Derek Jantz

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Moira: 00:00

Doctor Jantz, welcome to the program.

Derek Jantz: 00:02

Thank you for having me.

Moira: 00:03

Now tools are only tools until you use them for something. And in the case of TUNE Therapeutics, you're using a tool which pretty much everybody's heard of, whether they understand it or not. TUNE is using it in a very different way. So the biotech tool I'm talking about is CRISPR. So two part question here.

Moira: 00:27

Remind us, what does CRISPR do? And secondly, how is TUN using it differently?

Derek Jantz: 00:33

So CRISPR is a really revolutionary tool for gene editing. And what it does is it it has this pretty remarkable ability to hunt through the genome, which is this vast sea of DNA that, you know, includes the complete set of DNA instructions for a human being. And what it can do is it can find a unique address the genome. It can find a unique location in the genome where a particular gene might reside. Once it finds that unique address, it actually changes the DNA sequence.

Derek Jantz: 01:11

So it edits the DNA. And there's a lot of different things that we can do with that in medicine, most obviously is we can use a CRISPR to repair a mutation in the DNA that might be causing disease. What we're doing in TUNE, is a little bit different. We call it gene tuning. And it takes advantage of CRISPR's ability to hunt through the genome and find a unique address in the genome, but we disable the gene editing function of the CRISPR.

Derek Jantz: 01:47

So once it gets there, it doesn't change the DNA sequence. Rather, what we do is we attach to the CRISPR a gene activator or a gene repressor that has the ability to turn genes on or off, or up a little bit or down a little bit. So we can control how much of a gene is getting made in a given cell at at any time.

Moira: 02:14

Okay. So now we got how you're using it differently. But let's back up to a bigger picture. Why are you using it differently?

Derek Jantz: 02:23

So if we look at, human disease insofar as disease can be caused by genetics, there are examples of diseases that are caused by an actual mistake in the DNA, a mutation in the DNA. So, diseases like muscular dystrophy or cystic fibrosis that are really, really severe and are caused when a gene in the genome just isn't working properly. For diseases like that, really the best option medically is to think about something like gene editing or gene therapy where you're actually fixing the mistake in the DNA. But those diseases tend to be extremely severe and very, very rare. The vast majority of human disease that has some genetic component, so diseases that, at least to some extent, you're inheriting from your parents, the vast majority of those are caused by gene dysregulation, meaning the gene still works, it does what it's supposed to do, but you're making too much of it or too little of it, or you're making it in the wrong place or at the wrong time, and that's where a technology like ours really becomes relevant.

Moira: 03:36

So to treat disease, you basically wanna restore it to the correct position of regulation, either reduce it or or, upregulate it. We're saying, you know, upregulate, downregulate, reduce it, or or even eliminate it, perhaps in the case of, say, chronic hepatitis B. You wanna eliminate that virus forever. And so now when CRISPR locates the DNA you're looking for, that place we call the binding site literally binds there. Let's go one level down.

Moira: 04:09

What do you do when you're at that binding site? You've found that gene that's misbehaving, if you will. What are you looking for? What do you do?

Derek Jantz: 04:20

Yeah. So we we take advantage of a natural process called epigenetics. So when you when you hear scientists talk about genetics, usually what we're talking about is the genome. So, complete set of instructions that make you you. But if we look throughout your body, all of the cells in your body have the exact same genome.

Derek Jantz: 04:44

So, every cell in your body has the complete set of genetic instructions that encodes you. But if we compare a cell in your brain, for example, to a cell in your heart, those cells are very different from each other. And the reason they're different from each other is because they only read and interpret a subset of the complete instruction manual. So cells in your brain use genes that are specific for your brain, and cells that are in your heart use cells that are specific for your heart. And if you look at a cell in your brain, all of the heart specifics, genes in your brain are turned off.

Derek Jantz: 05:22

So epigenetics refers to this ability that your cells have to sort of determine what set of genes, what set of DNA instructions they actually want to read and follow. And everything else gets turned off and inactivated. There are a variety of different mechanisms that your cells have to do this. One that we frequently take advantage of is called DNA methylation. And the way this works is, a particular chemical modification called a methyl group actually gets added to a particular spot in sequence of a gene, and if enough of those methyl groups get added to the DNA, it ultimately inactivates a gene, so it can turn a gene off.

Derek Jantz: 06:12

And conversely, if those methyl groups get removed from the DNA, it can turn a gene on. So the way our technology works is by controlling epigenetics, in part through controlling DNA methylation. If we want to turn a gene off, we go in and we target a particular binding site in the genome and we add methylation. If we want to turn a gene on, we target a binding site in the genome and we remove methylation.

Moira: 06:42

Okay. So these methyl groups, what the heck are they?

Derek Jantz: 06:47

So a methyl group is a

Moira: 06:48

Pardon pardon my pardon my my quizzing, quizzical nature here.

Derek Jantz: 06:55

It's a it's a it's a small, molecule, CH three. So kinda like H two O is water, CH three is is a methyl group, and it literally gets added on top of the DNA sequence. So we don't change the sequence of the DNA. You know, genome sequence is a bunch of As and Cs and Gs and Ts that are sort of strung together this long sequence to make the genome. We don't change that.

Derek Jantz: 07:25

Gene editing actually changes the As and the Gs and Cs and the Ts. We don't. What we do though is we change some of these additional surface modifications like methylation that are added on top of the DNA, kind of like jewelry. And we go in and we can add and remove that in such a way that we turn genes on and off, again, using these very natural processes that cells use at every moment of every day.

Moira: 07:52

So, actually, what it's doing is finding the place and either taking them away or adding them as you say. And what what you're adding or taking away is so simple. I mean, we know these. You know, h two o, c o two. You can they're very basic.

Moira: 08:10

So so you're either adding or taking away c h three, one carbon, three hydrogens. These exist naturally. You're not bringing in some strange thing that the body has never seen before.

Derek Jantz: 08:24

That's exactly right. And and definitely because we are taking advantage of this natural process, and and really it's it's a very subtle change, That's the reason we refer to this as gene tuning. You can sort of think of this as fine tuning the genome. It is much less of a blunt instrument than something like gene editing, where you're actually going in and changing the genome sequence.

Moira: 08:48

Now let's get to the lead candidate that you have and the disease it's working on. And I have to say biotech companies usually pick very rare diseases or conditions for which we really need some treatments. We're having a really hard time treating them. And and the reason they do that is they get accelerated attention in getting through the FDA and and other regulatory agencies everywhere. But TUNE has picked a widespread disease.

Moira: 09:19

You picked hepatitis B. Tell us about it. How are we able to treat it today, and why, approach a widespread disease as your first treatment of choice?

Derek Jantz: 09:32

Yeah, great question. So hepatitis B is a virus that infects the liver, and it can cause very severe liver disease and liver cancer. It's a disease that affects about three hundred million people worldwide. So, a very, very common illness. The hepatitis B virus, just like you and me, has DNA, and it has genes.

Derek Jantz: 10:00

And the hepatitis B genome, has the same is subject to the same epigenetic effects as our genome is. So what we've developed at TUNE is our lead program, which we call TUNE four zero one, is an epigenetic silencer for hepatitis B. And the way this works is we administer it to patients who have hepatitis B infection. The medicine finds the hepatitis genome where it's hiding in the patient's liver, and when it finds it, it binds to it and starts to add methylation groups to the surface of the virus DNA. And when it does so, it turns the virus off.

Derek Jantz: 10:49

So we basically have a custom virus inactivator for hepatitis B. To your point about how this is a very common disease, you're absolutely right. Typically in biotechnology, when a brand new technology is developed, the first time that technology is used in human beings, it's generally in the setting of a very rare disease that is extremely severe and just doesn't have a lot of other treatment options. And that's because the industry and doctors and regulators are all very cautious and don't want to take any chances with a new technology. Once a technology is proven in the setting of a rare disease, it then generally gets applied to other diseases that are more common and may have other treatment options.

Derek Jantz: 11:46

So, our first program is a little bit unique in that we are starting out with a new technology in a disease that affects three hundred million people in the world. And the reason for that is because we really are taking advantage of these natural epigenetic processes that are happening in every cell of your body at every moment of every day. It is a fairly subtle change that we are making to turn the virus off, and it is a very specific change that we're making to turn the virus off. Our medicine is really able, because it based on CRISPR, it is able to find the virus genome and bind only to the virus genome and turn it off. So it is extremely specific.

Derek Jantz: 12:37

And so we think, and so far the experts agree with us, the doctors, the regulatory agencies generally agree with us, that this approach should be really, really safe. And so, we made the decision to start in, start our first evaluation of this technology in a disease that has a really, really large number of patients.

Moira: 13:01

Go big or go home, I think he said at the meeting. I don't know. I wasn't there, but I'm pretty sure. I'm pretty sure that was said. Now if I had hepatitis B today, before your medicine has come along and and and we're testing is in testing right now, how would I normally be treated?

Moira: 13:19

What's what we call the standard of care?

Derek Jantz: 13:21

So there there are treatments for hepatitis B. There's a vaccine for hepatitis B that's available in most of the Western world, which helps prevent, hepatitis B infection. It doesn't help all of those people, unfortunately, who are already infected by the virus. For patients who are already infected, they can take a drug cocktail every day that is able to sort of suppress the virus and reduce how quickly the virus damages their liver and how quickly the virus might lead to liver cancer. But it really is a daily treatment that patients have to adhere to.

Derek Jantz: 14:04

And in a lot of parts of the world, that's just not practical. It's not affordable. It's not easy to get access to the health care that they need to treat a chronic infection. So having a treatment that is a one time, hopefully, cure for hepatitis b really would be a game changer.

Moira: 14:24

Now every biotech company is a global company, and TUNE is no exception. You are already in humans and in two different countries. Where is it being tested, and what have you learned?

Derek Jantz: 14:37

We are treating patients with chronic hepatitis b, in a clinical trial that's currently open in two sites in the world. One is in New Zealand and one is in Hong Kong. And we picked those two locations because they have very, very good doctors who have access to a large number of patients who have chronic hepatitis B infection. And they also have very, westernized healthcare systems. So they generate very, very high quality data comparable to what we would generate in a clinical trial in The U.

Derek Jantz: 15:14

S, for example. The expectation is that once we have demonstrated that the treatment is safe and effective against hepatitis B, that we will really go truly global with the clinical trial and open additional clinical trial sites elsewhere in the world, including in The United States.

Moira: 15:35

Now I am so struck by this idea, now that we understand more and more about human biology and what such tools as CRISPR can do. I mean, the idea of why don't we we're only gonna use part of that tool and part of this tool. It's like that's how you use the tools you have every day. You know? You use what you want of each.

Moira: 15:56

And we have this new perception of disease about we went to an unhealthy state, and we could restore it to a healthy state. It gives us a sort of a new perception of how we intervene with disease.

Derek Jantz: 16:09

Yeah, this ability to precisely control epigenetics through our gene tuning approach really does have pretty enormous potential. If we think about, for example, heart disease, if we think about, Alzheimer's, even things like arthritis, that are sort of associated with aging generally, but there's a significant genetic component. You inherit high cholesterol, for example. A lot of people have high cholesterol because their parents got high cholesterol. There is a significant genetic component to that, and it's not because there's a mistake in the DNA, it's because your body is making too much cholesterol, or it isn't making enough of something that's involved in breaking the cholesterol down, or removing it from circulation, and that makes you prone to heart disease.

Derek Jantz: 17:05

These are the kinds of things that are controlled by epigenetics. It's just your body making too much or too little of soffe, or making it in the wrong place at the wrong time, and having the ability to go in and restore balance to a cell that's doing this, that's making too much or too little of a gene, potentially has enormous potential to treat a really wide swath of common and chronic human disease.

Moira: 17:35

Well, I wanna thank you for coming in, and I I especially wanna thank you for this concept of there's this huge user manual of how all our body works, with all the DNA we have, and all our cells get it, the poor cells. Can you imagine if every time you you you needed to look something up, the user manual for everything you ever had showed up and you had to go through it? So the concept that, yeah, your DNA is everywhere, but depending upon where your cell is and its function, it's only gonna do part of the part of the job, and that's what you're looking for. So I think that's a great concept to have, and and I hope you come back and, keep us updated.

Derek Jantz: 18:19

Absolutely. Thank you for the time.

Moira: 18:21

They really you've you're such a clear speaker. This works great. Well, then let me stop. Don't don't hang up.

Derek Jantz: 18:27

I don't think so.