Reprogramming the Future... Dr. Martin Borch Jensen and Dr. Francisco LePort, Gordian Biotechnology
Working on what are usually considered the diseases of old age when you're younger as they're developing. Not only that, doctor Martin Borch Jensen and doctor Francisco LePort from Gordian Biotechnology tell us how they've invented a way to develop and test many cell therapies all at once, all with an eye to making drug discovery faster and drug approval more certain. Doctor Borch Jensen and doctor LePort, welcome to the program.
Dr. Martin Borch Jensen:Thanks, Moira. Very
Dr. Francisco LePort:good to be here.
Dr. Moira Gunn:Now I'm actually going to start by quoting from an opinion piece which you, doctor Borch Jensen, wrote with UCSF professor, doctor Nicole Polk, some 4 years ago in cell and gene. You wrote, in reality, 2 thirds of people aged 65 plus have 2 or more diseases, which shocked me, But putting a pin in that, those diseases started in these individuals when they were much younger, before they were 65. Where and how do these diseases start?
Dr. Martin Borch Jensen:Yeah. Obviously, we don't know everything about every disease, but the way we can think about this is that your body made out of lots of different cells, it functions sort of as a society. All the cells are doing different things in order to preserve all the functions, your breathing, your movement, your digestion, and so forth. And diseases basically occur when that system is challenged, which can happen either through, let's say, an infection, you get the flu, and so there's some outside invader and your body responds, Or, as in the case of aging, the system of your body gets increasingly confused, individual functions sort of, get worse, and then your the ability of your body to sort of maintain this function while you're living your life drops. And that's kind of the thing that prefaces the things that we call diseases.
Dr. Martin Borch Jensen:Right? So you say, okay, I have, you know, Alzheimer's disease, or I have heart problems. That is the symptom of your body's reduced capacity to function normally, as happens through a variety of biological mechanisms, that we call aging.
Dr. Moira Gunn:And it all started a long time ago where from one insult to another or mutation changes as cells are replacing themselves, just little by little, eventually, it becomes one of these conditions, if not more.
Dr. Martin Borch Jensen:That's right. You have a complex system, and so as individual things fail here and there, it seems fine for a while until suddenly things go downhill.
Dr. Moira Gunn:So, what does that mean in terms of trying to cure diseases?
Dr. Martin Borch Jensen:Yeah. It makes it hard. Right? In the case of, a virus, you can point your finger at, like, one exact culprit. Here's the one thing that's wrong, that's causing us to be deceased.
Dr. Martin Borch Jensen:But for these complex chronic diseases that happen with age, it's an interplay of different factors that goes wrong and then causes disease. And so that means in order to find out how to treat the disease, we need to look at the whole set of things that change, and some of them change for various reasons. Imagine a busy office that's, about to have, you know, like a meltdown. Not every conversation in that office is something that's, you know, about to lead to a bunch of, buying whatever subprime mortgages. Right?
Dr. Martin Borch Jensen:So as a, you know, biologist, you go in and you can measure all the things that happened, but you have to cut through and find out what are the key things. And usually the way people do this is through interventions or putting something into the system and changing something, and then see whether you get the result that you want.
Dr. Francisco LePort:I think the interesting thing about aging, as distinct from, many of the other, conditions that we're going after is there isn't this this single kind of impact, this single, you know, insult that's happening to the body. In many ways, you know, we are programmed to age. That is kind of the the normal process, that happens to all of us as humans. And so there really is this big web to untangle, in terms of, you know, what is it that's going, quote, unquote, wrong as we're aging, versus these individual pieces. And this really makes it much, much more complex.
Dr. Moira Gunn:Now let's get to what I'm gonna call better gene targets, you know, which become the therapies. Today with gene therapy, we tend to address 1 or a few candidate mutations. And even with the highly vaunted AI, this is somewhat guesswork. And then 1 or several candidates are tried on animals with a similarity to humans, and, then one and only one drug candidate goes forward, is tested on humans, a successive group of humans, until we approve it's safe and effective. And this isn't strange.
Dr. Moira Gunn:This is how we've been doing drug development for a long time. What's problematic with this approach?
Dr. Francisco LePort:Yeah. So even as you were describing it, right, you can see that there are many, many steps, in that approach. And the reality is that each of those steps is extremely expensive and successively more and more expensive. So when you combine that with this web that, that I had mentioned before, you know, you look at the the number of gene targets that you could potentially pick. There are over 20,000 genes, in the human genome, so the space is very, very large.
Dr. Francisco LePort:And if the, methodology that you have, which is kind of what we've had, you know, traditionally, is to kind of pick a single one of those targets and then go after and then kind of interrogate it, you know, through 1,000,000 of dollars of process and preclinical study and eventually clinical study, you know, it's gonna take you a very long time and a tremendous amount of money to get through 1,000 of those targets. And I think that's really kind of the the issue. Right? We're not very good at guessing what those initial targets are. We've gone through a few of them for these age related diseases that are very complex, and then we've met with failure in the clinic.
Dr. Francisco LePort:And, I think, fundamentally, we need a very different approach to that.
Dr. Moira Gunn:Well, here's where Gordian's approach is so different, and I and I I kinda wanna say to the listener, pay attention now. This is what we call in math, a stepwise different approach. So this is very important. What is Gordian's approach?
Dr. Martin Borch Jensen:So taking everything that we just said, right, what you really would like to do is, to put a lot of different interventions, a lot of potential medicines into a system that has all that complexity, cells talking to each other, coordinating their responses, cells affected by aging, and then be able to test all of the different potential therapies at the same time, getting the answer that you want, which is, does this work when you have all the complexity included and all the barriers to this medicine potentially working for the disease. And so that's the sort of technology that we, invented early in the company's, life. The ability to combine gene therapy with reading out states of different cells and do these simultaneous experiments, where we put many therapies into the organ of an animal that has often spontaneously developed this disease that we're trying to study and then test them all simultaneously without them sort of affecting each other and and getting us a confused answer.
Dr. Moira Gunn:Well, of course, I'm gonna ask you for a first example here. And well before the age of 65, many people have problems with their knees. Cartilage breaks down and you took this example and decided that a horse's knee had a lot in common with a human's knee and racehorses and working farm horses, they have the same problem with their knees that humans do. The cartilage breaks down. Now tell us, what have you done with these horses?
Dr. Moira Gunn:And let me get this straight. You're looking to rebuild cartilage?
Dr. Francisco LePort:I think it's a great, example and actually points to one of the real advantages of this, new method. We are not only able to put, hundreds of different, targets or thousands of different targets in some cases into these animals. But because we can put so many, into these individual animals, we can go into these advanced animal models of disease. So normally, people would go into mice, for example, in osteoarthritis, and they would, you know, if they were to go into an an advanced animal model such as horses, they would do that only for their, you know, select very last target because that's so expensive. We can actually put, hundreds of targets, into individual, horses right from the very beginning of our process, which is really neat.
Dr. Martin Borch Jensen:As you were saying, do we want to regenerate, the cartilage of the joint? And when we go into these complex models, the idea is that we can capture all the different aspects of disease. So osteoarthritis is, you know, cartilage being worn away. But what you want to treat is both that and the pain that patients with osteoarthritis are feeling, which comes, in part from inflammation in that joint. And so with our technology, what we can do is go into this, system that captures all of the biology of the disease and then test hundreds of targets that each individually might be effective against some aspect of the biology that's going wrong and potentially in combination, or maybe there is, one gene we find that does everything you want to comprehensively treat, this disease and find treatments that will be really effective once we go into people.
Dr. Moira Gunn:So it's not just the I've a I'm a runner and I've run 20 miles a day for 40 years that creates this problem. There's a breakdown in your cells. There is for one reason or another, either because in aging, they're just not as good as they were. They've been mutations, weakened mutations, if you will, or some insult. And so you're able to go in and say, well, let's target and correct this gene.
Dr. Moira Gunn:Let's target and correct that gene. Let's target and correct that gene. And then so you have a whole number of targets lined up, gene corrections, that you can put in. But then how long do you leave it in the horse before you take a look at what's in the cartilage?
Dr. Martin Borch Jensen:Typically, let's say a month because, what we want to find out again is how do the therapies, affect the tissue with all of this stuff going on? So we don't want to know, you know, what happens immediately when you take this medicine. We want to know what would the, sort of biology of a patient look like, after they've gotten this treatment, right, in the long term? So, yeah, 1 month, let's say.
Dr. Moira Gunn:I'm speaking with doctor Martin Borch Jensen and doctor Francisco Laporte from Gordian Biotechnology in South San Francisco. Doctor Bortch Jensen is the chief scientific officer, and doctor Laporte is Gordian's CEO. Okay. So now here's the $50,000,000 question. You've put several 100 different
Dr. Francisco LePort:More.
Dr. Moira Gunn:Gene correcting, activities, if you will, into this joint, and you say, oh, look. This looks better. The genes look better. They look younger. They look they look like they're all gonna function.
Dr. Moira Gunn:How do you know which of the several 100 gene correcting, treatments you've put in actually worked?
Dr. Francisco LePort:Yeah. So, for that, we use a technology that's called single cell sequencing. So I'm sure everyone has, heard about, DNA sequencing. Right? This got, popular, in the 2000 as the price started coming down with the Human Genome Project and all of that.
Dr. Francisco LePort:So, at this point, there's technology out there that can allow us to actually sequence individual cells. And we use that to look at these individual cells that have gotten these individual perturbations or gene changes in the, living horse. So, we go in. We can identify, which cells got which, change, which gene target change. And then using this single cell sequencing technology, we can identify what exactly did that change about the cell.
Dr. Francisco LePort:It's kinda like looking at, you know, the the code of a computer program, and then getting a sense of, well, what is the the status of this, you know, computer? In this case, we can get a status of what is the cell doing? What are the functions that it's performing? How well is it performing those functions? Is it performing the functions that it would normally be performing, in a healthy environment?
Dr. Francisco LePort:And all kinds of other, you know, more complex or more nuanced things. Right? Is it, serving the protective effects that we want it to, in this diseased environment? So we get this very, very rich, rich data set by using this, single cell sequencing technology.
Dr. Moira Gunn:Well, you could certainly tell what's changed positively. That's right. But how do you trace that back to which of your several 100 gene targeting therapies that you would you injected all at the same time? Which ones worked?
Dr. Martin Borch Jensen:The fact that we're using gene therapies here to deliver these genetic payloads comes in really handy sort of by design. So when we deliver a therapy that, changes the expression of some gene, we also include this bar code. It's called a barcode, you know, in the in the industry, but it's basically a sequence that uniquely labels this therapy. And so when we detect that sequence in the cells that we, are analyzing, then we know which therapy was in there.
Dr. Moira Gunn:You know, if you are a computer programmer, you'll know that, sometimes you put in a series of things called no ops, no operation. They just kinda fill it in, and the computer thinks, oh, yeah. I'll just go along. It just does it's a instruction that does nothing. You can add such things in your GCATs, which are the particular nucleotides that are your programming your your DNA and then you could you could say, well, just put we'll put a sequence that means nothing in your body.
Dr. Moira Gunn:So that's enough variation that you can identify each one of these separately.
Dr. Martin Borch Jensen:Yeah. That's the basic idea.
Dr. Francisco LePort:Yeah. That's right.
Dr. Moira Gunn:You guys are pretty clever guys. I'll give you that. I'll give you that. Okay. I have more questions.
Dr. Moira Gunn:Don't don't don't stop now. You're also working on heart failure and fatty liver disease, NASH. Used to be called NASH. What are you doing in each, and what animals are you working with there?
Dr. Martin Borch Jensen:So in each, disease, we really are asking, well, which animals are similar to the patients? Which in terms of their, the anatomy of the tissue, but also how they get the disease. And so MASH is interesting because, it happens more with age, but diet also plays a big part. And so the way that, many people including us will, develop MASH models is basically to give the animals, which for most people is mice. In our case, we also use mice as well as monkeys, which you can imagine are more similar to humans.
Dr. Martin Borch Jensen:And we give them a diet that they actually quite like. The technical term is a Western diet. It's high in sugar, high in fat, and high in cholesterol. And then over time, and this is the key part and the part where, you know, some companies are impatient, but rightfully so, you want to run your studies quickly. You don't want to feed this diet over, let's say, more than a year, but that's how it works in the patients.
Dr. Martin Borch Jensen:So we have, animals on these western diets for a really long period of time, and the monkeys have been on it for more than a year, at this point. And then gradually, your liver experiences the same as the patients, this accumulation of fat and then eventually turns to disease.
Dr. Moira Gunn:Uh-huh. So you're doing this in in monkeys as well for the MASH, for the fatty liver disease?
Dr. Martin Borch Jensen:That's right.
Dr. Moira Gunn:Okay. What about heart failure? What are you trying to do on heart failure?
Dr. Francisco LePort:Yeah. So for heart failure, similarly, we look at what are the best animal models that, we can go into there. And, again, I think this is the real to me, the neat part about this technology and what it enables is the ability to really go into systems that are as close to human as possible, depending on the particular disease that we're going after. So in heart failure, we are looking at, actually 3 animals. We've got mouse and rat models of heart failure and then, pigs.
Dr. Francisco LePort:Turns out that, pigs have hearts that are actually quite similar, to humans, in many aspects of their, physiology, and we use those as well. And, in terms of the the mechanics of it, it's actually very similar to what we described with the horses, which again, is a real advantage, the technology that's available. We can really extend it to, any animal model of disease. It doesn't require too much fiddling with, in order to get it to work, for these various systems.
Dr. Moira Gunn:Now in those cases, are you looking to restructure the heart or replace cells in the heart? What are you looking for?
Dr. Martin Borch Jensen:Not replace, more like reprogram. And this is essentially what all drugs do. You have this, machine that is running different programs and they dysfunction. And so
Dr. Moira Gunn:Called your body.
Dr. Martin Borch Jensen:Yeah. Exactly. Your body. But then, you know, the subpart of your body, you can, call it the engine if you want. Right?
Dr. Martin Borch Jensen:The heart has to beat. The cardiomyocytes, that's the technical term for the cells that make up your heart, and cause it to beat. Right? They have to do a lot just to do that simple job. They have to metabolize a lot of energy in order to cause these contractions, and they have to do that in a synchronized manner.
Dr. Martin Borch Jensen:And so what we want is that the cardiomyocytes that have been working for your whole life, to keep your heart beating, are behaving similarly to what they were like without this, accumulation of dysfunction, that caused the disease. And we do that by going in and taking, as you said before, 1 or more genes and just tweaking those, to tweak the whole system.
Dr. Moira Gunn:Now in each of these cases, I'm assuming that you're looking to create some, combination of cell targets that that will be really great, and then taking that through the normal cycle of FDA approval, but with more confidence that this combination treatment or particular treatment will really make a difference.
Dr. Francisco LePort:That's exactly right. Yeah. We are looking to identify, gene targets, whether it's a combination, which I think this also really opens up, or, you know, if we find that that, you know, great single target that's been hidden, you know, up until now, we are looking to identify which of those, kind of best in class that we can then create a therapeutic for and take it into the clinic. And, again, the the nice thing about, the approach that we've got here at Gordian is we can look at that, you know, 100 or thousands of genes at a time. And so we can really explore that very large space.
Dr. Francisco LePort:Right? I mentioned 20,000 genes. We can really take a big chunk of that space and go and explore all of that and really try to find, you know, that needle in the haystack, right, that really best gene that's out there, and then go and move that into clinical trials, again, with that increased confidence, as you mentioned, as we go into human.
Dr. Martin Borch Jensen:It's sort of like, we do a lot of things that make life harder in the short term. You know, we're really picky about what is the system where we want an answer to this test and, like, what is not just something that could work, but what is the best gene or combination of genes to target upfront, because clinical trials usually fail. Even in, you know, across all diseases, 90% of them fail or more. And in these diseases that are extra hard, it's, it's even greater. So we wanna do everything we can to reduce the risk of failure, at the clinical stage.
Dr. Moira Gunn:Well, I can tell you the numbers. As you said, 90%. It's one out of 9 drugs succeed. On average, takes you $1,000,000,000 to get through the whole process. 2,000,000,000 if you if you had to borrow the money, get people to invest and and pay them back.
Dr. Moira Gunn:I mean, we're tracking high stakes, for, only 1 out of 9 will succeed. So anything that changes that number that reduces the, the the how many shots you have to take on goal to get there is is certainly welcome news.
Dr. Francisco LePort:That's right.
Dr. Moira Gunn:Returning to the original part of our discussion about how the diseases of those over 65 start much earlier. Would you anticipate different treatments for different stages of the disease?
Dr. Martin Borch Jensen:Potentially. I think, you know, as a scientist, I would say the data will tell us, and that's why we have different models that are modeling different aspects, different stages of the disease, for example. But, with what we know now, yeah, there are changes that happen early in the disease. Let's say, you get this loop of inflammation that keeps happening in the organ and it never turns off the way it's supposed to when you have sort of an immune response. And that's what later leads to scarring or dying cells in that organ.
Dr. Martin Borch Jensen:So depending on the stage, of disease, you might want different treatments. And that's something that we can examine with, with our system.
Dr. Francisco LePort:Yeah. And I'll I'll add to that, and just say when we go into these large animal experiments, the the neat thing about these large animals, as opposed to the kind of genetically identical mice that are typically used, these large animals are genetically varied the same way that humans are. Right? All humans have different genes that look different, different height, different weight, different, you know, whatever. And these diseases impact them differently.
Dr. Francisco LePort:And so we can actually explore some of that variation, in these, large animal experiments and really get a better sense for which of these targets that we're going after either will have kind of a a targeted therapeutic effect for this, you know, level of disease or this type of disease, it's called an endotype, or, have a broader effect, you know, that can actually be useful for a larger patient population.
Dr. Martin Borch Jensen:And that's really important for the trials. When you get really into these, clinical trials, for age related diseases, it quickly becomes evident that this is a huge factor, this heterogeneity, the differences between the patients. You often see companies that, test a drug in 500 people. And it looks like, you know, statistically, you have to sort of run the right tests and so forth. But it looks like, you know, maybe 40 of those people actually had a benefit from the drug.
Dr. Martin Borch Jensen:All those people supposedly had the same disease. Right? They all had osteoarthritis or heart failure. But that's a label that we put on to a diagnosis by a doctor. The biology is not necessarily identical in every case of this disease.
Dr. Martin Borch Jensen:And so the ability to probe that is something that, again, hopefully will increase the rate of success in clinical trials if you know what you're going in to target and who might benefit.
Dr. Moira Gunn:You know, there are so many diseases. You guys have been working on this for a while, and you've got 3 underway. Do you anticipate working with with others to bring them in, you know, so that there are more people or organizations or companies working with you so that more solutions can be found at this point?
Dr. Francisco LePort:Absolutely. I think, you know, even tackling one of these diseases and producing a cure, I think would be a real miracle, in terms of, improving, you know, health span and lifespan and and all of that. And as you said, you know, there are, you know, dozens, that are really the number one killers in the developed world. So we would love to work, and we do, collaborate with, other, biotechs in the industry, pharma companies, and partners that can really help us advance these things forward. Right?
Dr. Francisco LePort:We're still a relatively small company, and our focus really is, on identifying these novel targets and, producing these early stage drugs. And, we are definitely excited to get help from the industry in pushing these things through these very large stage, clinical trials and eventually to commercialization.
Dr. Moira Gunn:Well, I really appreciate you coming in. I hope you come back and speak with me again.
Dr. Francisco LePort:Absolutely. We had such a wonderful time. I really appreciate it. Thanks, Moira. Thanks, Moira.
Dr. Moira Gunn:Doctor Martin Borch Jensen is the chief scientific officer of the biotech firm, Gordian Biotechnology. Doctor Francisco LePort is Gordian's CEO. More information is available at gordian.bio. That's gordian as in Gordian not, gordian dot bio.
