In April 2020, as the COVID-19 pandemic spread through New York City, Louise Malle, an MD/PhD candidate at the Icahn School of Medicine at Mount Sinai, turned her focus to the disturbing statistics coming out on disease severity. She thought the data might inform her research to better understand immunity in people with Down syndrome.
Ms. Malle, who works in the lab of Dusan Bogunovic, PhD, surveyed thousands of patients diagnosed with COVID-19, and essentially found that individuals with the syndrome have about 10 times the likelihood of having extremely severe disease.
Hi everyone my name is and I'm a professor of immunology and oncological sciences, microbiology and the department of pediatrics and I'm also the director of central for inborn errors of immunity at Mount Sinai in new york. Hi I'm Louise now I'm an M. D. PhD candidate. I did my PhD in immunology inducing bogdanovich's lab. So motivation behind our study was multilayered one was that there was an absolute need to understand how does the immune system function in individuals with Down syndrome. Um Individuals with Down syndrome are rare and underserved population. Understudied population. Uh So we thought that it's it's pertinent. Um It's scientifically interesting. Uh And there is a very clear mission of helping individuals with Down syndrome who have multiple immune uh signs and symptoms that need to be addressing. And that's where really um Louise came in. Yeah and um kind of as Duchin said because I'm in the M. D. PhD program I always want to do research that will have the potential to translate to human health and that can actually help people. Um And so when they approached me with this um study with this project at the beginning of my PhD I thought it would be perfect because it not only uh kind of titillated my biological questioning side of things because it dives into a very interesting part of our anti viral defenses. But it also um was looking at people with Down syndrome who addition said aren't underserved population. And um I think that there's a lot of ways in which the treatment for people with Down syndrome can be um improved. So, um I wanted to do my part in that. I think this is very pertinent because louise when she started in the lab was as we all were caught in the COVID-19 pandemic and as she was interested in working uh and understanding the immune system in down syndrome. The first thing that she did is she did this survey of thousands. Unfortunately patients who have covid and she essentially found that individuals with Down syndrome have about 10 times higher likelihood of having extremely severe covid, 19. So this was an epidemiological observation that added to a body of literature suggesting that severe viral disease is a problem in Down syndrome individuals. And in part guided by that really led to this very detailed fundamental immunology observation of why that is the case. So, she saw what was going on in the clinic, she saw what was going on in the world and then came to the lab and ultimately figured out at least in part why this is the case. Okay, so what is the significance of these findings in simple terms? Um so I think the significance is um twofold. Um first and foremost, I think it um tells us something about not only the propensity for autoimmune disease in patients with Down syndrome, but more so tells us something about why people with Down syndrome can be more susceptible to severe viral diseases, which is something um that has is largely unknown today. Um and we even have an idea of how this could be targeted therapeutically because there are drugs on the market that target The pathway that we saw goes awry in people with down syndrome. Um and the second part is that it tells us a lot about also just general signaling uh for this central antiviral pathway that is called Type one interferon. Yeah. Louise did such a terrific work here because she disentangled a little bit of a paradox if you wish here, Individuals with Down syndrome are inflamed yet they're susceptible to viral infections. And and this study really points to one of the mechanisms through which this is going on. And in essence too much inflammation causes this immune suppression and it's a temporal so it's in time. So it's not always like that, it's like some sort since Oid function and Lewis has so well and so precisely showed that that I think this leads to potentially us monitoring health individuals with Down syndrome and knowing when to intervene with existing drugs. So we can have this less of inflammation, but also less of immune suppression. So basically to try and and tame these overt responses which go both ways. What are implications? Well, implications are many first, I hope this is gonna be inspiring to others to start studying uh individuals with Down syndrome at multiple aspects of uh pathologies that they present with. Uh this has an implication of uh introducing a different layer in uh clinical trials with drugs that are now used to tame their immune system and the clinical output of infectious diseases is not something that's built into these clinical trials. So I think now we can a sub segregate individuals with Down syndrome as those who are most likely to benefit from this therapy both in the context of taming their information, but also helping with the development of of severe viral diseases. Yeah, um I honestly don't have that much to add. I think the major implications is um trying to better understand um both the auto like the high inflammation and the immune suppression in people with Down syndrome and how actually targeting the same pathway could therapeutically um could solve both of these issues to an extent. And trying to study that right there. Yeah, well, that's a difficult question. Is a good question. Right? So, I think, you know, for me, I think this is an example of how something that people shy away from and that is, you know, working with a sensitive population population that that has sometimes intellectual disability issues. Population that has caretakers and including individuals with Down syndrome and other minority groups and other populations that are more difficult if you wish to work with and do that in a very rigorous ethical manner is the right thing to do. Uh that's how we help individuals who are marginalized that. That is how we advance medicine. That is how we promote equality and research and equality in medical practice. So I hope this theme comes through as something that others in science and medicine should be perhaps doing more. Um what should not be taken is that there is no miracle drug. Thus, that's gonna cure everything. Um, and this is one step forward. We hope extremely important step forward um because if we are going to solve complex issues such as multitude of medical problems that individuals with Down syndrome have, it's one step at a time and perhaps louise studies is three steps at one time, which is why I think it's very impactful, but that that's how things work. Things are not simple. Um, takes a lot of hard work, takes a lot of money to do this. We have to have funding to do this. Um, but both of us I think have quite enjoyed it and perhaps we should thank our cohort of individuals with Down syndrome without whom, I mean, this would be completely impossible. And, and uh, they are terrific group to work with and we've had nothing but phenomenal experiences with that. Um, I second everything that Duchin said, um, and I'll also answer this question from a more maybe biological point of view. I think one thing that's a bit difficult and intimidating when tackling a project on down syndrome, which is caused by trisomy 21 is that It's a lot of genes, it's 200 genes that are triplicate id. Um so you know it's a lot of less intimidating to study one gene going awry in one disease. Um so that makes it a very big challenge in studying um uh this mono chromosome oh um syndrome. Um so I think what people should take away from it is that studying the impact of each gene on chromosome 21 can be a way um to start chipping away at what is going on um in down syndrome. Um so and I think that you know, careful examination of each gene will bring us a lot but as solutions said, what should not be taken away is that this is the end all be all and that the application of it which is what we studied causes all of the immune um peanut Types of people with down syndrome. There's interaction between all of these genes on chromosome 21. There's interactions with other genes in the genome. Um so I think this is a great start and we have a lot of avenue straights floor. Um but we also want to study um all the other genes and their interactions. Yes, well put in simple terms, how is this study novel? Well, um to date it was not well understood how type one interferon mediated inflammation. So these individuals will be more resistant to viral infections and indeed they get less frequent viral infections but at the same time, once infected with viruses, they do so much worse? And we've seen this with COVID-19, this has been reported with a few other viruses. Um and it we just didn't understand why. And now we have one explanation which we are pretty certain is correct. There's probably multiple other things that are going at the same time because of the complexity of the syndrome. But in simple terms louise has discovered why too much interference can actually lead to insufficient antiviral response. And she even uses drugs that can short circuit this auto amplifying loop in such a way that she rectifies inflammation and rectifies ability to respond to viral disease. So it's pretty remarkable if you ask me. Thank you. I think that's really the main takeaway what Duchin said. Um and the only thing I'll add is that I think this is the first study that looks at the impact of the negative regulation of type one interferon on viral susceptibility. Um and you know, all of us use interferon to fight viral diseases. So um I think this idea that this is a dynamic system that not only turns on but has very um you know, intricate mechanisms to turn itself off um and its impact on susceptibility to viral diseases is something um that is novel. Yeah, and perhaps even a pliable to to general population, it's just that we think, you know, this is a typical response, hence that's the best response. Uh and maybe it isn't, maybe that can be modulated as well to the advantage of our health. Right? And even um as you know, a lot of clinical trials, have you tried to use interferon and back in the 80s or 90s thought that it would be this magical drug because it helps cells in a dish fighting to fight viral disease, but turns out that it never really worked in humans. Um so this starts like answer some of these questions of why interferon is kind of like a complex protein to work with, and it's not the magical drug that people thought it would be. Mhm. I don't think I was really surprised by what we found because um we really with this study, one thing that I loved about this project is that it was very hypothesis driven. Um so we had a very strong idea and with each step we kind of tested um what we thought was going to happen and generally like our knowledge of interfering in its negative feedback um kind of turned out to be true with what we expected um in Down syndrome. Yeah, yeah, I agree with Louise, it was very hypothesis driven. It was background data driven um you know, perhaps to me what comes as a as a surprise is that, you know, as Louise mentioned, these clinical trials that are partially effective with recombinant interferon and early in early phases of disease, uh maybe this allows us to use the same drugs in this case Jak inhibitors to perhaps short circuit the inflammatory response in typical population that can then be better primed to respond to interfere on in the context of the antiviral response. Right? Um It's of course even more complicated than that, but you know, the more we understand the more pieces of the puzzle that we put together, it becomes uh a better way to perhaps design a clinical trial that's going to have a more positive outcome. Um limitations of the study I think are um that as I mentioned, Down syndrome is a very complex disease. Um and we try to probe the questions that we wanted to ask. We use mostly cell models. Um but as we all know life um is much more complicated than uh cell models. And you know, people with Down syndrome are at each organ um into front is going to act a little bit differently. Um There is gonna be viruses that trigger this uh system. There's gonna be other um triggers throughout life. Um and so I think there's still a lot to do to understand how this dynamic into front response in Down syndrome happens uh physiologically we did use some immune cells but again in the dish. Um So I think pushing this to clinical trials and epidemiological studies and things like that is something that will really round out our findings. I agree with louise here, 100% you do everything you can in the laboratory. Ex vivo we say that uh and then the next step is to run a clinical trial with all this information that we are now empowered with. Right? So, the impact of this study I think is uh that of using existing drugs and you know, we can go into details what are the options either, you know, blocking interferon using jak inhibitors, you know, maybe, you know, some sort of stat inhibitors, who knows, or TBK one inhibitors um, and designing a clinical trial in which the output is not just aiming their information because we know they have problems with inflammatory diseases, but maybe a secondary outcome should be the incidence of viral disease or severe viral disease, which is what they can suffer from and have a much higher likelihood than the typical population. Um and I think knowing that and knowing the timing of that is perhaps what in in a few years can lead to a very specific tailored treatment. Uh there's gonna be personalized to the immune state in which that usually is at the time of examination, Right? Because, you know, just having Down syndrome doesn't mean everybody is the same. Actually. This is another study where we know that's not the case that can be segregated into a few different groups and that correlates well with this study as well in terms of that balance between inflammation and immune suppression. Um, so in short terms, hopefully Louise has put us a few steps forward towards the successful clinical trial that will then empower physicians to alter the management of pathology in individuals with Down syndrome. Let's hope. Let's hope. Yeah, this well I guess is probably better suited to answer this question as he's leading the lab and I left, but this study really spawned a bunch of different projects which I'm very excited about. Yes, I agree. I think this is just the beginning. Uh this is the tip of the iceberg Louise has implicated um you know, two important genes and implicated how their modification through existing drugs can perhaps help individuals with Down syndrome. Um but this this has also opened avenues into tissue specificity into understanding how central nervous system functions in Down syndrome in the context of this very inflammation. It has spawned interest into auto immunity uh and specific cell subtypes that also Louise has discovered. And we'll talk perhaps next time about that. Um so there is uh simply a lot to do. It's from the scientific point of view, very inspiring and challenging, which is what we like. Uh and I think hopefully it'll inspire also others to take this path of patient oriented, patient focused research for better mental, the understanding of fundamental immunological processes which then leads to better care of the very patients that we work with