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Many diseases do not have cures, yet have a foundation in deleterious genomic mutations. Dietrich Stephan of NewBase describes a novel custom drug design platform that shows amazing potential in animal models, and seeks to directly reverse currently untreatable disease.
Talking Biotech is a weekly podcast that uncovers the stories, ideas and research of people at the frontier of biology and engineering.
Each episode explores how science and technology will transform agriculture, protect the environment, and feed 10 billion people by 2050.
Interviews are led by Dr. Kevin Folta, a professor of molecular biology and genomics.
347 Stephan
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Kevin Folta: [00:00:00] Hi everybody. And welcome to this week's podcast. While we focus oftentimes on some of the big name diseases, the ones that catches head. Once I catch headlines, whether it's a latest pandemic or something, that's been a long-term scourge like HIV, or even something like sickle cell disease, you know, we're familiar with these names of these different diseases and disorders.
Uh, affect people everywhere. But as we start getting into the more rare diseases you find that there's just not a lot of research into them in a, not a, not a lot of pharmaceutical development in those areas, mostly because there's such a few number of people affected. To have these custom drugs go through the process is extremely expensive and laborious to maybe not even get them approved.
So companies focus on the big diseases, but yet there's so many people who suffer from rare diseases that need custom solutions. And I think that's what we're going to talk about today. So we're [00:01:00] speaking with Dietrich. Stefan is CEO and founder of new based therapeutics in Pittsburgh, Pennsylvania.
Welcome to the podcast.
Dietrich Stephan: Thank you so much for having me, Kevin.
Kevin Folta: Yeah, this is great. So you're in Pittsburgh, which I never, uh, have interviewed someone from Pittsburgh before. So is this a growing biotech presence in.
Dietrich Stephan: You know, Pittsburgh is interesting because of course it was the center of the world during the industrial revolution and the richest man in the world at that time, Andrew Carnegie hailed from Pittsburgh, uh, and those dollars still remain in Pittsburgh in the form of foundations, which have come to support.
Education and medicine. And so it's bird claims, uh, some of the best, uh, life sciences and technologies, universities, universities, such as Carnegie Mellon university, uh, and that's where our innovation came from. And so we decided to, uh, break new ground and build here.
Kevin Folta: Yeah, it's a really great town too. [00:02:00] I was really surprised when I got to visit there a few years ago.
I have a colleague who works or it's up there and just the, a number of really cool bridges and neat architecture. It's in that it's not that big of a town.
Dietrich Stephan: Yeah, it's a wonderful place to live and work. And, uh, great people are really authentic people that hail from blue collar backgrounds and, and, uh, and so we have just a wonderful, dedicated workforce and, and, you know, a nice advantage is.
Probably a half to two thirds is expensive to do business here, which is always a good thing. And in this market environment,
Kevin Folta: especially in a biotech, a young biotech company, that's fantastic. Well, I started talking about this idea of rare diseases, and I know on your website, you mentioned this idea of undruggable, you know, like the things that haven't yet found pharmaceutical cures.
And so this approach to buy rare genetic diseases comes from. At least in your company at the molecular level. So why is it important to focus on rare [00:03:00] diseases?
Dietrich Stephan: It's such a great question. And as a geneticist, by training every human diseases. And so when I say that people might be scratching their heads, but, um, you know, from a genetics point of view, there are really four categories of diseases.
The first are the rare single gene often called Mundelien disorders. And that's what we're going to talk about today. Uh, each of these diseases is caused by a misspelling in one particular gene that causes. That disease. Um, and while individually rare, they're between five and 7,000 of these rare genetic diseases that affect up to 10% of the global population now.
At the risk of belaboring, the point, these are often deadly. Uh, and so, um, children that are diagnosed, um, uh, with a genetic disease at [00:04:00] birth often, um, die before their fifth year of age and broadly written 95% of these diseases have no effect. Therapies whatsoever. So we're going to focus on that today, but the second category is cancer.
Cancer is a genetic disease, a purely genetic disease of a single cell, which causes that cell to grow uncontrollably. The third category is infectious diseases, something that's gotten a lot of, uh, airtime these days and that's in a foreign genome, uh, uh, getting into your body and replicating itself uncontrollably, purely genetic, albeit a different.
And finally the fourth bucket are what are called complex genetic diseases. These are the genetic diseases that are going to touch all of us, all timers disease, diabetes, heart disease, they're caused by inheriting a set of genetic risk factors, often in multiple genes that then predispose you to environmental triggers.
And so that's the landscape of disease from a geneticists point. Yeah.
Kevin Folta: Yeah. When you said [00:05:00] that all diseases are genetic at their base, you did have me scratching my head on that because we know that there are environmental triggers and different environmental influences, you know, smoking for instance, which doesn't necessarily have a.
Component, unless, you know, you're an affectation for, uh, you know, addiction or whatever, but it's so just to clarify, when you say that all diseases are genetic, you're really saying that there's these underlying predispositions that kind of lay a foundation where a more complicated disorder is more likely to form.
Dietrich Stephan: Yeah, that's right. I'd say in the first three categories we talked about single gene diseases, cancer and infectious diseases. Those are. Literally caused, uh, by, uh, genetics it's it's causal, um, in the cancer cancer, in the case of cancer that you alluded to, um, you know, the, the, the mutation [00:06:00] can come from an environmental insult in this.
Smoking. Uh, but the result of that is that you mutate the genome and drive that disease, um, downstream, just because of a genetic change, the fourth category. You're exactly right. Uh, you can think of it as a genetic predisposition. Uh, that must be as is necessary and, uh, but not sufficient to cause that disease.
Uh, and so you do have to bump into the environmental insult and those two together. Uh, trigger the disease, but the inverse is also true where if you don't have the disposition or predisposition, um, and you have the insult, you don't get the disease. So genetics are a key driver and in common diseases as well.
Kevin Folta: And what are some examples of some relatively rare diseases that, you know, maybe you can give me a good example of something that maybe just a single nucleotide change or very small polymorphism. Is the basis of that disease. [00:07:00]
Dietrich Stephan: Yeah. So your audience will know that every one of the trillions of cells in the human body has a 6 billion.
Deployed genome. That means you have two copies of each genome. Uh, each has 3 billion letters, and sometimes you get a misspelling on one copy or both copies. Um, some examples of these rare single gene diseases that are often caused by what are called point mutations include diseases like Duchenne muscular disc.
Uh, where a single change can cause, uh, that gene to be, uh, misread, uh, and, uh, truncated. Um, other diseases for example, are sickle cell anemia, um, beta Fallacemia, uh, and then there are diseases that are caused perhaps by a couple of misspellings. Uh, the most common assisting fibrosis, which is a three-letter, uh, the most common mutation.
There is a three-letter deletion and it causes that. [00:08:00] Very difficult lung disease. And so again, there were between five and 7,000 of these, um, uh, all available, um, in, in a series called the online Mendiola and inheritance of man, if folks are interested in going there. Oh, mm.
Kevin Folta: Yeah. I'll have to check that out.
I guess that along that line, how many of these diseases, or how many diseases that we have, um, you know, observed over the years are starting to find, or starting. Come up with causal genetic associations because of efforts like 23 and me, or, you know, maybe just genome sequencing and analysis of genomics.
How many of these are really starting to boil down to their causal mutations?
Dietrich Stephan: That's fascinating. And it gets into. Exactly what we're doing here at new base. And so, uh, we started, uh, with, with my description of diseases as, as all being genetic. Um, and we knew that decades ago, uh, because of inheritance [00:09:00] patterns through families and what's called heritability, uh, where even in these complex genetic diseases, they seem to cluster in families.
Um, and so we knew that there was. Genetic component to almost every disease. And it took a massive, a us taxpayer funded effort called the human genome project. In collaboration with the private sector, namely Craig Venters, Solera to sequence the draft human genome. So we actually had a roadmap and that was published in draft form in the year 2000.
And. And what that allowed us to do was set up genome centers across the world that would take samples from people with a wide variety of diseases and sift through their genetic makeup and compare them to people without those diseases. So very simple comparisons, uh, but that sort of decade plus long, um, [00:10:00] districts.
Academic effort, um, populated what are called variant databases. And so now you can go online and type in, for example, the human mutational database, M D and on your computer. Uh, literally look at the world's catalog of, uh, mutations in the genome that cause a myriad number of diseases. Um, now we didn't stop there as a committee.
Uh, thereafter, uh, we said, well, gee, what good is it in a database? We need to build the national and global infrastructure to be able to take a sample from a new person out there. Who's suffering signs and symptoms of the disease. And identify which mutation is driving their disease and get that information back to them.
And that led to several exciting companies out in the marketplace that can take a cheek swab, test you and send the information back. And you know, the [00:11:00] companies that I think are doing this in a rigorous way are folks like and garden center. Um, the first is for we're called germline diseases. The others are for cancers.
Um, uh, so, so that's how we arrived at today. Um, and new basis, the capstone on that body of work, where we now, um, are drugging genes directly in the genome to, uh, nip them in the bud before they cause disease.
Kevin Folta: And this is where I really started to have questions because I looked at the website. I really tried to understand exactly what was going on here, but you're talking about developing drugs that the drug itself is almost a in, in this where you'll have to just correct me, appears to be, uh, like a nucleic.
Yeah. Analog. It's not necessarily really even a nucleic acid though, but it it's binds with affinity to specific DNA basis or RNA in [00:12:00] a very specific way. And that's what it appears to be. So if you have a, uh, a disease lesion in a gene, because of, um, and we'll talk about a couple of examples in a minute, if you have a.
Polymorphism which lends itself to disease, these small drugs kind of silence those mutations. It appears at least from what I could, what I could glean from this. So why don't you tell me about what the technology is and, and how this really can apply to solve a problem such as a small polymorphism?
Dietrich Stephan: Yeah. Kevin it's, it's such a great question. And to preface my answer. So we started by saying every human diseases, genetic yet, um, almost all drugs that are on the market target downstream proteins. And so you have to scratch your head and say, well, wait, if root causality is at the genome level, because every disease is genetic, why are we dragging [00:13:00] proteins?
Which are. Uh, the, the final step in the central dogma. And, and, and the reason is because initially, because we didn't have the sequence of the genome, so we couldn't develop targeted nucleic acid therapies. And so we just started throwing small molecules at cells from patients and hope that some of them did some beneficial thing and didn't kill the cells.
And that's literally the drug development strategy, uh, which gave rise to the vast majority of drugs on market today. Now after we sequenced the genome and published it and developed genetic variant databases, we started being able to develop genetic medicines. Uh, now almost all of those are focused on drugging RNA, which is the intermediate step is, you know, between DNA and proteins.
And so you have to ask yourself again, Well, why are they dragging RNA as opposed to the genome and the answer there is because the genome has evolved in a double helix structure that we're all familiar with [00:14:00] from high school biology to protect itself. This is existential information. It's, it's the blueprint of life and it's, it's almost like it's a snail with a shell.
Um, Drugs have difficulty getting in there and engaging with a mutant gene. Um, and so that's the technology, that's the problem that we decided to solve open up the genome, query it, uh, with a synthetic oligonucleotide technology, which I want to describe to you, uh, but maintain exquisite precision of target engagement, such that we're only interacting with.
Mutated gene that gives rise to the disease and don't have any off target engaged. Elsewhere and the 6 billion letter duplex genome, uh, and then there were other technical challenges that we had to solve. So for example, how do you get the drug to the tissue at the site of pathology? Most genetic medicines, just [00:15:00] go to the liver.
How do we ensure that these are well tolerated in non immunogenic? How can we manufacture them at scale? You know, given the breadth of impact we hope to achieve. And then how can we really have a, an output that increases logarithmically so that we can keep up with the unmet needs? So that's the context.
And I thought it was important to, to give you that. So what is the medicine? It looks very similar to a short single strand of DNA. So you have a backbone and you have nuclear bases and the nuclear bases are arranged in a sequence that's complimentary to the mutant gene of interest. The third piece is that delivery shuttle that we tack on the end of it that allows subcutaneous, subcutaneous or intravenous administration.
Now it's the backbone, that's the secret sauce. And this is a synthetic. Uh, it's called a polyamide scaffold [00:16:00] and it confers an extremely high binding affinity to this medicine so much so that it can quote unquote invade the genome. But because it's also semi-rural. It does not tolerate mismatches, uh, like other genetic medicines do.
And that's where this exquisite precision of target engagement comes from.
Kevin Folta: Yeah. So let me really think about this. So when we talk about target engagement, you're talking about this, uh, this alago nucleotide, well, it seems like an algo nucleotide, but it doesn't have a traditional phosphodiester backbone, right.
That you would find on a normal oligonucleotide. Correct. All right. So it says, am I backbone? That's neutrally charged that this thing for some reason can go into the genome and displace the nascent strand from a target sequence and bind that target sequence in and bind it with a very high affinity. So essentially it goes into the genome and grabs [00:17:00] onto that sequence and locks it.
Dietrich Stephan: That's right, exactly. And it's the neutral charge, uh, that allows it to approach, uh, the genome, uh, which, uh, as you know, has two negatively charged backbones, uh, twisted into the double helix. And so the neutrality of the drug allows it to get close without being repulsed, uh, and that confers high binding affinity, but it's also helix.
Uh, and so we induce this. Helical structure that precisely matches the healing city of the genome, which means the drug and the target don't have to contort themselves to engage, which further increases the binding effect.
Kevin Folta: Yeah, it just seems to me that, you know, as a guy who teaches molecular biology, that genomes are very good at surveillance and that when they detect anything wrong, like single base pair mismatch, there are mechanisms that come in to correct it [00:18:00] or to, you know, do something to address it.
It would seem like this invading piece of synthetic polymer would be a red flag to the genome and it would immediately excise it and get rid of it.
Dietrich Stephan: It's such a brilliant question. Um, there were two, there were two modes that these compounds work in. One is temporarily engaging a gene, uh, to modular machinery that runs on the rails of that gene.
Um, and the most obvious machine, uh, uh, that runs on the rails of the genome is called, uh, RNA polymerase. That's what transcribes a gene into an MRN and by temporarily engaged. That mutant gene with our drug, we block RNA polymerase, eliminate the mutant downstream protein. So they're just not made. Now that drug does come off over time.
There's an offering in that binding mode. Uh, and so that is not [00:19:00] a beacon for a cellular repair machinery, but if we really clamped that drug down onto the genome onto a strand of the genome, um, and it just doesn't come off because it's either so long or we create a structure called a tail clamp, which we can go into it's suddenly acts as a.
For nucleotide, excision repair, uh, machinery that descend upon the genome. And if we can currently provide, uh, a DNA donor strand, uh, along with our PNA compound, we can actually do ultra high fidelity in vivo genome editing by leveraging the cells own machinery. As opposed to using bacterially derived base editors that are predicated on CRISPR CAS nine, which by definition, having gone through the millennia of evolution that the human machinery has and are not as compatible [00:20:00] with the genome is our own cellular repair machinery.
So two ways of, of. Of a modulating output, one temporary and one permanent.
Kevin Folta: Okay. You just gave me goosebumps. It sounds as though I know, like, you know, to, to, to someone who isn't in the molecular biology, who's listening to us have this conversation. They probably think I'm nuts. I totally get it because that was really my next question is why not just use these bacterial gene editors?
I mean, you know, they're starting to be able to try to think about that in. The Pacific somatic tissues, where you have access to the tissue, like, you know, cystic fibrosis or something like that. But, um, but this is the real magic to this, having a precise system that goes in and delivers this, but then at the same time, but it also can be targeted or does it just kind of go everywhere very efficiently and then find it's it's I guess that's the other big question?
Does it. Uh, is it [00:21:00] specifically targetable to something say in the brain or something in, you know, the muscle or whatever?
Dietrich Stephan: Yeah, definitely. Um, so, you know, I think I missed a key concept that I'd like to just touch on very quickly and then we can move to delivery. So, um, every disease is genetic and the genetic changes in a gene, uh, caused the disease.
I only three mechanisms. One is by pumping out too much of a good thing. That's called a gain of function mutation. The other is by reducing the amount of the resultant protein and that's called a loss of function mutation. So not enough of a good thing. And the third is a change of function where the mutation actually confers a new activity on the resultant.
Protein are single technology. Uh, can modulate all three of those different mechanisms. And so not only can we potentially address every disease cause every disease is genetic, but we can also increase, decrease or change gene output, um, [00:22:00] increase in, decrease through temporary engagement with a gene, uh, to do jujitsu moves on the machinery that, uh, control genome.
Uh, and the third by gene editing, as we just talked about now, how do we get it to where it needs to act? Um, this is a central challenge in genetic medicines. Broadly read in the vast majority of genetic medicines are heavily, negatively charged they're high molecular weight. And when you administer them systemically, they generally go to the liver and that's because.
Well, it was one of the first organs that the blood sees, but also there were these, what are called scavenger receptors in the liver that are geared to clearing out, um, negatively charged, um, nucleic acids. Uh, it's a form of protection from infectious disease. And so our medicine is negative, a neutral in-charge low molecular weight, so they can slip past the scavenger receptors.
And then we tack on a technology that allows them to. [00:23:00] Interact with the cell membranes of any cell type in the human body, um, and, uh, form an emulsion that's directly, um, translocate into the cytoplasm and then diffuses into the nucleus. So, um, generally speaking, uh, our delivery, uh, technology allows the drug to get into.
Every tissue. Um, now it's only the tissues where the mutant gene is activated that the drug will work. Uh, it simply bounces off that genome if the gene isn't turned on in those other tissues.
Kevin Folta: Okay. So as something to do with a gene being active. So is it something to do with like chromatin organization of the gene or is it something to do with it being actively transport?
Dietrich Stephan: Yeah. So actively transcribed, low PSI, um, are actually breathing and they meaning the duplex is opening and closing as the transcriptional machinery is acting and it makes them more accessible to the drug slipping in and [00:24:00] querying for sequence complementarity. And then when the genome tries to close back on itself, it can't because of the high binding affinity.
And so that's the. The detailed mechanics behind what we call invasion. Um, and, um, and so yeah, actively transcribed, low side, uh, are different across different cells and tissue in the body. Uh, but in general, if there's a disease that's manifesting in a certain cell type it's in a gene that's, um, Uh, actively transcribed and that provides a layer of selectivity for, uh, for the compounds.
Uh,
Kevin Folta: maybe another technical question here, and I hope I'm not getting too much in the weeds, but when we talk about specificity of binding, the seems to be so important, especially because we're talking about diseases that may be based on a nucleotide or two different. Specificity and base pair pairing is dictated by issues like physiological pH and salt concentration, and, you know, the [00:25:00] hydrogen bonding that happens between those bases.
So what is different about the drug that makes it have more affinity, but not too much because you know, if you, obviously, if you, uh, have. Maybe a bit of a mismatch, you can sometimes make it stick if the conditions are amenable. So how do you have a drug that is super sticky to find the right target yet?
Not so sticky that it goes to indiscriminant sites.
Dietrich Stephan: Yeah. And this is, um, this is a unique feature of these backbones that, uh, In late parlance they're semi-rigid, um, meaning they really cannot bend around a mismatch between itself and the, and the nucleic acid target. It would, it would rather pop off, um, and continue its uh, search for a perfect match elsewhere in the genome.
And. Yeah, the closest thing I can [00:26:00] think of as sort of visual references is nylon. Nylon is actually very similar chemically to, uh, our backbone. And you get a sense for, you know, how it's a little rigid and, and, and that feels very different than a traditional, um, sugar phosphate backbone, which is floppy and, and loosey goosey.
And, and for those of you that, you know, used to do molecular biology in the old days, you know, you could. You could get an oligo to stick to a mismatched sequence just by, uh, you know, reducing the temperature, uh, of hybridization and so forth. And so that, that doesn't happen with these by nature of this semi-rigid backbone.
Okay.
Kevin Folta: That helps a lot. So we're speaking with Dietrich Stefan, he's the CEO and founder of new base therapeutics. We're talking about drugs that can change the genome and allow different therapies to potentially be delivered, to solve rare. Pretty much any early gen or any genetic [00:27:00] disease. So pretty exciting stuff.
This is collaborative talking biotech podcast, and we'll be back in.
And now we're back on the talking biotech podcast by collabora. And if you haven't tried their free trial of their software, go ahead and give it a shot. Um, it really does help your laboratory efficiency. So we're speaking with Dietrich's to find he's the CEO and founder of new based therapeutics in Pittsburgh, Pennsylvania.
And we're talking about the drugs, which are nucleotides. Like analogs, which have the ability to bind and essentially derail polymerases or change the way in which genes are expressed in which means you can pretty much affect so many different diseases at the source. And in the second half of the podcast today, I wanted to touch on a couple of the examples that you're currently working on in the pipeline.
And the first one really is this idea of monotonic dystrophy type one. Um, what is that disease and what are some of the symptoms? Yeah,
Dietrich Stephan: so [00:28:00] myotonic dystrophy type one or DM one is a Mandalian disease. It's dominantly inherited, uh, and it has a mutation on one copy of the two copies of a gene called D M P K myotonic dystrophy, uh, dystrophy, kinase protein, um, and, um, that, uh, that, uh, Mutation that'll Lele uh, when it's copied into an Mr.
And a, uh, forms, an average. RNA structure, uh, it's called a hairpin, cause it looks like a Bobby pin. And that acts as a sink or a magnet for a whole bunch of really important proteins in the nucleus. They get sucked onto that hairpin and because they're stuck on the hairpin, uh, they can't do what they're supposed to do, which is regulate normal.
Cellular processing of a whole bunch of Preem or nays. And so you get what's [00:29:00] called a splice off apathy. I know that's, it's kind of in the weeds, but what happens in these patients, um, is that essentially they're splicing patterns revert back to an embryonic form of a splicing, uh, across thousands of different transcripts.
And so now they're resultant proteins. Again, thousands of these proteins are all slightly Dix disfigured, so still compatible with life. But they cause muscle weakness and wasting and inability to relax muscle often fatal, cardiac conduction defects, cognitive deficits. Kids are often on respirators. And so, um, it is a devastating disease and patients to come in midlife as a result of this, uh, you know, subtle genetic change on one copy of the DMPK.
Kevin Folta: And just for the listener, this is in a three prime UTR. So the three prime untranslated region, which for those of you who aren't in the deep molecular biology, this is not the protein coding part of the gene. This is not the part that has the [00:30:00] information that's translated into the final protein. This is a, uh, essentially if it was, if, if it was a dog, it would have a funny tale.
And it's that little bit of misinformation in the, in the tail, which causes this barren sequestration of these splicing factors and causes as is the root cause of this disease, which is really interesting because it just goes to show how these, how something so subtle could be so devastating. And, and that really is a, it really is interesting.
How, how has that currently.
Dietrich Stephan: Well, it's not, um, it, there are no effective therapies for my atonic dystrophy, uh, at all period. Uh, and so, uh, patients suffer with no hope currently. Um, devastating.
Kevin Folta: Is it real comp? Well, not isn't real common, uh, in terms of being a rare disease, how rare is.
Dietrich Stephan: It's actually the most common neuromuscular disease.
It affects [00:31:00] one in 8,000, uh, individuals globally. Um, which means that there are tens of thousands of people in the U S alone, uh, that suffer from . Um, and, um, again, most succumb to the disease in midlife.
Kevin Folta: And what's the new base approach then? So you're, uh, I'm guess targeting. Three prime UTR region.
Dietrich Stephan: Yeah, we are.
Um, this is a little bit of a divergence from our core focus of, um, dragging the double-stranded genome itself. Um, in this case we're drugging the double stranded. RNA that's toxic. Um, so it's still a double-stranded structure. It's still refractory to drugging using the other genetic medicines, uh, and our, um, our drugs simply slips in invades that hairpin, uh, really linearizes.
And sterically displaces, [00:32:00] all of those inappropriately sequestered splicing proteins. Uh, so they can now go do what they're supposed to do in the nucleus. Uh, and we've shown, uh, that a single dose Ivy, um, uh, completely rescues normal splice. Rescues the ability of, um, transgenic animals to normally relax their muscles.
Uh, and we'll be, um, entering the clinic early next year in, in patients.
Kevin Folta: So does it restore the normal function of the mutant gene itself or is it that, that one's just eliminated then, and you're basically have another copy from the other, you know, the other, uh, genome that allows this to function normally.
Dietrich Stephan: Yeah, so really great questions. So that mutant transcript gets stuck in the nucleus because of that hairpin and that aggregate. And you can actually see these aggregates under the microscope using a technology called fluorescence in situ hybridization. They look like little [00:33:00] speckles in the nucleus of patient cells.
The other. Uh, is transcribed and export it into the nucleus and forms a healthy protein, but there's not enough of it. There's only 50% of that result in protein product. And we believe that also contributes to the disease. Um, so not only do you have a splice off apathy, but you have, what's called a haplo insufficiency.
Half is not enough of the DMPK protein itself. So when we engage that target that stuck in the nucleus, that MRNs that are. Uh, hairpin it, linearizes it. And we believe that that then allows the transcript to escape, uh, into the cytoplasm and be translated. Um, and to your earlier point, the protein coding region is.
Not affected by the mutation and it's not engaged by the drug. Uh, and so that translational machinery can restore the haplo insufficiency. And we've seen evidence of that in our [00:34:00] preclinical work. So why
Kevin Folta: isn't this therapeutic molecule immunity?
Dietrich Stephan: Yeah, it's a great question. Um, this class of compound has been, um, reported in the academic literature to be quote unquote immunologically, inert, and.
Generally it's because it's a synthetic, um, polymer. Um, and again, I'll reference the nylon example. Um, I think it's just a good sort of intuitive example of how nylon is used to close wounds and as non immunogenic by nature of its chemistry. And, and so maybe to go down, uh, the next level, um, you know, the primary innate immune mechanisms.
Um, recognizes, um, invading foreign DNA and mounts, an immune reaction against it. Our intracellular, um, toll like receptors this specifically TLR [00:35:00] nine, and those are present in, um, in endosomes in cells. And when they see, uh, nucleic acids, uh, being taken up into these endosomes, uh, they recognize them by.
Negatively charged sugar, phosphate, backbones. And as soon as that TLR nine recognizes it, it amounts it, it mounts at T H one and eight response that's, uh, you know, triggered by the cell, seeing, um, uh, DNA floating around, uh, when it shouldn't be, and, and as a signal of a foreign invasion. And so in this case, um, our molecules don't have a negatively charged sugar phosphate backbone.
And so in that specific instance, I don't see an innate response. That's triggered by TLR nine. We don't see compliment activation. And even, uh, an acquired B or T-cell response has never been seen before, uh, after repeat chronic dosing. And it's a little less clear as to why, [00:36:00] um, antibodies can't recognize, uh, these compounds, but, uh, we've never seen an acquired response either
Kevin Folta: now.
Very good, because it seems like the big question, but that's great that it evades this. So according to your website, the other disease, which is, uh, currently, uh, focus of the company is Huntington's disease. And so Huntington's disease is also pretty interesting in terms of its molecular basis. Can you touch on that and maybe a little bit about the disease symptoms?
Dietrich Stephan: Yeah, Huntington's disease is among the most horrific diseases that, uh, any of us will, um, hopefully never encounter, but, uh, it's also a dominant genetic disease where one copy of a gene called Huntington has a trinucleotide repeat expansion and Exxon one and all of us have a short, uh, repeat, uh, Set of repeat units, uh, in Exxon, one of the HTT gene, but in some patients or in some [00:37:00] individuals, the repeat becomes unstable and expands excessively.
And, uh, when that happens, uh, uh, the result in protein, uh, has with. Uh, poly glutamine run in it. So there are more of these glutamine molecules that cause the protein to become very sticky and aggregate, uh, within neurons, we believe that's the dominant mechanism behind the disease and those intra neuronal aggregates actually kill the neurons.
And so, uh, what happens is, um, uh, neurons start dying and patients stop losing the ability to walk and talk and think, and eventually the patient dies because. Brain dies. Um, and, um, their children, um, 50% of them will carry the mutant gene and, uh, agonize over whether to get tested in the absence of any therapy whatsoever.
Kevin Folta: Yeah, that is a devastating one. I had a student who went to study this in Cambridge for a while and, uh, just a [00:38:00] devastating disease. So what is the approach from, uh, from your company in terms of a therapy.
Dietrich Stephan: So our compounds are targeted against that expanded CAG repeat unit. In the Exxon, one of the gene itself at the DNA level.
Um, and so this is sort of in our core sweet spot as a company drugging the double-stranded genome. And what we have shown is that subcutaneous injections into multiple transgenic animal models. So an injection just under the skin, um, um, with the delivery shuttle on the compound, uh, enables the drug to get across the blood-brain barrier.
Which is one of the grand challenges of delivering macromolecules broadly writ. Um, and we like that because we're coming up through the cerebral vasculature and getting even exposures throughout the brain. Um, because [00:39:00] every neuron is proximal to a vessel and then the compound enters the neuron body gets into the nucleus, uh, invades the gene in Exxon one and selectively shuts down transcription of the mutants.
Uh, and we've seen a statistically significant decreases in mutant, Huntington protein, uh, in the brains of those multiple transgenic animal models. And, um, we're extremely excited about this because we want to preserve. Normal healthy Huntington protein, which is essential for life. Um, so we think we've got a winning solution here.
Uh, the other nuance is that there are other tissues in Huntington's patients that are affected and, um, you know, other folks are simply trying to squirt their genetic medicines into the brain compartment itself and are ignoring those other, uh, Tissues that have pathologies in them. And so a systemic route allows us to address the disease as a whole body solution.[00:40:00]
Kevin Folta: It really is pretty amazing. So the, so the drug that your company has designed identifies the Cotons that encode this polynucleotide repeat and are able to shut down transcription from those apparent genes.
Dietrich Stephan: That's right.
Kevin Folta: Okay. So that, yeah, I just want to make sure I had that right. So is this something that if you were to be tested in, you know, you have the mutant Lele that you would maybe take this drug as almost a prophylactic against further expansion of the nucleotide repeats too, that would lead to the barren
Dietrich Stephan: protein?
Absolutely. That's our bullseye. That's our, that's our. That's our target, uh, on the horizon. And, um, you know, given an individual is born with a mutation, uh, but doesn't develop symptoms until midlife. It's a, it's a relatively slow progressing disease in the context of a lifespan. And so if we can get, um, an effected off, uh, an individual from an effective patient tested early in life, [00:41:00] Cause their family history and get in a decade before first and symptom onset, we, we firmly believe we can push out the onset of the disease, uh, significantly by decades or even balance it with a healthy lifespan and eliminate the disease.
Now the clinical development strategy around getting there is, is a little complicated and nuanced, but that's where we're driving. Yeah, but right
Kevin Folta: now you're clear. You're strictly working in animal models that express, perhaps the human protein in its mutant form and can show that it can be suppressed.
That's right. Yeah. So that's pretty good stuff. So what else is happening in the pipeline right now in terms of other diseases that you're targeting?
Dietrich Stephan: Yeah, so we decided we also wanted to take a run at, um, the two most prevalent cancer causing mutations on the planet. Um, these two point mutations, uh, account for.
15% of all cancers, uh, across the globe. And there are no [00:42:00] therapeutic solutions to address this, uh, activated oncagene. Uh, the oncagene is called K RAs, K R a S a and the two most prevalent mutations in KRS are called . D and G 12 V as in Victor, and they cause a myriad of different tumor types, pancreatic lung colon, and the list goes on and they're among the most deadly, because no one has developed any drugs that target these, uh, activated oncagenes or their result in proteins.
And so it plays to the sweet spot of our technology. So we can put a lock right on top of the mutation on top of the point mutation. Uh, and inhibit RNA polymerase from forming a mutant M RNA or a cancer driving protein. Uh, and we've shown that we can do this in, uh, in cells, from people with cancer, uh, selectively shut down the key red song.
Could gene inhibitor. The downstream signaling that drives [00:43:00] cells uncontrollably to divide. And we've also moved those into what are called xenograft animal models, where we've taken human tumors and implanted them into mice. And we can, um, slower. The growth of those tumors with these compounds. And so we're quite excited about these, um, and behind that, uh, you know, the opportunities are limited limitless, and this is actually the big challenge that we have as an organization is how can we.
Uh, possibly develop against all of the, uh, impact opportunities. And that's where partnerships
Kevin Folta: come in. Well, this is all really exciting stuff, because it just seems to me that so many different diseases, we don't look at hard enough or if evaded other types of therapies, because either something doesn't work or can't be delivered.
Right. So, so this seems to satisfy many of those, uh, check boxes. So if people want to learn more about what's happening with. Where can they look online? [00:44:00] Yeah.
Dietrich Stephan: Please visit us@ourwebsitenewbasetherapeuticsandheknewnewbasetherapeutics.com. Uh, we're also, um, on LinkedIn and Twitter, uh, if you simply search for new base, um, and please feel free to reach out if you have any questions.
Yeah.
Kevin Folta: And the new basis and you bait B N E U B a S. Correct. Yeah. Don't, don't look at and you base or any w base who knows what you'll get, but therapeutics. Well, Dietrich. Thank you very much for joining me today. I really appreciate it. And do me a favor and as breakthroughs happen, I would love to have you back and talk about more of this because it's an intriguing technology that apparently has the potential to do a lot of good things.
Dietrich Stephan: Well, I, I salute you for what you're doing to educate the world as to all of these exciting, uh, new breakthroughs in healthcare. And it would be a real pleasure to join you again [00:45:00]
Kevin Folta: and as always, thank you very much for listening to the talking biotech podcast, your reviews, your. The information about the podcast really does work bigger followings every year as we're entering into year eight of the podcast.
And it's all because we have excellent listeners that share this podcast. Thank you very much for listening and we'll talk to you again next week.