing to satin of incarcerating to physician and it's going to be two three day courses over that are amongst the part with the main endpoint again being targeted safety and also target engagement and then looking at gait speed so that trial is funded it's going to actually begin enrolling probably in june
we found with collaborators at harvard that transplanting organs from old to young animals results in spread of senescence from the transplanted old organ to the young individuals own organs and this isn't because of cells migrating out of the old organ it's because senescence through its secretary state can cause the recipients own cells to start becoming senescent because of the factors that senescent cells produce so this this just shows that if we transplant hearts from old to young mice we start seeing senescent cells in the recipients lymph nodes and their liver and these are the recipients own cells and this is because in particular have something called mitochondrial dna which is released by senescent cells but other factors as well the transplant surgeons have known that organs from old donors don't work very well in recipients this is part of part of the you know an outcome of this is that in people who die say in car crashes are over 50 surgeons are reluctant to use their kidneys even if they've signed a donor card and and they've got the kidney so we're throwing away 35,000 kidneys a year that could be used for transplantation because they're from older donors so in these heart transplant animals if we treat the donor the heart the heart being transplanted or the recipient was settled Next, we're able to reduce the spread of senescence and we're able to increase survival of the recipient. In fact, we're able to increase the survival of the recipient to the same point that we see in recipients of hearts from younger individuals. And where we recreate the kind of transplant rejection treatment that is given to people and in the end and plus or minus sign analytics. So we actually get very, very good survival on these animal models. So that is led to early phase trials, taking kidneys that are being discarded because they're from older donors and asking if we can regenerate them so they could be used. kidneys are put on to perfusion machines after they're removed from the deceased donor. And that allows us to measure senescent cell burden by looking at various parameters in the kidney while it's on the profusion apparatus, and also to look at the function of the kidney and we can administer some analytics to the kidney on the profusion machine. We're doing a similar thing with the University of Groningen in North Holland, trying to rehabilitate liver transplants from older donors. The physician trials for Coronavirus. The one which is underway is in hospitalized patients who are admitted with Coronavirus infection and have respiratory difficulty and it's to test the efficacy of analytics in alleviating respiratory dysfunction. We know that Coronavirus activates the secretary phenotype and senescent cells and can also cause cells to become senescent and an animal models of Coronavirus. If we treat with young animals infected with a version of Coronavirus don't die older animals do much like humans. And if we treat the older animals with analytics, we prevent their dying we reduce cytokine storm and we improve antibody responses. So this trial is underway to see if we can recreate that in humans. It's just over halfway done now. But you know, it's it's a double blind placebo controlled trial. So we don't know whether there are any positive results or not. The main thing we're looking for side effects, we do know that we're not seeing much in the way of severe or serious side effects, but I lie awake every night worried about that. The the trial includes people over 60 with a recently positive PCR for Coronavirus or 18 to 59 with risk factors, including things like obesity, diabetes, asthma, and so forth, which are also states and younger individuals that are linked to early accumulation of snacks and cells. The protocols along one we're trying to see if we can reduce not only respiratory difficulty and look at side effects and so forth. We're also trying to see if we have an impact on long haul or syndrome.
There's a trial which is just beginning. It's going to be in when it's fully rolled out in 129 nursing homes across the United States. It's funded by the NIH. And this will be for patients who have have who test positive or have tested positive for Coronavirus, who are nursing home residents, we know that they have that they don't do very well. So this trial is beginning in a small way at Mayo affiliated nursing homes, then it's going to spread across the translational neuroscience network. And, again, the main endpoint here is going to be looking at safety and tolerability. But the primary endpoint is to test if there's reduced progression using a wh o related scale. And there are a whole lot of secondary endpoints
the
if it is a double blind placebo controlled trial, but it would provide a rationale for larger scale trials to look at other conditions as well. So in conclusion, the target of sunlight it's isness itself is not a single molecule or pathways. I mentioned the last time we spoke, we're targeting networks. We're not going after a single molecular target. We're going after senescent cells. In other words, intermittent treatment looks like it may be effective. In animal models, we can alleviate multiple conditions. We don't know if they work in humans. They could be dangerous in humans. senescence is a very fundamental process. We don't know at all the downsides of clearing senescent cells are going to be we've done a lot of work in animals to try to make to try to be as safe as possible. But our view is the only place for these agents at the moment is in carefully controlled clinical trials. for serious conditions until we know if these agents are safe, we don't think they should be taken by the general public at this point, or prescribed by physicians, we want to make sure they're safe. And we're trying to do this as fast as we can, in multiple clinical trials in parallel, instead of in series. We're not doing trials in healthy people to try to slow down processes that might take 10 or 20 years to develop, where we're using these agents in conditions that are serious, that don't have good treatment options. Where we know that cellular senescence is at the is is a causal contributor, where we've got good animal study data. And we're we're following the patients very closely, especially for side effects. So we're trying to do these trials in parallel rather than in series to speed things up. I would I cannot predict at this point, whether these drugs are going to work. That's why we're doing these trials. And well, I can't predict whether they're going to be safe or effective. Things often look good in mice, and then turn out to be bad in people. So we've got to be very, very careful. And again, like the last time, I'll just thank a lot of people and sorry for talking so much. So I'll stop sharing at the moment.
Wow. Fantastic. Thank you so much. I yeah, I think you know, call I mentioned in the chat. This is really a plethora of, of really incredible studies. And there's there's a there's a lot of questions in the chat. I hope you don't mind me immediately jumping in. But this was really, really wonderful. Thank you so much. I also love the I love the the way of the presentation, and I hope you don't mind if I share the slides with the rest of the group? Sure. Okay, good. Just want to make sure. Okay, well, we have Korean patient quiz question with which can upload it and then we have Christine cow, and let's say Korea and go ahead and perhaps say one sentence about your background.
My background is I'm interested, amateur. I'm an applied physicist for NASA and for space companies, but I know something about molecular biology. And hence, I'm going to ask you, the minute you made this comment, mitochondrial senescence cells released mitochondrial DNA, that sounds like a pretty big deal. What the heck is going on with that? Why does that happen? Is it purely maladaptive? Or is there's some good reason for it and and just looks like a serious failure inside the cell system?
Yeah, so one of the major changes that occurred there are many changes that occur in senescent cells that there's a very complex transcription factor cascade that enforces senescence, so, literally 1000s of genes expression gets changed. mitochondrial dysfunction is a hallmark of senescence. So senescence cells are resistant to dying, but they have what's called a partial Warburg shift. So much like cancer cells, they depend on sugar instead of fatty acids. There's mitochondria, a lot of turnover of mitochondrial DNA and changes in mitochondrial dynamics. So they release mitochondrial DNA. But senescence cells don't just release mitochondrial DNA, they release a lot of other noncoding nucleotides, so they release a lot of micro RNAs that affect a lot of tissues at a great distance. mitochondrial DNA is recognized as what we call a damper danger associated molecular pattern of protein. So other cells, if they if they detect that cells around them are breaking down or in trouble, one of their responses is to become senescent. So this is how senescence can spread. Even even at a great distance. And by the by the way we're working with were quite engaged with some of the space agencies about cell analytics space radio,
zero gravity, probably introduced senescence introduces everything else bad.
Yeah, we've got we've actually got cells going up on the axiom flight in 18 months, and we're tricking the astronauts on that flight.
follow up question, if you don't mind. Based on what you said about the Warburg effect, doesn't that suggest that a very low carbohydrate diet might be senolytic
not necessarily sent a lytic as such, but there are metabolic ways of getting at senescent cells. And you do find that, you know, diet might indeed might impact senescence cell generation the same way as it does with cancers. So, senescence cells have some of the same metabolic shifts as cancers. Thanks. So caloric restriction, for example, as I mentioned earlier, that Sharpless, you know, back in 2004, published in Journal of Clinical Investigation that that delays senescent cell accumulation and simultaneously improves healthspan.
Yeah, but it might very well be that it's not so much the caloric restriction but the carbohydrate restriction with its
sugar and we don't know that so a lot of work needs more work needs to be there has been some work in that direction. But lifestyle interventions have to be looked at but actually introducing lifestyle interventions in sick elderly people is a much taller order than small molecule. Pills as much as I hate to say it. I mean, I'm a geriatrician, amongst other things. I've looked after nursing home patients for many years, and I know what's possible and what isn't in some of these populations.
Thank you.
Awesome. Thank you so much. I'm asking Christine Aikens two questions. So first of all, she says this is fascinating. And then she wants me to ask what the difference is between senescence and terminal different differentiation? And how do synthetics achieve specificity.
So, terminal differentiation means the cells acquired a specialized cell fate and stops dividing. senescence is, in a way, a terminally differentiated state, you know, that would be another way of looking at it. But that said, some supposedly terminally differentiated cells like neurons, or like cardiac myocytes can acquire a senescence like state, even though by that, you know, that's why it's really hard to define senescence, because you know, soon as the the only definition is a normally replicating cell type that loses replicative potential, but it's beginning to look like non replicating cell types can acquire a senescent like state with many of the things that you see in senescent cells, including some of the organelle changes that we're talking about changes in a lot of pathways in in as far as gene and protein expression go upregulation of anti apoptotic pathways in a number, many, many other things, actually. So there's a lot of debate in the field about it. But there's a view an emergent view, that terminally differentiated cells can acquire what looks like senescence related fate.
Okay, thanks a lot. And next one up, we have cow and then Alexei. And then Jim.
So I have a couple questions, but some of them are super fast. Are you going to be doing an interim analysis at the halfway point of these trials that are at their halfway points?
Some of them? Yes, most of them? No. These are FDA regulated trials. They've got DSM B's data safety and monitoring boards that are following results. One of the charges, especially of NIH, supported, you know, because they the NIH chooses a DSM B's for NIH trials, we don't. One of the charges in those trials is to stop the trial, either if there's futility, or if, if you demonstrate an effect, it's overwhelming early.
Right course, if you've got good reason I asked is because if you had good enough power for an overwhelming effect, then you should see the signal. Okay, so fisetin and cursor 10 are not being drugs aren't as tightly regulated in terms of manufacturing. And, you know, that's why there are companies like consumer lab that tests them for whether you know, what actual level of active ingredients they have, how to use source and ensure that the doses being done in the trials or the doses you think you're giving based on labels.
We have, we had to get a full ind for that. And the minute you use an actual product, to treat a disease, it's considered a drug, we had to register it with the FDA as a drug. It was took two years, 450 pages, we had to set up something called Good Manufacturing, practices manufacturing. We had to do stability testing, we had to look for degradation products, we had to test and multiple species, we had to do safety and tolerability. We had to do all of that just like it's a brand new drug. But
we learned to do clinical trials, meaning your meaning you are producing it yourself. Yes. Got it.
Well, we contract to a GMP manufacturer, and then
get off market got it. Okay.
And then and then we monitor the male mass spec facility monitors are their product and we have to furnish to the FDA every couple of months safety and stability data.
Understood. So wound healing, we all agree is is good, and we don't want to interfere with that. That's why we don't want to stop cells from becoming senescent. We think that most of the time when a wound happens, you get this influx of senescence cells that call this immune response response that helps heal the wound and then the body mostly cleans up the senescent cells.
Do we Oh, it's a bit different than that actually what some senescence cells produces platelet derived growth factor which helps wound healing. Those are the senescent cells that are not pro inflammatory, so analytics do not target those cells. So So analytics target the 30 to 70% of senescent cells that have what we call a SAS or senescence associated secretory phenotype. They do not target the senescence cells that produce pdgf So, we do not find unlike what we see in animal models, if we get rid of P 16 expressing cells or B 21 expressing cells, we do not see the inhibition of wound healing with sunlux.
So, are you saying that all the types of senescence cells that are involved in wound healing, do not have SAS or just some of them?
The SAS may be necessary early on to clear away dead tissue, as you said, but later on, if you it's been shown in some of the animal models that were you clear cells, some of which are senescent because neither neither p 16 or P 21. are completely sensitive or specific person acids. But if you target p 16, expressing cells and remove them, you delay wound healing. And part of and it's been shown that if you know by a group in California that if you add back platelet derived growth factor, you restore wound healing. And it turns out that it's the senescent cells that don't have a sauce that produce that. So you do need them early on to help clear up the wound. You wouldn't want to give it right these drugs right away. But in a chronic wound, they may help.
So I guess my question is, as the immune system as we go undergo immuno senescence and maybe the cleanup is imperfect, would we expect that animals that get higher rates of repeat, idiosyncratic repeated wounds will end up with a higher senescence cell burden?
We're not sure about that. But we see that in other kinds of scenarios. So there's what we call a stairway effect, you have a burden of you know, you have something that causes senescence, all burden, and then you get a bit better than, you know, and but you don't get back to baseline
questions. So I'll let other people do
a boundary above a certain threshold. senescent cells start in impeding immune system function. Could they prevent macrophage diabetes, for example, they cause fibrosis they have donate new signals, they produce proteases that cleave off fast like and so above a certain threshold, they'll start impairing their own clearance.
Thank you. Next up, we have Alex eight.
Are you here?
I think you had a few questions. Like say, if you here, let us know. Connections bad. Okay, then we'll go to someone else. And you let us know when the connection is better. No, we're gonna go with Jim O'Neill. Now, because we have a few more people in the queue. Please, just say a question in the chat.
Alexei said his connections bad and he wants you to read his questions.
Okay, um, Jim, you asked me a question, then. I'll wait. Alexis.
Yeah, you said that monthly dosing was as effective as continuous, I wonder if like annual dosing would would be expected to have a beneficial effect.
It depends on the the rate of formation of new senescence cells. So it's condition dependent. For example, if you blast a mouse with radiation of one leg, you just need to give a couple of doses in the animal's entire life. To alleviate the dysfunction if you've got continued high fat feeding, new senescence cells are generated at a particular rate. If you've got other stimuli that are inducing senescence, it depends on the stimulus. And it depends on the cell type that's becoming senescent and a lot of other things. So we're only just beginning to get a handle on that. And, you know, one of the things where we use the blood test for is to try to figure out when senescence cells are coming back, we're trying to miniaturize that and make it as fast as possible so that we can do in some of these trials, intermittent blood testing, like every few days, and determine when there's a takeoff of senescence cells again, so we could dose at that point.
All right, I'm gonna read out excess questions. Now. He's asking, how much is the senescence of several layers of cells in liver and adaptive responses to the aggressive environment? And how much goods analytics interfere with this response? Question number one, question number two, how much is this in essence?
Oh,
no. We have that was the first one. Maybe you just want to tackle the first one for us.
Sorry, I didn't quite catch it. I heard liver but you said something about layers.
Yeah. How much is the senescence of several layers of cells and liver and adaptive response to the aggressive environment and how much good sunlight is interfere with this response?
Well, you don't see much in the way of senescent cells and younger, healthier individuals, you know, you in the liver, you see them in conditions like primary sclerosing cholangitis, where they're they're very abundant, and they occur in one particular part of the liver around the bile ducts. There's a clinical trial envisaged in that because Nicholas Cruz So here has done some really great preclinical animal studies. So that'll be coming along in the case of hepatic steatosis, where there's fat tissue that gets into the liver in the context of obesity and diabetes. There are different kinds of cells in the liver than in sclerosing, cholangitis, or biliary tract disease. So in in in diabetics, for example, or people who have obesity and hepatic steatosis and scatto hepatitis, it's a different set of cells in a different part of the liver that are affected, but you tend not to see many that we're able to detect at least using current methods and depending on your definition, senescent cells and healthier individuals in the liver.
Alright, and his second question is, is there any no negative interaction between the human immune system and synthetic therapy?
I think it depends on the drug there, they're probably well over 100 drugs now. Some drugs are very toxic, you know, like things like novita clacks, which we and another group found was so analytical around the same time, it's a bcl two family member inhibitor. It's used for trading. I mean, it's not an approved drug. It's an Investigational Drug. And, you know, it, it does have a lot of side effects on the immune system, it can cause it. It mainly affects platelets, but it can cause unpredictable, decreases in the white count, especially of neutrophils. And after a while there starts to be fairly severe neutropenia, where other satellited drugs were not able to find a big effect on immune cell numbers, we find correction of immune cells in situations like Coronavirus, because one of the things senescent cells produce amongst many others that attract and and anchor immune cells is something called ip 10. And it attracts certain kinds of T lymphocytes and one of the things you see in Coronavirus infection that severe is deficiency of T lymphocytes. And, you know, when we when we in animal models, when we treat with analytics, we, we reverse that?
Alright, we're now on time, there's two more questions. Do you have to hop off? It's totally fine.
I'm okay for a short, but I guess.
Okay, good, then let's see if we can if we can make it I'm sorry about this bumbling, but people will have a few people do have a few more questions. And Joe, you you are next.
Just really quickly, since I'm involved from this angle, I'm curious of what you ended up paying for that GMP work like the CMC and also the ind enabling studies for Pfizer. Quite a lot, I can't go into that very much. Because I don't know the exact numbers. And we we negotiated with different manufacturers. And so it depends on the study where it is. And, you know, some of the particulars of the study. The nursing home study, as you can imagine, is very complex. It's not so much the manufacturing, it's the drug delivery, which is very complex. And that was one of the big stumbling blocks to getting that trial going. So we had to figure out ways to get the drug packaged and to the nursing homes without, you know, contact with people in or around the nursing homes because they're on lockdown. So it depends on the situation. Okay, one thing about design is we're finding it's pretty stable in our hands, you know, when we do mass spec on it, so we were worried it would have it would break down easily. This stuff is like in the right storage conditions, it's remarkably stable. When they
when they would really
is that is that data available in terms of what the purification and stability testing and all that kind of stuff, it will be when we it will be when we start publishing some of the trials and also the NIH with us is developing a website about that particular trial. And it's that the website should be coming on stream in the next week or so. But it won't have the stability data and all that stuff on at the beginning. But eventually it will it's more to share protocols and so forth and slps that that particular website to begin with, but we want to put everything that we can on that's not considered business confidential. Business, okay. Thank you. Well, business confidential by our lawyers. We don't you know, male does not make money out of this. Yeah, I understand. Oh, for I mean, we're, you know, we're a academic organization and it's, you know, I've just always covered it. government funded, you know?
Yeah, yeah.
I was trying to look at the website and share it in the group and find it.
It'll start off very small and hopefully get bigger and bigger over time.
Lovely. We have another question by Alex and then call with a final word. And then I think we're, we're good. Alex, do you want to unmute yourself?
Oh, sure. Hi, everybody. Alex uncuff. Gray, quick question. I'm just wondering if you have the blood tests on clinical blood tests and the expanded by chemistry from the patients before and after analytics, and maybe after an extended time? I am. If you have tried the aging clocks that Chi utilize this kind of type of data?
For the long and short answer is yes, that's all being done.
And what do you see? Do you see any?
We don't know yet. It's too, you know, the the data are just coming in. And they're, they're blinded, and so forth. So so we don't know. But the group at Yale, for example, that's interested in that, you know, the epigenetics actual processing is done at University of Minnesota. And then Morgan Levine and others at Yale are looking at the results.
Are you making this data public so others can see it?
Eventually, we will Yes, because these are publicly funded trials, a lot of them.
gram.
We have Morgan, I think in a few months, so perhaps we can also ask her a few follow up questions on this. And then call you had a final question. And then I think we had really,
Lynn also made this comment and that that I also made in the chat, which is kudos on just exploding so many different trials in parallel. This is great. It's great for the world. It's great for science. So I know, you made a decision A long time ago, when you started this kind of thing to go with systemic administration, just you know, world dosing, you know, partially because of the signaling aspect. And of course, we all know that unities local administration trial for knee arthritis failed. But you know, given how many things are starting, have you have you started to reconsider, or at least getting, you know, taken at some portion of trials and looking at some kind of local administration. You know, these trial didn't fail because of that, but because of the chosen molecule, or the indication itself, or,
or both. But the the, we find their spread of senescence. So if we transplant small numbers of senescent cells into one part of the body and experimental animals, we find spread of senescence throughout the animal. And we've got early data showing that in humans, this appears to be the case as well. So we're, we're concerned that if there's a local accumulation of senescent cells, that may be a harbinger of a systemic problem.
Right, but
the other the other issue is, how do you give things locally, for example, in a knee joint with osteoarthritis, more than half of whom by the time, they're severe enough to require a lot of intervention don't even have a snowmobile membrane left anymore. If you're injecting something locally into that kind of knee joint, you're basically giving a systemic injection, because the knee joints destroyed, if you're injecting into the eye, through the central through the canal, in the optic nerve, you're delivering even large molecules into the part of the brain that controls breathing, consciousness, sleep wake cycles, etc. You can show that anybody's injected into the eye wind up in that part of the brain very quickly. So it's really hard to know what a local injection is, I think skin is a different issue. And there's certain other things like inhaled agents, there might be there might be a place. But it's really hard to know what you mean by local injection, if, you know there's a damaged tissue and there's a lot of blood supply to that tissue. And you could be giving at least equivalent to an intramuscular injection if not an intravenous injection.
I suspected especially doesn't make sense to do local when you're looking at the very, very frail, which your trials seem to be, though, as you start considering trials for younger, healthier people possibly there are conditions where there's a very local high senescence cell burden that hasn't spread too much yet,
but Well, we've got some stuff emerging from Johns Hopkins that in indeed, in fact, in some younger people with local accumulations of senescent cells, they're everywhere when we look.
Thank you so so much. One final question to make those your last words What can this group potentially do? I mean, you know, a little bit who's in this group at least, and to help with your work what what would you what would be helpful
um, You know, I think we've, we've gotten a lot of help from the government and from foundations, I think what's very important is for people to get the message not to be taking these drugs at this point in an uncontrolled way, we don't know if they're going to be safe or effective. I give it maybe a 5050 chance we're doing the trials, because we don't know if they're going to work.
We wouldn't be, you know, so
I'm, as a physician, I'm very worried about the first principle and the Hippocratic oath, you know, first do no harm. And,
you know,
we are playing with a very fundamental process here. And I don't know whether this is all going to work out or not, you know, humans are not big mice. And we'll have to see what happens. So I, I prefer sort of a conservative approach to all of this, at this point. And that's, we're trying to move quickly, because we feel it's important to know one way or the other. But, you know, I worry,
yeah, you are doing the work of a lot of people, I think in parallel at the same time. So I really am moving full steam ahead on this. Thank you so much for your work. Thank you so much for taking the time and for sharing your work with this group. It was really fantastic. Thanks, everyone, for your great questions. Yeah, I'm really, really appreciative of the time that you're devoting to this group. Thank you very, very much. I'll be following up with the video. And whenever if you ever want to come back onto an update, we would, we would love to have you on again. Thank you from everywhere. Thanks. And yeah, I'll be I'll be in touch. Alright, everyone, it was lovely to see you all. What a full packed meeting. I'm really looking forward to our normal keynote meeting next Thursday, and it's going to be a very, very, very exciting one. And check the schedule, and I'll see you next Thursday. Have a lovely rest of the day, or evening or morning. Bye, everyone.