Kiran Musunuru Interview Transcript
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DR BRUCE MCCABE: Welcome to FutureBites, and I am here this morning to talk to Professor Kiran Musunuru, Professor of Medicine and Genetics at the Cardiovascular Institute, and Scientific Director at the Center for Inherited Cardiovascular Disease, at the Perelman School of Medicine. Kiran, welcome. Thank you so much for making time for me this morning.
DR KIRAN MUSUNURU: Oh, it's my pleasure. Thank you for having me.
BRUCE MCCABE: And quite an esteemed day here at Perelman because we have two new Nobel Laureates right here this morning.
KIRAN MUSUNURU: Just announced a few hours ago.
BRUCE MCCABE: Yes. Where are they? In another building or are they in this building?
KIRAN MUSUNURU: They're in another building. Actually Drew Weissman's lab moved to a building not too far from here, but a little distance away from here. Brand new building, fancy new digs, wonderful lab space. And so, I'm not surprised. [laughter] He definitely earned it.
BRUCE MCCABE: Exactly. I'm looking forward to coming back and seeing the streamers and balloons later. And I've been in and out of these facilities all week, and as we're just talking it seems like this is the center of the medical universe here now, especially for the future of medicine.
KIRAN MUSUNURU: Sure feels like it.
BRUCE MCCABE: There's so many wonderful things going on here. And that's why I'm so excited to talk to you, because what you are doing is really big, when it comes to what the possibilities are in the future. And I'm all about looking at the optimistic possibilities and pathways and trying to inspire people as to where we can go. So I'd love to talk to you about your work.
KIRAN MUSUNURU: Absolutely.
BRUCE MCCABE: And to extend on—I heard you give a talk last year at MIT and that's where we met, and so it's been a year. I've been busting to come and talk to you more. [laughter] I wonder if you could give a little summary of what you're doing, because what I understand is we're tackling the genetics of heart disease here, and you are really shooting for really, a ‘one-shot’ treatment for people who are at high risk of cardiovascular disease, and to inoculate them, if you like, almost vaccinate them. So, could you give a little overview for people as to what the goals are?
KIRAN MUSUNURU: Absolutely. So first and foremost, I'm a cardiologist. I take care of patients who have heart disease in various forms and flavors. And looking out my window right here in my office, you look across the way and you see this brand new hospital pavilion that just went up really just a couple of years ago. And that's where any patient who has a heart problem in the community comes in, either through our emergency room or is referred to us, ends up in that hospital, and that's where I take care of patients. And it can be anything from what I think of as garden variety heart disease, heart attacks, stroke, rhythm issues, heart failure and so forth, to very rare forms, genetic forms of heart disease like cardiomyopathies. So really running the whole gamut from very common disease to very rare manifestations of disease.
And I would be remiss if as a cardiologist, I did not emphasize as I always do in any meeting I have, and any talk I give, that cardiovascular disease is the number one killer worldwide, bar none. And that is true not just in countries like the United States or in Europe, but really everywhere in the world now. This wasn't true maybe even 25 years ago, but if you look at the latest World Health Organization statistics, in their latest report, what you will find is that over the last 25 years, even in the poorest countries on earth, so broadly speaking, across middle income countries, low income countries, cardiovascular disease has become the leading cause of death. It used to be infectious diseases in many cases but now it's heart attack, it's stroke, it's all the various manifestations of cardiovascular disease.
BRUCE MCCABE: And is that because we're getting better at treating the infectious diseases as well as... Or is it, as well as the cardiovascular is on the increase in all of those countries?
KIRAN MUSUNURU: It's a combination of things. So this is what scholars call the ‘epidemiological transition,’ where we've become better, exactly as you say, at addressing infectious diseases and the root causes of infectious diseases like sanitation and so forth. And people are living long enough to get non-communicable diseases.
What we have traditionally thought of as more lifestyle diseases, but that probably isn't the right way to look at it. I think if you grow to be old enough and you don't die from some devastating infectious disease, there are other metabolic diseases that invariably crop up. I wouldn't call it exactly the natural aging process because there are definitely things you can do to prevent it, but in any given society, if people are getting to be old enough, you will start to see heart disease, diabetes, other sort of things like that. Non-communicable diseases start to become prevalent. And so you have this epidemiologic transition where we haven't by any means beaten the infectious diseases. Just look at the SARS-CoV-2 pandemic over the last few years.
BRUCE MCCABE: Yes.
KIRAN MUSUNURU: There's still a lot of challenges there.
BRUCE MCCABE: And Malaria, there's so many things, yeah.
KIRAN MUSUNURU: And Malaria and HIV, and I can give you a whole laundry list. But collectively cardiovascular disease has become the predominant killer. And just let me give you one other factoid to put that in context. It's a little bit hard to estimate how many people have died of COVID-19 since the beginning of the pandemic. It's been almost four years now, I guess since the pandemic formally began in very late 2019. And over that time, maybe 10 million people. Again, it's a little bit hard to pin down an exact number, but that's probably not too far off from what we think has been the mortality directly from COVID-19 worldwide over the last four years. During that same time period, more than 50 million people, at least probably more, have died of cardiovascular disease. And yet we don't talk about it. Everyone, of course, quite naturally, and understandably, has obsessed about the COVID-19 pandemic. But there's this ongoing endemic disease, cardiovascular disease, that's killing many more of us.
BRUCE MCCABE: Interesting. It's like an acceptance, if you like because it's been with us for so long.
KIRAN MUSUNURU: Exactly.
BRUCE MCCABE: That this is just the natural, perhaps, course of things, rather than perhaps a treatable condition.
KIRAN MUSUNURU: Exactly. I think there's a widespread perception that a lot of it is aging, a lot of it is things you do to yourself or lifestyle choices, things you may not necessarily have so much control over. And so many people die from it. Everyone knows someone who's died. Everyone has had family members who died of a heart disease.
BRUCE MCCABE: Absolutely. Everyone.
KIRAN MUSUNURU: It does not discriminate. It affects... It's a leading cause of death in men, leading cause of death in women. Whether you're a minority or non-minority, whether you're in a wealthy enclave in the United States, or whether you're in the poorest countries on earth, it is indiscriminate.
And to me, cardiovascular disease is well on its way to becoming, if it hasn't already, the preeminent global health threat of the 21st century, bar none. This is the quintessential challenge we are facing as a healthcare community.
BRUCE MCCABE: Now, there's a number of factors that we just touched on. One is sort of this demographic shift as we get older. And therefore we are living long enough to become exposed to this as a possible disease. Then there's the genetic component. And then there's the lifestyle component and the lifestyle component, I had in my mind, when you're talking about the whole world is rising, I'm also thinking, well, a little sub-question in my mind was, are we all just living terribly worse lifestyles around the world? Is that actually part of this? Dietary-wise and...
KIRAN MUSUNURU: I think that is absolutely a part of it.
BRUCE MCCABE: … sedentary lifestyles.
KIRAN MUSUNURU: Absolutely. Okay. So you've hit exactly on the right point, which is that cardiovascular disease is a complex disease. And so I'm oversimplifying a little bit, but it's not too far of a stretch to say it's about half genetics, half what you are born with, what you inherited from your parents and really don't have any control over, and half of it is lifestyle and environment, a lot of which you do have control over, but a lot of which you don't, just because of the way modern society is now – built communities where it's harder to get out into nature and exercise and be physically active. The food that we eat, it's predominantly processed foods, at least in a place like Philadelphia in the United States, where we are now. [laughter] It's not so easy to access fresh foods, unless you're wealthy, ironically. Didn't use to be that way for many, many, many centuries, millennia, for most of human history. And so that's definitely a contributor. Pollution in our environment is a big driver of heart disease. And there's not a whole lot any one individual can do about that except try to move somewhere else.
BRUCE MCCABE: No one talks about pollution and linkages to heart disease.
KIRAN MUSUNURU: Absolutely. And that's been going on for a while.
BRUCE MCCABE: They talk about smoking and things …
KIRAN MUSUNURU: Smoking for sure. But even...
BRUCE MCCABE: … but not air pollution.
KIRAN MUSUNURU: Exactly. Exactly. So lifestyle/environment, we have control over some aspects of it, but not as much as you might think. But what we do know is if you were born with bad genes, you can overcome that to some degree by good lifestyle choices, being healthy, being physically active, eating well, not eating too much. Definitely not smoking. Smoking is one of the biggest drivers of heart disease.
These choices that you make can certainly influence, and to some degree, counteract the effects of bad genes that you might've been born with. You can flip it around too, which is that if you were born with good genes, you're not out of the woods. because if you make poor lifestyle choices, you'll neutralize whatever advantage you might've had from what you inherited from your parents. So it cuts both ways. So it really is a mix. But I've been very interested over the last, say, 15 years of my career and understanding why some people, even if they make bad lifestyle choices, seem to be protected from disease.
BRUCE MCCABE: I see.
KIRAN MUSUNURU: They're not so easy to identify. It's actually much easier to figure out the reverse when someone has no risk factors, runs marathons, is perfectly healthy, has no family history, and then they show up in a hospital with a heart attack, a massive heart attack. And that really makes you go, "Huh! They must have something going on, that's predisposing them to the disease." because it certainly isn't anything they're doing as far as we can tell. So those cases are easier to identify, but I'm not that interested in finding the things that cause heart disease or predispose heart disease. I'm actually more interested in finding ways to protect against heart disease.
BRUCE MCCABE: And starting with people who perhaps stood out as being, for some curious reason, more resilient to this.
KIRAN MUSUNURU: Exactly. And let me give you an example. So a family in St. Louis, in the St. Louis area, one of the women in this family, she actually had, is one of 10 siblings as it turns out in this family. And she was visiting a health fair sponsored by her employer. And they offered the ability to blood pressure check and spot cholesterol check and so forth, and she took advantage of that. And it turned out she had... She was found to have very, very, very low cholesterol, which came as a surprise to her. I guess she had never had her cholesterol checked or whatnot. Not necessarily a bad thing. We think of high cholesterol as bad, low cholesterol is kind of a question mark. So like, "Okay, something weird's going on there, but I don't really know what it means."
And so, properly, she was referred to her physician who referred her to the local expert in cholesterol, if you want to think of it that way, who turned out to be a world-class lipidologist who had devoted his career to studying this. And sure enough she was confirmed to have very, very low cholesterol levels, but not just cholesterol levels, also triglyceride levels, which are the fat content in the cholesterol-carrying particles in the blood. And so they're not perfectly related, but they have a lot to do with each other. And we think high cholesterol is bad and we think high triglyceride is bad in a different way. But she had extremely low, rock bottom levels, of both of them. Something that really hadn't ever been seen or appreciated before.
BRUCE MCCABE: I see. Yeah. So she's a real outlier.
KIRAN MUSUNURU: Real outlier. And it turns out three of her siblings turned out to be exactly the same.
BRUCE MCCABE: Ah, okay.
KIRAN MUSUNURU: And then the other six siblings, not so much. And so this gentleman, this world-class lipidologist, as I mentioned, the scientist, he passed away a few years ago, but his name was Gus Schonfeld. He recruited her and her siblings and actually three or four generations of the family into a research study to try to study their genes and try to figure out what the issue was that was causing them to have so low cholesterol and so low triglycerides. If you think of a bell curve where most people are in the middle and then you have the extremes, they were definitely like way, way, way to the one extreme, very, very, very low levels. To the point where you basically had to think that they were going to be immune to heart disease, naturally immune to heart disease.
And in fact, what has occurred over the last couple of decades as they've been studied and evaluated and imaging has been taken of the arteries that feed their heart muscles to see if there is any disease there – no hint of disease. And they're elderly now and have kids and probably even grandkids by this point and you really have to think that they're going to ... Everyone dies of something, but they're not going to die of heart disease. They're protected against it.
And so Gus Schonfeld tried for many years to try to figure out what was going on in their genetics in these four siblings that protected them. He wasn't able to do it. No fault of his own. The technology simply wasn't there.
BRUCE MCCABE: It's a tough problem, too, because you're basically, what, sequencing and looking for something different? And how do you look for something different? It's very hard to find something different and isolated.
KIRAN MUSUNURU: Yeah. Exactly.
BRUCE MCCABE: There are lots of things that are going to be different.
KIRAN MUSUNURU: Exactly. And so you have to figure out just the right thing and there are 20,000 genes in the genome. And so it becomes a scavenger hunt. And back in his day, he could only sequence one gene at a time. So imagine the challenge in trying to find that needle in the haystack of 20,000 genes. And so he wasn't able to figure it out, but he published his work, published the milestones as he made progress, but never went anywhere.
Now, fast forward some years later. Now we're talking 2009, 2010, when I was a postdoctoral fellow at Massachusetts General Hospital and the Broad Institute. So I became interested in this problem. Can we find these individuals who seem to be naturally protected against disease? And can that give us some clues as to how to protect everyone from this? Is there some magic in them that we can bottle and then give to everyone, if you want to think of it in those terms. And so how am I going to find these individuals? It's easier to find someone who shouldn't have had heart disease, but somehow got a heart attack. We see this every so often. But to find the opposite is very hard. But I did what any good trainee should do and read up on the literature and try to see what has been published, what is out there, and I came upon Gus Schonfeld's papers. And it was very interesting, this four-generation family with more than 50 members he had recruited. Right in the middle of that, this generation of 10 individuals, four of whom had this condition.
BRUCE MCCABE: So he'd gone back and looked at the previous generations.
KIRAN MUSUNURU: He looked at the parents, he looked at the kids, he got DNA from all of them. He just wasn't able to find the answer.
BRUCE MCCABE: Did he keep samples?
KIRAN MUSUNURU: Well, okay, so he did, and that turned out to be critical. So late 2009, I was reading this paper, or his papers, and I got all excited. It's like, "Okay, here are these individuals." And here's why I was excited. Because things had changed as of late 2009. There was a new technology called exome sequencing, which I should add now, 14 years later, is now routinely used in the clinical setting in hospitals and clinics. Now we don't even think twice about exome sequencing, like literally millions and millions, and probably many more than that have been done now. But in 2009, it was new. It only had been done a few times. And one of the places where it was just starting to be done was the Broad Institute, where I was a postdoctoral fellow. And we had the opportunity to actually do, basically, two people. We had two shots on goal. We had this opportunity. And I read about this family from St. Louis in these papers and I said, "All right, let's go after them." So I talked to my research mentor and we reached out to Gus Schonfeld and it turned out he had retired. But in the fine tradition of research laboratories, nothing ever gets thrown out. And so, stuck in some freezer that had never been cleared out, that was still in a hallway somewhere and had been inherited by some other scientist, the DNA samples were still there.
BRUCE MCCABE: That's wonderful.
KIRAN MUSUNURU: And so we were able to get them sent to us fairly quickly. And I chose the two most... Two of the four siblings because we had two shots on goal. So the ones that had the very lowest cholesterol levels, triglyceride levels, all four were more or less in the same place and took those DNA samples. And we had them exome-sequenced. And I'll never forget it. I remember because it was a Saturday morning, my colleagues and I had spent quite a lot of time setting up the computational pipeline because no one had ever really done it before, so we were doing everything from scratch to search all the genes, all 20,000 genes. And try to find differences, exactly as you said. And the beauty of exome sequencing is that it's brute force. You don't have to sequence one gene at a time. It sequences all 20,000 genes all at once.
BRUCE MCCABE: Okay.
KIRAN MUSUNURU: So you're getting all the data. So then it becomes a different exercise, which is to computationally analyze all the data from the 20,000 genes and look for those differences across all the... And as you said, there are going to be many differences.
BRUCE MCCABE: Well, exactly. And what's your control? You've got to sequence a population. Sample population.
KIRAN MUSUNURU: Yeah, exactly. There were some number of people who had relatively normal genomes, if you want to think of it that way. Several dozen whom we could rely on as controls. But you're right, it was a shot in the dark. There was absolutely no guarantee this was going to work.
BRUCE MCCABE: It's a lot of data, too.
KIRAN MUSUNURU: Yeah, it's a lot of data. And what we needed was a smoking gun, because if there wasn't a smoking gun, we'd have no way of being able to differentiate any particular difference we found in any given gene from the many differences you see between genes.
BRUCE MCCABE: Yeah.
KIRAN MUSUNURU: But it's better to be lucky than be good because we in fact found that smoking gun. And I'll never forget it was Saturday morning, late Saturday morning, the pipeline, the computational pipeline spit out it's data output. And we started looking at it. And within a few minutes we knew we had the answer.
BRUCE MCCABE: Really?
KIRAN MUSUNURU: Because there was one gene and one gene only where there were two misspellings, two mutations in the two copies of the gene. Because almost all genes come in two copies, we get two versions, one from mom, one from dad, different misspellings, but they were both misspellings that we call nonsense mutations, which means basically these are severe mutations that unequivocally kill the gene's function. Because they basically chop the protein product right in the middle. And so you don't even make the full protein.
There was no question that these are what we call knockout mutations. You're killing the protein product. And to find two of them – different ones, but two of them.
BRUCE MCCABE: Yeah. And two different people.
KIRAN MUSUNURU: And both shared by the two siblings. And then once we had the clue that, "Okay, that's probably what we're looking at," we later went on to the entire family and everything tracked perfectly. The four siblings had both the mutations, some of their siblings had just one, and so they didn't have the full condition and some had zero. And it turned out mom and dad each had one of the mutations, but they didn't have the condition. And it really looked like one of the parents had sort of married into a family that already had the mutation running through it, so brought in the second mutation from the outside, and then they ended up, they had 10 kids and then just by luck, four of them ended up with two...
BRUCE MCCABE: Talk about a needle in a haystack.
KIRAN MUSUNURU: Totally. Totally. But as I said, within a few minutes we knew we had the right answer. It was just, it was so obvious and it made so much sense. And that was a gene called ANGPTL3, which is like an acronym for Angiopoietin-Like 3.
BRUCE MCCABE: ANGPTL3. I love these... Easy to remember.
KIRAN MUSUNURU: It's probably Greek letters and numbers and...
BRUCE MCCABE: There's a lot of that in biomedical science.
KIRAN MUSUNURU: But this was clearly the gene.
BRUCE MCCABE: And I'll bet there was... Was there a lot of excitement when you published?
KIRAN MUSUNURU: There was. Not necessarily overt excitement. It didn't light the world on fire, it didn't necessarily make world press, but among a certain group of people, it was highly interesting. Drug developers.
BRUCE MCCABE: So people tuned into why it was exciting to you? Other people in the field got it instantly [that] this might be a pathway to...
KIRAN MUSUNURU: And particularly drug developers. Okay, so here's the deal...
BRUCE MCCABE: That would've been incredible.
KIRAN MUSUNURU: You have this gene ANGPTL3 naturally turned off in these four siblings. That tells you a few things. One; the reason they have very low cholesterol levels and triglyceride levels, a double whammy, is because this gene is turned off. Two; these are naturally born people, entirely lacking the protein product of ANGPTL3. And they're walking around totally fine, totally healthy, no adverse consequences of having this gene naturally turned off.
BRUCE MCCABE: Because genes often have multiple roles to play. So a key thing is if we're going to play with this, to understand that we're not turning off something important.
KIRAN MUSUNURU: Exactly. You want good effects, but you don't want bad effects going along with it because then it becomes a wash. What you want is the good effects with no bad effects. All upside, no downside. And this turned out to be a gene just like that. And we knew that because we had these four siblings who were totally healthy, had kids of their own, living into their 60s, 70s, 80s, you can't ask for a more perfect situation.
And then there are a few other features of this gene that are very attractive. It's a gene that is only expressed in the liver, by which I mean the protein that's made from the gene is only produced in the liver, but once it's made in the liver, it's secreted into the bloodstream and it's beneficial effects turn out to be largely happening in the bloodstream.
So this is useful in a few ways. One; if what you're trying to turn off is a protein floating around in the bloodstream, we know how to do that. We can make a monoclonal antibody, a biologic. And there are many of these now on the market for various proteins many of them with immune diseases, but for a whole variety of other things as well. You make an antibody that you just inject into the bloodstream or even just inject subcutaneously and it gets into the bloodstream from there, it finds the protein binds and basically clears it out of the blood. And so we had made the discovery of ANGPTL3 being a cholesterol gene in 2010 and 10 years later, a decade later, which is incredibly short time, a company, in this case, Regeneron, had an approved drug, a monoclonal antibody against ANGPTL3 approved by the FDA for use in patients with very high cholesterol levels. 10 years from basically discovery to an actual drug that is available to patients. Monoclonal antibody. Now the downside there is you have to take injections every few weeks.
BRUCE MCCABE: I was going to say how frequently, so every few weeks?
KIRAN MUSUNURU: Actually it's not even just, it's not even the subcutaneous, at least not yet. Right now it's an infusion intravenously.
BRUCE MCCABE: So you need to go to a hospital?
KIRAN MUSUNURU: Yeah. Or a clinic, and be hooked up to an IV and get it every few weeks.
BRUCE MCCABE: And effectively it's cleaning out the blood, if you like.
KIRAN MUSUNURU: If it's cleaning out the protein, the effect of cleaning out the protein is that your cholesterol falls by half.
BRUCE MCCABE: I see.
KIRAN MUSUNURU: Now that's great this is a huge thing for those patients who are born with sky high cholesterol levels, have premature heart disease because of this. Not a lot of treatments, one of the actual treatments is to be hooked up to a dialysis-like machine that cleans the cholesterol out of your blood. So once a week, hooked up for a few hours and it's a big deal.
BRUCE MCCABE: It's far more invasive. It's asking far more from the lifestyle.
KIRAN MUSUNURU: Exactly. So that's exciting. But remember I said that this gene is expressed in the liver. So there are other ways where we can target genes directly in the liver before the protein is even in the bloodstream. So two technologies both based on RNA as it turns out, one is called siRNA short for ‘small interfering RNA.’ Also known as RNA interference. I apologize for the technical terms, but...
BRUCE MCCABE: No, that's okay. That's okay. That's what we call them for better or for worse.
KIRAN MUSUNURU: And the other technologies known as antisense oligonucleotides or ASOs. And without getting to the details of exactly how they work, they can both be given as injections, usually subcutaneous injections. And they can find their way to the liver, get into the liver cells, and actually almost like a homing beacon it can find just the gene. Or really not the gene, but the messenger RNA, the RNA molecule that's made from the DNA gene. Find that messenger RNA, bind to it and cause it to be broken down. So it's a way of turning off the gene at the RNA level rather than at the DNA level.
And the reason why it's important that it's at the RNA level is DNA is permanent, and the DNA is continuously being, what we call transcription, transcribed into RNA, and the RNA is short-lived. The RNA gets translated into protein. That's how this whole process works, DNA to RNA to protein. And so if you target the protein with a monoclonal antibody or you target the RNA with an siRNA or an ASO, it's going to be short-lived because that RNA and that protein are continuously regenerating. If you really want to make a permanent change, you have to go to the DNA level.
BRUCE MCCABE: Yeah, so it's just moving up the supply chain, if you like.
KIRAN MUSUNURU: Exactly. Exactly.
BRUCE MCCABE: Yeah, if you're targeting RNA, it's... In nature, it's a very short-lived mechanism while it's doing what it's doing. So your efficacy can only be short-lived as well. Which takes to the real source of what creates the RNA at the...
KIRAN MUSUNURU: Yeah, you want to go to the ultimate source, which is the DNA. And so it's wonderful that we have these medications. There's a monoclonal antibody I mentioned that's been approved for ANGPTL3. There is an siRNA, there are actually multiple ones, there are ASOs that are in development in clinical trials and they look pretty good. But they're all going to suffer the same limitation, which is that they have to be taken over and over and over again. And let me tell you why that's bad. And then we'll talk about gene editing, which is a little bit long-winded but we're eventually getting there.
BRUCE MCCABE: No. It's good. It's good. And I can see already some of the reasons why the first lot's bad, but yeah it's interesting. We're building the story up and I'm actually in the middle of, Ben, is it Ben Stanger?
KIRAN MUSUNURU: Yeah, yeah.
BRUCE MCCABE: He put out this book 'From One Cell'. I thought I'm going to read that because he's gone back to first principles and it's the sort of book I love, where he's blending the history with the science and that gives me some context and it gives me something to hook onto. And he is building it up layer by layer, which is what you've just done for me as well.
KIRAN MUSUNURU: Yeah, exactly, exactly.
BRUCE MCCABE: So... Yeah, it's very, very, powerful.
KIRAN MUSUNURU: So let me tell you why it's bad to have to take a medication over and over again. And we intuitively, I think, all understand it. And that is because as a physician, when I give a prescription for a drug, and it can be one of these fancy biologicals where it's injections every few weeks or it can be the standard pills that we take every day, sometimes multiple times a day. And when we're talking about something like heart disease, when we're talking about managing cholesterol, these are pills that, it's not like an antibiotic where you take it for a week and then you're done and you don't have to think about it again. These are pills you have to take for the rest of your life to manage cholesterol, to manage blood pressure, to manage how much your blood clots, these sorts of things that all feed into heart disease, every day for the rest of your life. So when I write that prescription, that is what I'm consigning a patient to. I'm putting a huge burden, a huge responsibility on them to commit to taking that pill, or pills, more usually forever.
BRUCE MCCABE: And the financial burden as well to go with that.
KIRAN MUSUNURU: And so there are... There's all sorts of burdens, they have to be willing to do it, they have to be able to afford it, they have to commit to continuous contact with the medical system. Coming back every few months, or every year to get prescriptions renewed, to get checked up, everything that goes along with it.
BRUCE MCCABE: That's interesting because it gets beyond the patient burden to the systemic burden as well.
KIRAN MUSUNURU: It's both. And I put much more blame on the system than I do the patient. In my mind, it's hard to blame the patient. These are incredible expectations we're putting on people. But part of it is just intrinsic just to the philosophy of chronic treatment to chronic disease. They have to take it over and over again. And the real eye-opening statistic, and this is being confirmed in a variety of studies now, so it's not just a one-off thing, if you look at patients who have been admitted to a hospital like the hospital of the University of Pennsylvania, right across the way out the window here, they come in with a heart attack. We do whatever we can to fix it up, there's a blockage in one of the arteries that feeds the heart muscle, we go in, we use balloons, open up the blockage, we put in a stent to keep the artery open. All this fancy technology.
What we absolutely have to do, because it's the standard of care, before they leave the hospital, is we give them a prescription for a high dose of a statin drug, statin drug being a cholesterol-lowering drug. These are drugs that are taken by millions and millions and millions of people. So we've been taking them for decades. We have a lot of experience with them. They're relatively safe, there's no issues there. And they're not even that expensive in the grand scheme of things because they're generic and there are many versions of it, and you can pick and choose. But we have to give that prescription because we know that taking that statin will reduce the chance of the next heart attack. There's absolutely no question. The clinical trials have shown this unequivocally. And even if you provide the statin for free, what we find is that a year later, after they've left the hospital, only about half are still taking that statin.
BRUCE MCCABE: Yeah, so adherence is the real problem.
KIRAN MUSUNURU: Adherence is the issue. And again, I don't put the blame on the patient.
BRUCE MCCABE: No, no. It's life.
KIRAN MUSUNURU: It's life.
BRUCE MCCABE: It's just nature.
KIRAN MUSUNURU: Some people don't like taking pills. Or after they've had their heart attack, they get treated, they feel fine. And then over time they say, "Well, I don't really like taking that pill. I just don't like philosophically taking the pill and I feel fine. It's not making me feel any different." So they stop taking it. Or they don't have insurance and they can't afford the copays. Or they can't get back in to get the prescription renewed. And so these are systemic problems. They're built into the chronic care model. And I wish I could say the United States has such a dysfunctional healthcare system that we're the only ones where this happens. But it's not true. If you look in other countries...
BRUCE MCCABE: It's everywhere.
KIRAN MUSUNURU: It's the same phenomenon. It's just human nature perhaps. And just unreasonable expectations. And so what we really would like to do is be able to give a treatment that deals with the issue durably and even permanently. What if you could give a single treatment that then offers lifetime protection. So anytime a patient leaves the hospital after heart attack, they get that one-time treatment permanently reduces their cholesterol levels, like taking a statin every day for the rest of your life, but with one treatment. And then adherence is off the table. That burden is off the patient.
BRUCE MCCABE: Yeah. After that buildup, it's so obvious just how incredibly powerful that would be.
KIRAN MUSUNURU: Yeah. And now here's the key. Bring all this together. All we've been talking about for the last, I don't know, it's been half an hour or more now. [laughter]
BRUCE MCCABE: No, no, that's …
KIRAN MUSUNURU: You asked one question and I'm just going on and on and on.
BRUCE MCCABE: Yeah, no, it's perfect.
KIRAN MUSUNURU: But it all comes together in that how can we make the permanent change to reduce someone's cholesterol levels and protect them against heart disease. So you need two things. You need some lever to pull, in this case a gene to turn off, and we have answers, I mentioned ANGPTL3, and it's not the only gene. There are a few other genes that are similar to that. Where you can turn them off safely. There are no negative consequences. It's all upside, no downside and we know will protect against heart disease because there are people who were naturally born with the gene turnoff. So we have those answers.
The second piece is the technology that will give you the ability to go into a person's body and turn the gene off. And the way I look at it is you have those genetic superheroes or people who have won the genetic lottery, however you want to frame it, who happen to have the right parents and inherit the right genes and get the right good mutations. We think of mutations as bad, but in this case, the mutations that turn these genes off are actually good. These are the mutations you want. And these people who won the genetic lottery, they're rare, they're unusual, they're outliers, as we said, they have the key in their bodies.
So what if we can take, now that we know about these mutations, these good mutations that turn off these genes, what if we can take those mutations and put them in patients with heart disease or patients or people who are at very high risk of having a heart disease in the near future? Or if you want to extrapolate looking down probably decades in the future, doing it in patients who are at risk, any future risk, of having heart disease in their lifetimes. Which is pretty much everybody because it's the number one killer worldwide. And so now we're talking about something very different from a chronic care model. We're talking about more of a preventative.
BRUCE MCCABE: Yeah, avoidance.
KIRAN MUSUNURU: Or almost like a vaccination. You used that word earlier, vaccine, like a vaccination-type model. It's not immunological in nature, although there are some similarities to a vaccine, as I'll tell you in just a minute. But what if you had that one-time treatment? Certainly if someone's had a heart attack or someone has genetically high, very high cholesterol levels.
BRUCE MCCABE: It's a no-brainer.
KIRAN MUSUNURU: It's a no-brainer. A genetic therapy to counter a genetic problem. Or someone who already has a bad disease. It's a bit of a leap to go, let's take any young healthy adult, say around 20 years of age, and offer this to them, and it's up to them whether they want it to take it or not. But the upside, if they take it, as long as this is a hundred percent safe or as close as you can reasonably manage, they take it, it permanently reduces their cholesterol levels and they're protected for life. And they would push off heart attacks and stroke by decades. It doesn't mean they won't eventually die of a heart attack. But it's the difference between dying of a heart attack at age 60, still in the prime of life, still a lot to live for versus dying peacefully in your sleep from a heart attack at age 100 when you've lived your full life. So you're never going to get rid of it, but you can push it off by decades. And certainly I think you could make it so that it's no longer the number one cause of death worldwide. Which would be huge. And if you deployed this widely enough across the population and enough people agreed to take it, it would improve life expectancy substantially. There's absolutely no question about it.
BRUCE MCCABE: Yeah. Globally. And you can't prevent the overall risk because half of the factors are genetic and half are not, right? So we're only addressing half...
KIRAN MUSUNURU: It's true. Right. Yeah...
BRUCE MCCABE: We're pushing off the half.
KIRAN MUSUNURU: So I think of it as shifting the bell curve.
BRUCE MCCABE: Yeah. Okay.
KIRAN MUSUNURU: Right. So almost everyone's in the middle, then you have extremes. People who are going to get heart disease no matter what they do. And people who are absolutely not going to get heart disease because they're genetic superheroes. But what if we could deploy those good mutations across the entire population? Basically what you're doing is you're shifting the entire bell curve. There's still going to be people who are still at higher risk than the general average population, but they're still much better off than they would've been if they hadn't taken the treatment.
BRUCE MCCABE: Yeah. And it's interesting hearing you talk because it's very powerful. You talk – and this is what was so exciting to hear you last year – ww're talking very big here. We're not just talking about people with, well first of all, at the moment we're talking about, with hypercholesterolemia people who are just born making too much of this stuff. Then it's people who've had a heart attack in a hospital and instead of just giving them a statin, we actually give them, perhaps gene edit them and then we've really attacked the cause and left them so much better off than before they arrived in hospital. And then it might be people, just ordinary people, who have a high risk profile because of family history or maybe gene testing, I'm not sure.
KIRAN MUSUNURU: Yeah, absolutely.
BRUCE MCCABE: But one way or the other, that leads them down the path of, "Wow, I'm at high risk." And then potentially it's everybody.
KIRAN MUSUNURU: Yeah. [laughter] So it's a stepwise progression and we're not going to jump from A to Z immediately. But you can see where things could unfold over the next few decades, absolutely, and that's the vision. That's the big vision.
BRUCE MCCABE: That's the dream.
KIRAN MUSUNURU: That's the dream. Now the last piece as I started to get into was you need a way to transfer these changes into the DNA in any given person, and that's where gene editing comes into the mix. This transformational technology, that just three years ago, 2020, the Nobel Prize in chemistry was awarded for the discovery and the implementation of CRISPR as a gene editing tool.
BRUCE MCCABE: Yeah. This was Jennifer Doudna and Emmanuelle Charpentier.
KIRAN MUSUNURU: It's Jennifer Doudna and Emmanuelle Charpentier. Yeah. So almost exactly three years ago this day. [overlapping conversation]
BRUCE MCCABE: It seems too recent, doesn't it? Because all the work was done, or a lot of that work was done earlier.
KIRAN MUSUNURU: Yeah, yeah.
BRUCE MCCABE: But that's the Nobel [laughter]
KIRAN MUSUNURU: Yeah. It's usually 6, 7, 8 years behind. That's just how it is. And that's okay. But transformational technology, and you don't need me to tell you, I'm sure in your podcast you've talked about CRISPR in many different contexts and how miraculously it's helping patients with diseases like sickle cell disease, and other diseases, and it's going to be able to treat a whole variety of rare genetic diseases. And I'll get to that because part of my vision actually does extend to that. But I think it can be used to tackle the world's leading cause of death, which is heart disease and the way this works conceptually is very simple. Let's use CRISPR to make the changes to the DNA, to turn off genes like ANGPTL3. These genes that we know if turned off will protect you from heart disease because we know from those outliers that it's all upside, no downside. Let's do that. Let's deliver it into the liver, which is where the action is and make changes in the DNA in the liver cells that will turn off a gene, maybe even multiple genes, but at least one gene. And by doing that permanently reduce cholesterol levels.
BRUCE MCCABE: And the liver, it's a happy coincidence that the activity is there, isn't it? Because the liver regenerates so much that it improves the efficacy of the...
KIRAN MUSUNURU: So in this case, it is true, the liver is highly regenerative and that can be an advantage in many situations. But in this case, the method by which we're introducing CRISPR into the liver is so powerful, it basically hits every single liver cell.
BRUCE MCCABE: Really?
KIRAN MUSUNURU: So you don't need any regeneration at all.
BRUCE MCCABE: Really?
KIRAN MUSUNURU: Yeah.
BRUCE MCCABE: Wow.
KIRAN MUSUNURU: And this actually ties to this morning's announcement. The Nobel Prize in Physiology or Medicine for mRNA vaccines. But here's the cool thing. The same technology that's in the COVID-19 mRNA vaccines and will eventually be deployed in vaccines for all sorts of infectious diseases. That same technology can be used to deliver CRISPR into the liver in the body at high efficiency. So that it's hitting every single liver cell. The COVID-19 vaccine, what is it? It's basically a fatty sphere, what we call lipid nanoparticles. So it's made up of four or five different fat molecules, different types that weave together into this ball or this sphere. And within these lipid nanoparticles, these spheres, are contained messenger RNA molecule. COVID-19 mRNA vaccines, that RNA molecule codes for the spike protein of the SARS-CoV-2 virus.
BRUCE MCCABE: And so it's teaching the cell to make a little piece of that spike so that it activates the immune system.
KIRAN MUSUNURU: Exactly. So you get a jab in the arm, typically. It's delivering it locally to the muscle, the cells that are there, including immune cells. And the lipid nanoparticles get into the cells and deliver the cargo, the RNA. Once the RNA is in there, it starts using the cell's own machineries to start making the spike protein. And then that kicks the immune system into action. And that's how you get protection against COVID-19 infection, or at least severe COVID-19 infection.
Now, all you need to do is take that same technology, the same lipids, more or less, maybe with some slight tweaks, but more or less the same fatty spheres. But replace that mRNA that encodes the spike protein with an mRNA that encodes CRISPR. And it turns out you need two RNAs instead of one, but that's fine. You are putting these RNAs inside the fatty sphere. Now you have your lipid nanoparticles. And instead of a jab in the arm, you infuse it intravenously directly into the bloodstream. And it's a much larger dose. It's like a hundred times to a thousand times the dose you get from a little vaccine, a little jab in the arm. But when you do this you get this infusion, it takes about an hour. It goes straight to the liver. And the reason that it gets taken up by all the liver cells is that is the liver's purpose in our lives. It's to clean things out of the blood. So it is adapted to filtering all sorts of stuff out of the blood. So if you put lipid nanoparticles, if you put almost anything into the blood, the liver will take it up.
BRUCE MCCABE: I see.
KIRAN MUSUNURU: So it goes straight to the liver, hits every single liver cell, and delivers CRISPR, or at least the RNA encoding CRISPR, into each of the cells. And then once the RNA is in there, it takes advantage of the cell's own machinery and then produces the CRISPR protein.
BRUCE MCCABE: So it actually teaches the cell to manufacture CRISPR.
KIRAN MUSUNURU: Yeah, internally within it. And then the CRISPR...
BRUCE MCCABE: It goes to work.
KIRAN MUSUNURU: Goes to work.
BRUCE MCCABE: Oh my goodness.
KIRAN MUSUNURU: And one of the components of CRISPR that went in along with the lipid nanoparticles tells you exactly where to go in the genome. It's like the GPS. It's 20 letters. And it says, find those 20 letters in the right context, in the right gene, in the genome, in the nucleus of the human cell, which is where all the genetic information is contained, and CRISPR, once it's made in the cell, the cell has made its own CRISPR effectively, or has been taught to make its own CRISPR. That CRISPR goes into the nucleus of the cell and it scans the entire genome, all 20,000 genes, as we talked about before. It finds the one gene and it makes a change. And it changes, at least the version that we're using, it changes exactly one letter out of the three billion letters in the genome. It's that precise. And that one change turns off the gene.
BRUCE MCCABE: That's astonishing.
KIRAN MUSUNURU: And the thing is, the CRISPR doesn't stick around because that RNA, it breaks down pretty quickly.
BRUCE MCCABE: Yeah, it's transient.
KIRAN MUSUNURU: So yeah, so you get a short burst of CRISPR activity. It makes the change that you want. And then it goes away as if it had never been there, within hours, or maybe a few days.
BRUCE MCCABE: Incredibly powerful. So I'm just trying to imagine from a patient experience point of view, how quickly they're going to... I guess perhaps they don't feel different the following day sort of thing, because it's cholesterol and perhaps it's... But it's an instantaneous. Almost instantaneous.
KIRAN MUSUNURU: Yeah, so you get an hour infusion. And then it probably takes on the order of days to weeks before the full effect occurs.
BRUCE MCCABE: If you were taking blood samples each day and looking at your cholesterol over a week or two, you see this plummet.
KIRAN MUSUNURU: We don't have human data yet. There is a clinical trial that is ongoing. And next month we'll hear the first results of that clinical trial. So I can't really speak to what happens with actual human beings, actual patients who've received this therapy. What I can speak to, ad nauseam, is what happens in mice, what happens in monkeys, the animal models where we tested it first before starting the clinical trial. And in monkeys, same sort of thing, intravenous infusion takes about an hour. And then it takes about a week. And then their cholesterol levels fall something on the order of 60%.
BRUCE MCCABE: And stay down forever.
KIRAN MUSUNURU: And stay down.
BRUCE MCCABE: Forever.
KIRAN MUSUNURU: At this point years.
BRUCE MCCABE: For life.
KIRAN MUSUNURU: Yeah. We haven't tracked them for life, but we've tracked them for years and it has not budged. It is down. What looks like forever.
BRUCE MCCABE: Your confidence level would be pretty high. That it'd be for life. Because this looks permanent.
KIRAN MUSUNURU: Yeah, it looks permanent. It should be. And it's... Conceptually it's the DNA, it's the source code of everything in the body…
BRUCE MCCABE: It's amazing.
KIRAN MUSUNURU: It's changed.
BRUCE MCCABE: That's amazing. And just to imagine cholesterol plummeting off for a week and that's it forever, as an outcome. It's just amazing. Can we talk a little bit about the trial because I know there's bits and pieces out there and I know... I always refer to patient number one.
KIRAN MUSUNURU: Yes.
BRUCE MCCABE: Like, out of this hospital, there was patient number one in CAR T-cell therapy, which was Emily Whitehead. And I've tracked her story really closely and the family story. So it seems like when I'm looking for your future Nobel Prize – and I think I am looking at someone who qualifies – patient number one, kicked off human patient number one, about a year ago in New Zealand. Is that right?
KIRAN MUSUNURU: Yeah, in July of 2022. So yeah. A little more than a year ago. New Zealand. As I understand it, since then, a number of patients, several patients have been dosed both in New Zealand and the United Kingdom.
BRUCE MCCABE: I see.
KIRAN MUSUNURU: Again, no specific information as to exactly who they are and how bad their disease is or what the exact circumstances are or how they responded to the drug. We'll find out some of that information next month at the American Heart Association meeting in Philadelphia.
BRUCE MCCABE: Okay. Presumably they had... Were at high risk if they were qualified for trial.
KIRAN MUSUNURU: Oh, absolutely. Yeah. The criteria to be included in the trial where you already had to have had a genetic condition that gives you very high cholesterol and have already had active cardiovascular disease, already had a heart attack or something along those lines.
BRUCE MCCABE: So in a month's time, we will find out.
KIRAN MUSUNURU: We'll find out something.
BRUCE MCCABE: How it's gone.
KIRAN MUSUNURU: Yeah.
BRUCE MCCABE: Well, given what we just talked about, theoretically, that could be exciting in a month. That's something to look for, those results.
KIRAN MUSUNURU: Yeah. Yeah.
BRUCE MCCABE: Because we'll now get a bit of an idea.
KIRAN MUSUNURU: Now I have to emphasize it's early days. This is a phase one clinical trial. Which is first and foremost about safety.
BRUCE MCCABE: Yes.
KIRAN MUSUNURU: And so the way this often works or typically works is when you give the drug, no person has ever received that drug before. So you have no idea really what's going to happen, you guess from what happened in monkeys, what happened in mice and so forth. But you don't really know. So you start with an absolute lowest dose that you feel you can get away with.
BRUCE MCCABE: Of course. I see.
KIRAN MUSUNURU: And so you're just trying to see if the patient is okay with that very, very low dose. And there's no expectation that it's necessarily doing much at that very low dose because you're starting so low. You do that in a few patients and then you say, "Okay, it looks like those patients have tolerated it fine, it's safe. Let's go to the next higher dose," and then a few patients and see, and then typically you go through three or four levels where you're escalating and adjusting the dose. And so it's hard to predict what will happen in that given circumstance. It's usually not till phase two, the second clinical trial, where you're really starting to look for efficacy, where you're looking for the desired effect, which in this case would be substantial reduction of cholesterol levels.
BRUCE MCCABE: Got it. Yeah.
KIRAN MUSUNURU: So who knows what'll...
BRUCE MCCABE: So I should not—I shouldn't jump ahead of the curve with the trials. This is that earliest one.
KIRAN MUSUNURU: It's unusual—There's celebrated examples of like patient one, as you said, like Emily Whitehead, who had a tremendous response. And quite properly they get a lot of attention and are held out as exemplars.
BRUCE MCCABE: Spectacular. Yeah.
KIRAN MUSUNURU: This is the power of modern medicine, and rightly we should celebrate that. But with most drugs it's usually not quite so simple. It's more like maybe patient 10 or patient 100 or whatnot before you really actually get to a position where your drug's being given at a high enough dose to see a large effect.
BRUCE MCCABE: Yeah. Okay.
KIRAN MUSUNURU: But we'll get some information next month. And if all goes well, then we'll ... Hopefully there'll be some patients who've received the drug who've had some response in cholesterol. And that will be a great starting point. If that is the case.
BRUCE MCCABE: That would be awesome.
KIRAN MUSUNURU: Yeah. Because then it tells you, "Hey, as a proof of concept, it works." And then in my mind, once it's working, then it's about optimization and figuring out the right conditions and tweaking this and that, and figuring out the right dose and going from there. And this is drug development. It's challenging, and things often don't work. More often than not, they don't work. But if this trial, you see some promising results in phase one, then I feel good for the future. I feel good for the future.
BRUCE MCCABE: Well, one of the hardest things in doing what I do is when you talk timeframes, and I know that every scientist I talk to hates talking timeframes because there's so many unknowns. There's so many variables here.
KIRAN MUSUNURU: Yeah, yeah, yeah.
BRUCE MCCABE: But the dream... When we go to something that's available to anyone, it's not a 50-year shot. It's maybe a 20, or ... ?
KIRAN MUSUNURU: I think that's probably like 20 is a reasonable timeframe. Let me put this in context. So my laboratory first started working on this back in 2013 when CRISPR was relatively new on the scene. And we really were curious about the question, if we put CRISPR into the body of an animal will it work? Up until that point, it had only been tested in cells and we were actually one of the first labs to try it in cells. And it worked so well that natural next question was, "Okay, what if we put into the body of an animal can this actually have therapeutic use?" We didn't know what was going to happen. And being a cardiologist, I said, "Okay, well if we're going to go after any gene, it's going to be a cholesterol gene." because that's what I'm interested in long-term. And so we tried it against the cholesterol gene in the mouse, and it worked spectacularly well. So this was 2013/2014, and then we published it. And it got some attention from the press. And I did some interviews and I got that same sort of question, what's the timeframe? When is this going to be available to patients? [laughter] And I made a not-well-informed sort of back-of-the-envelope or pulling numbers out of thin air. I said, "I think we could get this to patients within 10 years." I really had no basis to say that except just some fond hope that maybe somehow this will happen.
BRUCE MCCABE: Right. Emotionally, it felt right. [laughter]
KIRAN MUSUNURU: It's far enough away that it feels safe, but close enough that it feels like it's just around the corner.
BRUCE MCCABE: I'm familiar with this.
KIRAN MUSUNURU: Yeah. You know how this works.
BRUCE MCCABE: People are constantly asking.
KIRAN MUSUNURU: But here's the thing. So the first patient was dosed with our drug in July of 2022, which is less than 10 years.
BRUCE MCCABE: Hey. Yeah.
KIRAN MUSUNURU: And I was actually not too far off the mark. It ended up being a little less than 10 years. And so I think, if you're looking forward, it'll probably take another five years if all goes well, that's a big assumption.
BRUCE MCCABE: Phase two and phase three.
KIRAN MUSUNURU: Another five, six years before you go through phase two and phase three. And then any physician can prescribe it to any patient they want. Now, the FDA, other regulatory agencies, will say, "Well, for now it's only for these patients." And it'll probably start, as you said, with the highest-risk patients. But the way things work is any physician can prescribe any drug off-label for anything they want. So in theory, if you can get some physician who's willing to prescribe it to you. And you're willing to pay for it out-of-pocket because insurance is not going to pay, if it's not specifically intended for you. There's really no reason why, if you're sufficiently motivated, you could get the therapy once it's actually on the market.
Now, that said, if you're doing things properly in say five years, six years, seven years, by the end of the decade, I would expect it's approved for use, in at least patients with very high cholesterol that's hard to manage with other types of drugs or who have cardiovascular disease or at high risk for cardiovascular disease. And then it'll probably take about 10 years, I would guess, before there's enough experience for a regulatory agency like the FDA to say, "Okay, we've observed this long enough patients who are getting this, there are no adverse long-term consequences." We're in the clear, now we can start to think about giving it to patients more broadly in the population.
BRUCE MCCABE: Yeah. So that's 10 years on top of the first period with the trial though. So that does get us around 20.
KIRAN MUSUNURU: 20 yeah yeah.
BRUCE MCCABE: As a timeframe.
KIRAN MUSUNURU: I think so.
BRUCE MCCABE: Oh yeah. How are you doing for time?
KIRAN MUSUNURU: Oh, totally. Fine. Yeah. We can keep going.
BRUCE MCCABE: Just a check on that. That's so wonderful. Yeah. And I promise I won't hold you to the timeframe.
KIRAN MUSUNURU: No, no, no.
BRUCE MCCABE: I know the problems, but it does... It's good to give people a sense that this is not far in the future. It's something that they...
KIRAN MUSUNURU: Absolutely.
BRUCE MCCABE: They'll probably end up seeing it.
KIRAN MUSUNURU: Yeah I think that's right.
BRUCE MCCABE: And it gives them some optimism and, it gives people who are into science or students into science, that listen to this, also a little bit of motivation to get into the field and see things happen in their lifetime rather than theoretically at some point in the future.
KIRAN MUSUNURU: Exactly.
BRUCE MCCABE: So at some point I was going to ask you if at some point I could eat as much ice cream and have as much beer as I want, and eat whatever I want. But that's never going to be the case because it's only 50% [of the factors].
KIRAN MUSUNURU: Yeah. There is the moral hazard. I do, in darker moments, I do worry about this, which is that if you give this, if you don't get the messaging right, and you give this to a young person, they may come away with the, with the misconception that they're in the clear that they have a license to do whatever they want and they're never going to get a heart attack, which as we said is not really true. And might feel licensed to just engage in all sorts of bad behavior. Eat bad stuff all day long, day in, day out, and gain a lot of weight, get diabetes, obesity, all the bad consequences of those diseases. You can really mess yourself up. Yeah. You may not get a heart attack as quickly as you otherwise would have, but there are all sorts of reasons to be healthy, and I do worry that it might come back to bite us a little bit.
BRUCE MCCABE: Yeah. Well, that'll be a progressive educational process.
KIRAN MUSUNURU: But this is, yeah, this is it. It's still much better to have this than to not have it. No question.
BRUCE MCCABE: Exactly. That's no reason not to do it. Exactly right. It'll be about messaging and teaching, like everything in life. And you mentioned earlier that you had some hopes for other rare diseases.
KIRAN MUSUNURU: Yeah. Yeah. Absolutely.
BRUCE MCCABE: Was that because of the mechanism, the delivery mechanism? Because it's so powerful?
KIRAN MUSUNURU: Exactly right. So I've been working on this cardiovascular disease vaccine, if you want to call it, or CRISPR therapy or 'one-and-done' therapy, or however you want to frame it, for about 10 years now.
BRUCE MCCABE: One-and-done. I like it.
KIRAN MUSUNURU: Yeah. One-and-done. Yeah. About 10 years now. And so I feel very good and I feel like, "Okay, this will be an important part of my life's work and my legacy," but in a way it's taken on a life of its own it's now into clinical trials. It's sort of out of my hands. It's now being pursued by a company I co-founded Verve Therapeutics. Other companies are starting to get into the mix and do similar sorts of things. So I think one way or the other we kicked off a trend. I don't know who will get to the finish line or who will be most commercially successful. That's all a little bit outside my realm.
BRUCE MCCABE: That's harder to predict.
KIRAN MUSUNURU: Yeah. And outside my realm as an academic. But, I feel that's in a good place. And as an academic, I'm starting to thinking about, "Okay, where do we go next? We can help address the world's leading cause of death, but are there other groups of patients we can help?" And so, to me, one of the more astonishing things about what we've been able to do here is this idea that we can combine two as of today, I can say this, two Nobel-Prize-winning technologies, CRISPR on the one hand, and then mRNA therapies on the other hand and combine them, and it gives us a straight route into the liver. Which means we can put whatever editing tool, like CRISPR, we want into all the cells in the liver and make changes in the DNA. And it's great to talk about turning off cholesterol genes that can help so many people. Clearly. But it can also help a totally different group of people. And those are people with rare genetic disorders. It's really the other end of the spectrum. You're talking about a very, very common disease.
BRUCE MCCABE: Yes. You're talking about one that anyone might benefit from.
KIRAN MUSUNURU: Almost so common that it's almost ignored, as we talked about. No one really gets too worked up about cardiovascular disease compared to any of a variety of other diseases. But what about the other end of the spectrum with this huge unmet need, patients with terrible metabolic conditions, what we call inborn errors of metabolism, where from day one, they're born with a defective enzyme and that causes them to be really, really sick. And from day one till the day they die, they have to manage these condition. And it's many of these inborn errors of metabolism. There's no treatment. You try to manage them, but despite the best management the most severe of these diseases, they will die within one or two years unless they get a liver transplant. And liver transplants are not so easy to come by.
BRUCE MCCABE: No.
KIRAN MUSUNURU: And it turns out a lot of these inborn errors of metabolism, the enzymes that are responsible, are centered in the liver because the liver's ground central for metabolism. And there's a lot of production of things, breakdown of things. It's all happening in the liver. So a lot of these enzymes, they're in the liver. So if we have a way to deliver CRISPR or other tools like that into the liver, really an open door, straight route in, in my mind I'm thinking, "Wow, what if we can take all of these patients with these different conditions in born errors of metabolism, which you can think of as misspellings in the genome, in specific genes that make these enzymes, what if we can actually correct those misspellings with a single treatment and permanently address the root cause of their condition?" And it would take a lifelong genetic condition that they're suffering from, from the day they're born, in some cases even before birth, at the fetal stage and transform their lives. Entirely rid them of their genetic condition. To me, that's incredibly powerful.
BRUCE MCCABE: Yeah. And it's as if you've got the toolkits and it's a matter of tweaking the programming.
KIRAN MUSUNURU: Exactly.
BRUCE MCCABE: For the right target. For a new target.
KIRAN MUSUNURU: So let me give you an example. I've been working on a disease called PKU that's an acronym for phenylketonuria. It's a pretty well known genetic disease. Anyone who's ever drunk a diet coke, there's a warning on it. Like, "Do not drink this if you have phenylketonuria" or PKU because there's phenylalanine in there.
BRUCE MCCABE: Okay.
KIRAN MUSUNURU: It's an amino acid. And the problem in this disease is the enzyme that breaks down phenylalanine, this amino acid, is defective. And so phenylalanine builds up to very high levels in the blood because it has nowhere to go. And it turns out at a very high level, this amino acid is actually toxic to the brain and will cause all sorts of neurological issues. It actually doesn't cause liver disease. Liver's fine. But it's because the enzyme is made in the liver and is defective in the liver. It causes the buildup of this amino acid in the bloodstream. It crosses over into the brain and it causes all sorts of bad things, seizures, developmental issues, impaired cognition, intellectual disability. If you're a mother, and you have high levels of this amino acid while you're pregnant, it causes a lot of damage to the fetus. And so there are all sorts of bad consequences. Now we pick up everyone who has this disease on newborn screening. In fact, PKU is the disease for which newborn screening was started back in the 1960s.
BRUCE MCCABE: Really?
KIRAN MUSUNURU: Because we understood back then that if someone has this disease, they're already starting to suffer damage if you don't control the phenylalanine levels from the day they're born. And so what you do is, when someone's identified as having PKU on newborn screening, you immediately put them on a low protein diet, phenylalanine-free diet. And that helps. It's not a cure. And they have to adhere to that diet as best they can all through childhood, all through adolescence, all the way till the day they die. Otherwise they're going to start to have these neurological problems. That's their life, that's a huge burden to put on patients.
BRUCE MCCABE: Yeah.
KIRAN MUSUNURU: There are a couple of medications now, one of them's a pill, but it doesn't work in most PKU patients only a subset of them. The other one's an injection you have to take every day, and it has a high degree of getting an allergic reaction. So there's warnings from the FDA it has to be close to monitored. It's very, very, very expensive.
BRUCE MCCABE: Once again, there's no comparison to getting a one-shot therapy.
KIRAN MUSUNURU: What if you could give a one-time treatment, correct the misspelling, and then definitively treat the condition.
BRUCE MCCABE: Yeah. Right.
KIRAN MUSUNURU: And so we've done this in mouse models. Where we take in mutations that are found pretty commonly in PKU patients, in the general population and made the mice so that they have PKU because of this mutation and ask, what if we use this lipid nanoparticle messenger RNA therapy, deliver CRISPR into the cells in the liver and correct that misspelling, correct that mutation, directly change it from the misspelling to the correct spelling.
KIRAN MUSUNURU: So we're doing something different, with cardiovascular disease we're turning off a gene, we're introducing a chain to turn off the gene. Here we're going in the opposite direction. We're taking away a mutation. We're restoring it to normal, or wild type, is the technical term. And what we found, which utterly blew me away when we got these data, is we give it to a mouse and within 48 hours, the phenylalanine levels, the amino acid levels in the blood, have fallen to the normal range. So they had this lifelong genetic condition very high. And they had the consequences of the disease, within 48 hours, it's as if they never had the disease. [laughter]
It's mind blowing. And I think that will probably turn out to be true in PKU patients when we get to the point of treating them. As well as patients with all sorts of inborn errors of metabolism. because once you fix that enzyme, it should very quickly restore normal metabolism.
BRUCE MCCABE: Yeah. That's incredible.
KIRAN MUSUNURU: And so I'm very, very excited about this. In some ways, even more excited than the work on cardiovascular disease.
BRUCE MCCABE: Yeah. because there's all these pathways, all these possibilities now.
KIRAN MUSUNURU: Yeah. And it's a much smaller groups of patients compared to the world's leading cause of death. But they have such a devastating disease that affects them for their lifetime. They're suffering it from their old lives. In many cases they're dying because they can't get that liver transplant utterly devastating it. And now we're potentially in a position to make these drugs, these gene-editing therapies, CRISPR therapies, that you can give very shortly after birth and make it as if they never had this disease to begin with.
BRUCE MCCABE: That's perhaps a good way to end it. That is incredible. Those new pathways.
KIRAN MUSUNURU: Yeah. And then you hit upon something very interesting, this idea that you're just re-coding, the therapy.
BRUCE MCCABE: Yeah. Exactly.
KIRAN MUSUNURU: And so as it turns out, I can take the same exact therapy. Lipid nanoparticles messenger RNA for CRISPR, that same exact therapy and just change that GPS I mentioned, 20 letters that say where in the genome should CRISPR go to make a change, go to gene A versus gene B, all I need to do is change 20 letters, everything keep it exactly the same, change 20 letters, and it would cure patients with PKU. Totally different disease, totally different circumstances, but more or less the same.
BRUCE MCCABE: Okay. We have to step through that again. So I didn't realize the punchline that was coming there. So exactly the same chain of events in formulating this treatment for a patient.
KIRAN MUSUNURU: Yeah.
BRUCE MCCABE: Where we can repurpose by just changing 20 letters. So this would, if you would imagine you working away on this, it would be done on a laptop somewhere that would actually...
KIRAN MUSUNURU: Exactly. Yeah.
BRUCE MCCABE: Do you know what I mean? Like at some stage.
KIRAN MUSUNURU: Yeah at some stage yeah.
BRUCE MCCABE: But yeah, it really is truly re-programmable medicine...
KIRAN MUSUNURU: Absolutely. Right. Now it's a while before we get there, and that has more to do with regulatory law than the actual science. The science is very clear, but we...
BRUCE MCCABE: Yes. because each one's a new treatment technically.
KIRAN MUSUNURU: … for now, the FDA is viewing each of these as a new treatment and wants us to go through the full process. But I think, give it a few years, and enough of these getting to the clinic, the FDA will relax that stance and come to view this more as a platform, as programmable medicine, as you say.
BRUCE MCCABE: A “platform.” That's nice.
KIRAN MUSUNURU: Yeah. And then it really will be just recoding. Just do it on a computer, change it, predict the consequences, and then manufacture and give it to your patient. Even if that patient has a unique mutation, that they're the only person in the world who's ever been found to have that mutation.
BRUCE MCCABE: You could actually deliver something to them.
KIRAN MUSUNURU: You could actually... You could do something for them. That's the potential power here.
BRUCE MCCABE: Wow.
KIRAN MUSUNURU: So it's going from...
BRUCE MCCABE: I came in here to talk about cardiovascular, I'm talking about everything now.
KIRAN MUSUNURU: It's totally opinion [laughter] Yeah. You came here to talk about a one-size-fits-all deployable cardiovascular disease vaccine that would protect the entire population, protect the world against cardiovascular disease. But with just a little bit of switching the model around, you're actually talking about the ultimate programmable platform for therapeutics where you can craft therapies for individual patients with their own unique mutations, what we call N-of-1 cases. It really does have that versatility and that power.
BRUCE MCCABE: Isn't that incredible?
KIRAN MUSUNURU: So that's the future that's coming.
BRUCE MCCABE: That's such a wonderful thing to ponder. And in terms of impact on the world, if the Nobel is awarded for impact on the world, I know it's for a variety of things, but ultimately, I can't think of anything that qualifies better than the work you're doing. So I'm certainly going to be...
KIRAN MUSUNURU: Well, in a way, it's already been recognized. There was the Nobel for CRISPR in 2020 …
BRUCE MCCABE: Yes. For two of the ingredients, yeah.
KIRAN MUSUNURU: …[and] this morning, for messenger RNA. So, I'm an early adopter. I'm the excited guy who's like, "Wow, this stuff is like kid in the candy store," all these technologies that I can draw from and pull together and we can help so many patients.
BRUCE MCCABE: Well, that's very modestly said.
KIRAN MUSUNURU: That its own reward.
BRUCE MCCABE: That's very modestly said. But I do think it's just, if you look at the efficacy there, all the potential outcomes for people at a humanity scale, it is just astonishing and wonderful in terms of impact on the planet. You're working on something and there's nothing bigger, really, medically. Thank you so much for the time.
KIRAN MUSUNURU: My pleasure.
BRUCE MCCABE: It has been a total privilege for me, and a pleasure, and you've given me a lot more to think about than I arrived thinking about [laughter] So yeah, I'm going to keep tabs on this announcement next month with the trials and hopefully we can stay in touch.
KIRAN MUSUNURU: Absolutely. Yeah. So, next month will be the first results from the trial for the cardiovascular drug. And then stay tuned. I mentioned PKU and developing a therapy. That's not just theory, that's something that's happening in my laboratory. And just a couple months ago we received $26.5 million grant from the US National Institutes of Health to take the PKU therapy from the laboratory here in this building all the way to the clinic and start a clinical trial. So hopefully in a few years we'll be talking about that.
BRUCE MCCABE: Awesome. Thank you, Kiran.
KIRAN MUSUNURU: My pleasure.
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