Can We Edit Genes to Lower Cholesterol?

Dr. Michel Koren and Dr. Mitchell Rothstein host a presentation in front of a live audience to discuss the current state of gene editing. The doctoral duo discuss developments including new-to-market medical therapies, clinical trials, and the legal issues surrounding gene therapy patents. They also explain the difference between gene silencing techniques, which temporarily stop genes from creating proteins, and gene editing techniques which permanently alter the genome. They also touch on controversies, risks, and the comprehensive considerations that take place before a participant can partake in a gene editing clinical trial.

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Music: Storyblocks - Corporate Inspired

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Transcript

Live Rebroadcast And Big Question

Dr. Mitchell Rothstein 0:00

Welcome to the MedEvidence Podcast. This episode is a rebroadcast from a live MedEvidence presentation.

Dr. Michael Koren 0:06

Hey Mitch.

Dr. Mitchell Rothstein 0:07

How are you doing, Mike?

Dr. Michael Koren 0:07

Very excited about this talk.

Dr. Mitchell Rothstein 0:09

So am I. It's taking a lot of preparation to catch up with everything.

Dr. Michael Koren 0:13

Yeah, we've been talking about gene editing for decades now. And so you want to ask the audience the first question: do we think we can edit genes to lower cholesterol or not? Who thinks that we can do it right today as we speak? And who thinks that it's just aspirational that maybe some point in the future we can do it? Okay. All right. Well, I guess we're going to find out the answer.

Dr. Mitchell Rothstein 0:42

I hope so.

Dr. Michael Koren 0:43

Yeah. So I guess we've got to start with the basics. So as Alyssa very nicely said, we try to bring everything down to a very understandable level. And we use a lot of terminology in science, and sometimes we assume that people really understand what it is, but you may have just a vague understanding. So it's always good to go to the basics and define things.

Dr. Mitchell Rothstein 1:05

Absolutely.

What A Gene Really Is

Dr. Michael Koren 1:06

So let's start with the most basic thing. What is a gene? Okay. And that we, as you probably know, most of you have been here before. This is not a free lunch. You have to work for this lunch. And the way you work for this lunch is by being part of our audience response system. And it's really important just to have fun, but also to help educate everybody and also for us to know the things we need to get into more detail on in terms of explanations.

Dr. Mitchell Rothstein 1:36

Right.

Dr. Michael Koren 1:36

So let's start with a very simple question. What is a gene? A pair of pants made of denim material, famously modeled by Sydney Sweeney. So that's one possibility. By the way, I did not know who Sydney Sweeney was until I prepared for this lecture. So I learned a lot during these lectures as well. Okay. The name of your favorite bartender could be, what is the gene? Now, I was just in New York and we don't they don't have bartenders anymore in New York, they have bud tenders. Oh. So if you're more people are using marijuana as their drug of choice than alcohol, so now you go to your favorite bud tender, just to share that little cultural insight with you.

Dr. Mitchell Rothstein 2:22

Thank you.

Dr. Michael Koren 2:23

Okay. Is it C a sequence of base pairs that codes for an active biological protein? Is it D, all the above? Or is it E? I think this is a trick question. So a show of hands. Who thinks it's A? B? C, okay. D or E. Okay, and the answer is it's actually all the above. Including a trick question. So we'll get more into what is a gene, but of course, going back just the slide there. In the context of science and in medicine, a gene is in fact a sequence of base pairs that code for an active biological protein. But it could be the name of your favorite bar or bud tender as well. So it is a bit of a trick question. Okay.

Dr. Mitchell Rothstein 3:17

All right.

Can We Change Gene Expression

Dr. Mitchell Rothstein 3:18

Your next question is can we modify gene expression? So the dogma in biology is that genes are made of DNA. They code for RNA, it codes for proteins. And that's the dogma. That's the way it works. So can we modify what the gene is telling the rest of the cell to do? A, no, nothing can change our genes. B, haven't you heard about cutoffs?

Dr. Michael Koren 3:44

That would be a gene expression.

Dr. Mitchell Rothstein 3:46

Absolutely. A modification. C, several Nobel Prize winning technologies have shown an ability to modify gene expression. D, all of the above. E, I think it's a true question.

Dr. Michael Koren 3:59

Got a little momentum going on here. So show of hands there. I guess the technology's not catching up with that. The cat's out of the bag. Anyhow, so the answer here is C. Several Nobel Prize winning technologies have shown an ability to modify gene expression. And that's going to be our job for the next uh 45 minutes or so is to explain some of these Nobel Prize winning technologies that have in fact changed medicine to a point where we now can indeed modify gene expression.

Dr. Mitchell Rothstein 4:34

So, Mike, with that in mind, why don't you talk about the kind of two major pathways we have of working with gene expression?

Editing Vs Silencing The Two Paths

Dr. Mitchell Rothstein 4:42

Sure.

Dr. Michael Koren 4:42

Okay. So when we talk about gene expression, we're going to talk about two ways of changing things. And we're excited to report that we can now edit genes. We can actually change the DNA sequence and make genes do something differently from what they started to do. And we'll tell you there's actually approved drugs in the market to do these things. But now more and more we're able to take a bad gene and turn it into a benign gene. So I used to joke about that one of the most important things in life is to choose good parents, right? And that's because you get certain good genes from your parents and maybe other genes that are not great. But in the new world, you can keep all the good stuff and you can start to maybe edit the stuff that isn't quite as good.

Dr. Mitchell Rothstein 5:33

Yeah. Could be a little controversial.

Dr. Michael Koren 5:34

Yeah, it's very controversial, but we're getting to a point where, in fact, this is in a clinic nearby, and we'll talk more about that. So you who's heard of the term CRISPR? Okay, so we'll learn more about this. It's an acronym, and it's a name of a company that actually owns some incredible technology that actually edits genes. So you'll find out that it takes a particular base pair in a sequence of DNA and changes that to a different one, which will change the function of the gene. So absolutely mind-blowing, but we can do that now. And then the other mechanism is called silencing. And this is an idea where the DNA is untouched, but the expression of the DNA is modified. And we actually have a lot of products already on the market that do these. So and these are products that we've been working on here in Jacksonville at Jacksonville Center for Clinical Research for over a decade. So one is called RNA interference, and that's the concept of silencing a gene with a specific part of our cells called the RISC or the RNA-induced silencing complex. So 20 years ago, when we were in medical school, we didn't know about this stuff.

Dr. Mitchell Rothstein 6:51

No, we didn't.

Dr. Michael Koren 6:52

This is all new stuff. But it turns out there's a part of the cell that's responsible for silencing genes that the body doesn't want expressed. And the most common example of that is with viruses. So one of the reasons why we become immune to viruses is that once our body is introduced to a specific virus, we have the development of a way to silence the genes of that virus. Because as you probably know, basically, virus is just a bunch of either RNA or DNA that expresses itself. And now our bodies have the ability to silence that gene expression. And with medical technology breakthroughs, we are now able to take that part of the way our genes work, the way our cells work, and apply it to our own genes.

Dr. Mitchell Rothstein 7:38

It's incredible. Yeah.

Dr. Michael Koren 7:39

And then there's another one called antisense oligonucleotides or ASOs, that's a similar concept, but instead of working through what's called the RISC, it's another strand of nuclear material. It's an RNA-type nuclear material that will match with the messenger RNA that comes out of the nucleus and prevent it from being expressed.

Dr. Mitchell Rothstein 8:02

And that's mostly synthetic, right?

Dr. Michael Koren 8:04

Yes, that's correct. That's right.

Dr. Mitchell Rothstein 8:05

When the RNAi is mostly natural that we're kind of activating.

Dr. Michael Koren 8:09

Yeah, we're we're teaching the cell to identify a certain type of gene that you don't want expressed. But the RISC complex is something that we all have.

Dr. Mitchell Rothstein 8:19

Yeah, it's fascinating.

How CRISPR Cuts And Repairs DNA

Dr. Michael Koren 8:20

Yeah.

Dr. Mitchell Rothstein 8:20

All right. So those so those two types. So one is editing, like Dr. Koren said, changing the DNA itself. The other is modifying the expression of what the DNA is doing with RNA, and thus that affects the proteins, whether they're produced or not produced, or altered. Now, getting back to the editing part, this whole history of how editing developed and how we were able to recognize it is fascinating. So the major one of the major ways to do it, and there's several different models that can perform that, is called CRISPR-Cas9. And it's a combination of a protein that can actually change and dissolve a portion of DNA with the and it uses a guide strand of RNA to kind of find where on the DNA it needs to kind of couple, and then it can cut the DNA in two places at the same time, since the DNA has that double helix. So by doing that, all our DNA and our nucleus wants to do is repair any defects. And if you think about it, during the day, there's tons of things that could mutate our DNA, change our DNA, and if that was allowed to go unchecked, we'd all be mutated and we wouldn't survive as a species, nor would anything. So we're programmed, our DNA is activated all the time to repair any cuts or defects in the DNA.

Dr. Michael Koren 9:49

So And that that's a hugely important point. So I'll just interrupt you a second, just to make sure everybody understands that the concept of your DNA changing is part of being human. And the most common example of that is going out in the sun. So you've got into the sun, you get all this UV radiation, and that affects your DNA and that changes your cells. And your body is constantly repairing that. But if you get too much of that exposure over time, you can develop a cancer because your body can't keep up with the repair work. So again, the key point is that changing DNA and changes and breaks of DNA happens all the time. And it's the way it's repair that's the key feature.

Dr. Mitchell Rothstein 10:28

And actually, there's kind of two ways to repair it. And not to get too deep into this, but one is kind of a rapid band-aid technique where the ends that have kind of broken apart are just spliced back together instantly. And another is a kind of a more detailed form of repair that requires a prototype, and you can actually, that gives you the opportunity to kind of change the DNA if you want to. So for the first time in 2020, there was a Nobel, the Nobel Prize in Chemistry was awarded to Emmanuel Charpentier and Jennifer Doudna for discovering this system could work in eukaryotes in mammalian cells, and actually showed how it was able to work, cut the DNA, and allow the opportunity for changes in DNA. First time two women ever were awarded the Nobel Prize. And actually, this occurred about eight years after they had actually published their work that showed it was possible.

Dr. Michael Koren 11:26

Which is typical for Nobel Prize, yeah. But all right, girl power.

Dr. Mitchell Rothstein 11:30

So, Mike, if you want to take us through this?

Dr. Michael Koren 11:32

Sure. So again, we talked about those two ways of modifying gene expression, and we talked about RNA silencing or RNAi, I standing for interference, and ASO, which is antisense oligonucleotide. We don't expect to remember that, but that's what it stands for. And as I mentioned, they have different mechanisms, and the RNAi will block the gene message. So the message can't get to the point where it produces a protein. Whereas the ASO has a similar concept, but it actually blocks the message earlier. It doesn't even let the message get into the cytoplasm of the cell. It blocks it at the border of the nucleus in the cytoplasm. So they're slightly different mechanisms with the same end result. Next line shows you where it works, and I just mentioned that cytoplasm versus the edge of the nucleus. What changes the DNA? In the RNAi, the DNA is not touched. And in ASO, the DNA is not touched. Again, it's the product of the DNA, which is RNA.

Dr. Mitchell Rothstein 12:38

And I think that's so important that everybody understand that in these silencing techniques that the DNA is not touched. We had enough trouble getting people to understand, even with the vaccines, with messenger RNA, that the DNA wasn't touched. That same we're trying to avoid that problem with these technologies.

Dr. Michael Koren 12:57

Right. And then the other thing people get confused about is the difference between DNA in certain cells and the DNA you pass on to the next generation. And we'll get into that more, but it's completely different. None of the techniques that we're talking about affect the DNA that gets passed on to the next generation. It's really, really important. And part of the technology is our ability to make sure that the therapy just goes to the bad cells and not to your germ cells, not to your ovaries or your or your sperm. And then finally, recognition the RNA interference has been awarded a Nobel Prize, and we believe at some point the ASO technology will be, but Stockholm is still out there.

RNA Silencing Saves Rare Kidney Patients

Dr. Mitchell Rothstein 13:38

So with that idea and RNA interference, now when I left clinical practice after 30 years, I was very happy, my own little shell doing sleep disorders and pulmonary medicine. And Mike was kind enough to help let me join the research company. And one of the first studies I got involved in was a study about kidney stones. So I'm a sleep doctor, lung doctor, I'm fine with that. But now all of a sudden we're talking about treating kidney stones. And this particular type of kidney stone is an autosomal recessive problem for people where their liver doesn't metabolize glycolate to completely, and it leads to the buildup of oxalate stones. And the reason it doesn't do that is because the enzyme responsible for the final metabolic pathway of oxalate is work, it doesn't work correctly, so oxalate builds up. So the scientists figured out, well, if we hit the enzyme that produces the oxalate and make that not work well, maybe these stones, the oxalate levels won't rise and the stones will go away through one of these silencing RNA techniques, and that's exactly what they did. And we had patients come in from Afghanistan. I think our youngest patient was eight years old. We had a kidney doctor from Nebraska coming in, and sure enough, over the course, the study lasted five years, I believe. And if you look at who the fourth author is on this study, it's a very it was a very dramatic study in the field of medicine, and it happened right here in Jacksonville. That we were able to show that silencing that gene that produced oxalate was able to inhibit the form of oxalate stones and save, change people's lives. So it was really a fascinating introduction to this whole area.

Dr. Michael Koren 15:32

Well, well, well said. And Jacksonville was the leading center in the world for the development of this particular product. And again, it's not all kidney stones, but for a particular type that actually affected kids and teenagers. Right. Now there's a solution that's on the market because of the work that was done here in Jacksonville. So great teamwork from everybody. And also an example of silencing a gene product. So with that in mind,

Dr. Mitchell Rothstein 15:58

why don't you take us

FDA Approved CRISPR For Sickle Cell

Dr. Mitchell Rothstein 15:59

through this?

Dr. Michael Koren 15:59

Which of the following gene editing has received FDA approval? Now we're talking about editing now. Is it A permanently eliminating seasonal allergies with one treatment? Is it B treating DNA to reverse aging by 20 years? Is it C treating sickle cell disease? Is it D helping people with Lyme disease? Or is E turning a boy into a girl or vice versa in utero? Anybody think it's anything other than C?

Dr. Mitchell Rothstein 16:34

Okay.

Dr. Michael Koren 16:35

All right, you're right. So it is C. So go ahead and tell everybody about the approval.

Dr. Mitchell Rothstein 16:40

Yeah, so Casgevy is applying CRISPR. Now we're back. We're not silencing RNA anymore. Now we're changing the DNA. So Casgevy was just approved for treating people that have hemoglobin ophthales, specifically sickle cell disease and beta-thassemia. Both those conditions have an aberrant adult hemoglobin gene. And if we could change that gene to appropriate normal adult hemoglobin, it would eliminate the problems that these patients have. So there was a CAS9 CRISPR therapy designed to do that. And it requires patients to donate bone marrow cells. The bone marrow cells are then treated with CRISPR that edits that gene out and turns it back to normal hemoglobin. There's also some augmentation of fetal hemoglobin. Those cells are then grown and then reinfused into the patient, and it seems to work. So it's a very complicated step because it requires harvesting, it requires suppressing the patient's bone marrow, and then reintroducing this as an auto-transfusion, and the transfusion has to work, and then we've eliminated a bad gene, and now we're producing normal hemoglobin again. And it was just amazing. It was just approved by the FDA in the United States and by the European Medical Association.

Dr. Michael Koren 18:06

Yeah. So this is again a cure by changing the genes and a disease like sickle cell anemia. So really just

DNA Scale And Genes Switching On

Dr. Michael Koren 18:13

remarkable.

Dr. Mitchell Rothstein 18:13

So Mike, why don't you talk a little bit more about DNA itself? Sure.

Dr. Michael Koren 18:18

So we call this DNA facts to impress your friends. I assume all you guys are like me, and when you go to a cocktail party, you talk about DNA, right? Is there anything else to talk about in a cocktail party?

Dr. Mitchell Rothstein 18:30

But the weird part about this is that that is what happens with Mike.

Dr. Michael Koren 18:35

Well, any event, so there are three billion DNA base pairs in the average human. And if you remember from high school or college biology, there are base pairs that match up with each other: guanine, cytosine, adenine, and thymine. And it's A and C and G and C that hang out together. And this is what makes up all of our genes. It's basically a relatively simple chemistry that was discovered by Watson and Crick back in 1954. And you can see the picture on the slide is that wraparound double helix, which was really a Nobel Prize-winning, earth-shattering way of understanding how genes in biology works. The average gene has 62,000 DNA base pairs, but there's huge variation. Some genes are very, very complex with a million base pairs, other genes are relatively simple with maybe a couple hundred base pairs to produce a particular protein. And humans have between 20,000 and 25,000 active genes. But here's the interesting thing is most of our chromosomes is information to switch our genes on and off. And again, this is stuff we didn't know when we were in medical school, but such a big part of our genes is actually suppressing certain expressions and then deciding when you need them. So for example, if you get pregnant, you need certain genes to start to kick in, right? When we're we're born with this the same DNA, right? But how do our genes know what to do during adolescence versus during old age? Well, it's amazing, but our genes turn on and off. So when you need that big testosterone surge when you're a 12, 13, 14-year-old boy, your gene turns on.

Dr. Mitchell Rothstein 20:18

Well, and a 60-year-old man, you need that. Well, we need it, but it doesn't always turn on so well.

Dr. Michael Koren 20:23

I'm waiting for that gene eating study. Anyhow, so it but it's fascinating, is that it it's and it's obvious when you think about it, but at different points in our life, we need different genes to turn on. Absolutely. And then we also want them to turn off at certain points. So obviously you don't want to keep on growing ad infinitum, so those genes have to turn off. So it's really fascinating how our bodies have the ability to really control gene expression.

Patents And The Business Of Breakthroughs

Dr. Mitchell Rothstein 20:50

So there's been some legal, like everything else, there has to be some controls on, you know, how this new kind of power is controlled and regulated, and that's entered the legal field, right?

Dr. Michael Koren 21:03

Yeah, yeah. So this is a, you know, it's a part of medicine that doesn't get a whole lot of discussion, but it is an important part of medicine. And so why do drug companies develop drugs? Obviously, they make money off of it, but why can they make money off of it? The reason they can make money off it is because they have patents, which protects them against competition. Because if you are a drug company and you spent a billion dollars on a drug development program and then it got released, and then somebody created a copycat drug the next day, you're not going to get your billion dollars back, right? So there has to be systems throughout the world, and there, and there are from most parts of the world, where medical technology breakthroughs are protected by patents.

Dr. Mitchell Rothstein 21:51

Right.

Dr. Michael Koren 21:51

But now something gets some things get a little controversial. So if you learn something about the way genes work, is that Patentable, or is it only like the actual product? Well, this is where the war is. And this there's a place called the Broad Institute, which is a combination of MIT, Massachusetts Institute of Technology, and Harvard. And that was the place where a lot of these discoveries were originally made about 20 years ago. And they applied for and were granted broad patents on all these technologies. And then other important research institutes, including Berkeley and places overseas in Vienna and in France, are saying, well, you know, we made contributions to this as well. And so you shouldn't get this whole patent for yourself. So they're litigating this, and it's it's big money because the Broad Institute will get, for every treatment that uses this technology, maybe $100, whatever it is. But that adds up. And the other companies that want to develop this particular technology for whatever the disease is will have to license the technology from the Broad Institute. And for the RNA silencing, Alnylam pharmaceuticals, who we work with a lot here in Jacksonville, they're the ones that own the basic science patents. And then for the antisense goal nucleotides, it's Ionis pharmaceuticals. The ASOs haven't taken off quite as much as the Si RNAs. But you know, these are the these are the wars that are happening. And it it's fascinating. Now the good news is that it hasn't really stopped development. They'll figure out how to split the money at some point in the future after lawyers get their 40%. But but you know, it's it's interesting to know that when you get when you do some sort of gene editing thing, chances are it's using CRISPR technology.

What CRISPR Stands For And Origin

Dr. Mitchell Rothstein 23:48

Yeah, and they're commercially available. I mean, you can go on the web and you can see there's CRISPR technology for this kind of mutation or that mutation, and you can order it actually almost in kits. So since you still have to pay attention for the rest of this. So what does CRISPR stand for? A completely random insertion of stable protein repeats. B. Cookies require icing sprinkles, pecans, and raisins. C, changing really important stuff permanently and responsibly. D, clustered regularly interspace short palindromic repeats? R, don't confuse CRISPR with Crisco. One at its genes, the other makes a flaky pie crust. I like that answer.

Dr. Michael Koren 24:35

Alright, so who thinks it's A? Who thinks it's B? Who thinks it's C? Okay, B. All right. It probably is. It's at some some sweet store somewhere. Who thinks it's C? Who thinks it's D? And who thinks it's E? All right. Well, the answer is D. So it's actually an acronym, and it's also the name of a company, but it stands for clustered regularly interspersed short palindromic repeats.

Dr. Mitchell Rothstein 25:09

And a palindromic repeat is something that reads the same forwards and backwards. And some scientists uh found this and was one of the hints to discovering the whole technology. So, Mike, why don't you talk a little bit about it? How gene editing got started?

Dr. Michael Koren 25:27

Sure. So again, you know, I went to medical school in the mid-1980s, and back then we were just studying DNA and bacteria. But we started to learn that there was these spacer regions between the sequences of genes, even in something as simple as a bacteria. And this is where people started thinking, okay, well, maybe when you look at a huge chromosome, only a relatively small portion of it is the actual expression of the gene, and everything else is this on-off switch and just spacers to separate genes. But as we learn more and more, we said, in fact, this pattern is in multiple organisms, including humans. And then we started to understand that when bacteria, excuse me, when a virus infects a bacteria or infects another cell, it leaves a piece of DNA in it. Oh my God. So now we know that DNA can be changed and that viruses can change DNA. And that got people thinking, well, you don't kill the organism when you get a virus, so organisms can survive when they're when their DNA is changed. So this is kind of learning that we that we went through over the course of two decades. So basically, based on these observations, we learned that DNA is dynamic, it changes, it's not static for your entire life.

Dr. Mitchell Rothstein 26:51

That's true. And I I think one of the interesting parts about this was this was our first hint that it not only was it static, but you could use it like as a defense mechanism because the bacteria were using these little stiff snippets of the viruses like a mugshot, so they recognized the virus the next time it came around and they were able to protect themselves from it. So the CRISPR-Cas9 system works by first identifying a region of DNA that it wants to change. It does that by using the trace RNA. And remember, the RNA is complementary to the DNA. It kind of scoots along, it recognizes where this matching DNA is that it wants to change, and then the Cas9 complex call it's called dissolves the DNA, which opens up that double helix. It cuts both strands of the double helix, and then because, like we talked about, our DNA is always in a preservation mode. It doesn't really want to change, it doesn't want to mutate, it wants to get things back together, and it does that one of two ways. One is that quick kind of band-aid fix, and the other is an opportunity to insert a new kind of region in DNA that can code for a protein that we want to code. And that's the beauty of this Cas9 system is it open up it opens up the DNA very, very specifically, only if there's a complete match with this RNA trace that we program into the protein. If it doesn't match, it won't open up and there won't be a change. And then the repair process is our opportunity to either knock the gene out so it doesn't work, or insert a new gene, a replacement gene, that then can perform the way we want it to.

Ex Vivo Vs In Vivo Gene Editing

Dr. Michael Koren 28:48

So yeah, and we we alluded to this already is that the gene editing, the gene editing products that are approved are doing this outside of the body. So we call that ex vivo. So you can see this side of the slide to my left, an example of that which we talked about, which is sickle cell disease, which was approved in 2023. There's a lot of cancer research that's looking at this as well. So there are a lot of cancers that involve the bone marrow, and now we're doing similar things where you pull all the cells out of the bone marrow, you treat them, you then use radiation or some chemotherapy to wipe out the bone marrow, and then you put out the repaired bone marrow back into the patient. And so this is now being looked at for a number of diseases, including stuff like lupus and rheumatoid arthritis, a bunch of other stuff. But what we're doing here in Jacksonville now is what's called en vivo gene editing. So we're not actually pulling your genes out of your body, but we're using a way of targeting the exact genes that we want to get to. And we're doing this by going after certain gene products that are only present in very specific cells. So again, ex vivo is you pull the stuff out, you treat it in a test tube, you get rid of the bad stuff, and you put the good modified stuff back into the body. What we're doing is to give an infusion of a medicine that finds the bad genes and fix it while it's still in your body.

Dr. Mitchell Rothstein 30:20

Yeah. Absolutely. So some of the applications that are going on right now, and some of the studies we'll talk about that we're doing involve CRISPR research where we're taking for CAR-T T cells in cancer, we take immature T cells and we take them out. We treat them with CRISPR to get them to identify a protein on the surface of the cancer cell that we want to treat. And then after they multiply, we infuse them back in. And those killer T cells now go directly at the cancer. They're very specific to help treat cancers, and we have patients, especially like in conditions like myeloma and multiple myeloma, where this CAR- T cell therapy is actually very effective. We're going to talk about some of the cholesterol and triglyceride studies that we're actually doing. In Duchenne muscular dystrophy, there's an abnormal protein that's produced, and over time it kills nerve cells, which then leads to the destruction of creates muscle atrophy and the muscular dystrophy that follows. And we can actually, by setting in a CRISPR complex Cas9 to shut off those abnormal proteins that are being made and switch on the proteins that we want to be made, can actually l can actually potentially change the course of muscular dystrophy for patients. We can also use this in non-medical conditions. And if you think about it for like agriculture in agriculture, we can put in proteins that would code for surface components that would make certain plants resistant to infection by viruses or fungus. We can actually code for plants to perform much better during droughty conditions. And then in from an ecological standpoint, we can actually program bacteria to eat hydrocarbons, plastics, oils, and clean up the environment. And then there's things about people are talking about species diversity. So if you have a very small population of Cape Buffaloes and there's only a few of them left, you can use CRISPR to kind of help them diversify their genome so they could be more adaptable to changes in their environment.

Dr. Michael Koren 32:44

Yeah. Some fascinating stuff.

Dr. Mitchell Rothstein 32:46 Dr. Mitchell Rothstein 32:46

Risks Ethics And Irreversible Choices

Dr. Mitchell Rothstein 32:47

So with that comes a big ethical and risk kind of question. And Mike, why don't we talk a little bit about that?

Dr. Michael Koren 32:55

You can just run through these for everybody, and I'll, you know.

Dr. Mitchell Rothstein 32:58

So the issues with gene editing, like we talked about, is this is not silencing. So we're changing the DNA. So unlike a pill or anything else, it's permanent, and there's no undo. So for if I had a problem with my I was making a protein that was bad for my skin, and we injected it, and it was taken up by my liver, not germinal cells, but somatic cells, and it cured that skin problem for me, I'm one and done for the rest of my life. So the issues then come, well, is there anything downstream from that that could happen? Because the rest of your life is always a long time. And you don't want to all of a sudden be faced with situations that are off-gene expressions that we didn't count on. Is it better than what we're doing now? So just because you can fix it, if we can treat it a different way, should we be going through this type of risky, potentially risky approach when we can manage it well with what we have now? So the target specificity is, and this is a big issue, is that we know that we can aim to change just one gene, but if we change that one gene, are there downstream effects that affect other cells in our body and could cause problems? So these are off-target effects that we worry about, that we're getting better at kind of forecasting, especially with AI, about you know, how these things will interact with our body down the down the uh pathway. And then the other aspect of this is we're not talking about germinal cells, ovaries, eggs, or sperm. We're talking about somatic cells. So the treatment that I get for my skin condition doesn't get passed on to my children. Whereas if we were treating eggs and sperm, they would be passed on to our children.

Dr. Michael Koren 34:58

Right. So I'll just make a couple of comments on that. So the concept of irreversibility is actually common in medicine, but not so common in drugs. So it's common in medicine and it's called surgery. Right. So we used to treat cholesterol problems by actually chopping out a piece of the bowel. And that's not reversible. But it was shown to actually increase uh the likelihood of surviving heart attacks and preventing heart attacks and strokes in the first place. And we don't do that regularly anymore because we have better ways of doing it. But that was an example of an irreversible way of treating a cholesterol problem.

Dr. Mitchell Rothstein 35:38

And that also wasn't passed down to your children.

Dr. Michael Koren 35:40

That's right. But now when we look at the drug world, drugs typically have a half-life. So they're in our body for a period of time and then they go away. With the small interfering RNA drugs, their half-life is pretty long. So it lasts for four to six months. But now we're looking at one and done, one treatment, and you're done for life. So the good part of that is it's one and done. The bad part is, well, if you decide you you don't want it for whatever reason, well, it's too late. Right. And and it and that's no different than doing surgery. So if you do surgery, if you have your appendix removed, you can't put it back in. So it's an important concept for people to understand. And then just a quick comment on the computer.

Dr. Mitchell Rothstein 36:21

And that applies to the gene editing, not to the silencing or the RNA, the ASO or the RNA. This is just for the gene editing.

Dr. Michael Koren 36:30

Exactly. And then you made a really good point about comparing to existing options, which is the stuff that we're doing now with gene editing, one and done, is taking things that we know work based on existing options. So the question, and this comes up when we're now evaluating people for these clinical trials, and quite frankly, uh, as the principal investigator, I need to know that the patient has a good reason to want to not use what's already on the market and to go to this next stage of technology. And people come up with a good reason. You know, some people say, Oh, I can't remember to take things, or my my insurance company doesn't want to pay for it, or this has been such a devastating problem for my family that I know that a permanent solution is the best thing for me. It gives me peace of mind, right? So those are the type of things that people come up with. But there's always should be that analysis is that people should make the choice about getting these new options after that thoughtful process.

Cholesterol Targets Trials And How To Join

Dr. Mitchell Rothstein 37:30

Absolutely. Now, with that in mind, so we have a couple of gene editing trials at the Jacksonville Center for Clinical Research. The ones that we're going to talk about here are are really directed toward cholesterol. And since I have a cholesterol expert right next to me, I'm going to let Mike kind of talk about these to kind of present them.

Dr. Michael Koren 37:50

Yeah, so we talked about this concept of specificity of just going to the genes that are the bad genes and no place else. Well, in the cholesterol world, and you and people who have been to our lectures before have heard us talk about these things, but there are certain genes that are associated with higher levels of cholesterol or triglycerides that you don't need to live. So one of them is called PCS K9. We've talked about that many, many times here. And it's a gene that was only discovered in 2003, and some people have it and some people don't. If you don't have it, you live a perfectly normal life, except you still don't have a heart attack. And similarly for NHPTL3, which affects triglycerides a little bit more than LDL, but similarly, people are born without this gene and do perfectly fine. So isn't that cool? So we know that silencing or getting rid of these genes is something that is associated with living good lives, except you don't have cardiovascular complications. And so this is a very important rationale for targeting these particular gene expressions. And there are approved products in the market that already block PCSJ9 and NHPTL3. They're very expensive drugs. PCSK9 drugs are finally starting to come down. There was just an oral PCSK9 drug that got approved this week, Enlicitide. You might have heard that on the news. It's a MERCK product that we've been working with for about five years now. But these are all, again, short-term solutions. And now with the gene editing, we're going to eliminate that gene expression for the rest of your life, whether it's PCSK9 or NHPTL3. And we have programs that are targeting both of these genes as we speak.

Dr. Mitchell Rothstein 39:28

And then when we're talking about this in general, we have a number of gene modifying trials now, especially centered about LP(a) , which is a kind of a brand new actor on the whole cholesterol-cardiovascular scene.

Dr. Michael Koren 39:45

Right. And you'll get that analysis. So if you come to our office because you have a cholesterol problem or lipid problem, whether it's LP(a) or triglycerides or LDL, we're going to do a thoughtful analysis and say, okay, quite frankly, you're doing pretty well on the drugs that are already in the market. I'll just keep on doing what you're doing. We tell a lot of people that. Other people come in and say, Whoa, you know, you have this problem that is not really fully treated by what's out there. You would be a really good candidate for a clinical trial. And then we'll direct you to the right clinical trial, depending if you have a more triglyceride problem or more LDL problem, more LP(a) problem. But one way or another, we can target the bad guy and fix it. And so that's what we do in clinical research. And right now we probably can offer about a dozen different trials that hit different lipid molecules.

Dr. Mitchell Rothstein 40:35

And cardiovascular is still a cardiovascular disease is still the leading cause of death in the United States. So this is a target-rich, yeah, target-rich environment. For sure. So with that, we have, and this is one of those trials now, uh, that one of the gene editing trials for PCSK9 that kind of wipes it out so it doesn't bind to the LDL receptor. That receptor isn't then metabolized and doesn't take up cholesterol out of your bloodstream anymore.

Dr. Michael Koren 41:04

So this is a study that we're doing right now in Jacksonville. You can come up to me and we can get you signed up for it. Doesn't mean we're going to put you in it, but we can sign you up to be on the waiting list. And uh this involves the Verve technology, which is targeted against PCS canine. It's really reassuring. The first 30 patients approximately that got the drug were published in the New England Journal of Medicine just uh in at the end of May. We're really excited about these were all people outside the U.S., they were from uh New Zealand, uh England, and Australia. But there were no deaths, there were no major complications. So the first 30 people got through it without really any major issues. And so that's reassuring. About 50 people around the world have been dosed with this particular product so far. No deaths, no major issues, et cetera, et cetera. So it's it's reassuring. We're past that very, very early first and human stage. And we're now in a stage where you can still do a phase one trial, which means you actually get the product. Remember, when we go to phase two and three, it'll be placebo controlled. But you can still come to our office and actually get the product as we speak. Of course, if you pass a number of different uh analyses and you're an appropriate patient for it. But this is really earth-shattering information about this new gene editing technology.

Dr. Mitchell Rothstein 42:16

And like and like you said before, this is one and done, and you don't have to deal with cholesterol anymore.

Dr. Michael Koren 42:21

Yep. So all right, and this is uh why people get involved in the trials. Most of the people here have been part of our presentations before, but again, there's a lot of reasons people love research. My favorite statistic is to tell people, and it's true, it's not made up, is that if people have done a clinical trial, if you ask them, would you do another one? 97 to 99% say yes. So there are very few products out there when you've been exposed to it that you're so confident that you would absolutely go back for another for another round. Right. So these are the reason people do it. They they like to be medical pioneers and help the next generation. They get a lot of attention. And in our unfortunately, in the routine medical world, we're all so busy that it's hard for us to give the patients the attention that they deserve. But in the research environment, it's a very, very nurturing environment. There's all kinds of additional tests, it's all free of charge. We have outside grants that cover all the expenses, and you're a hero when you're when you're part of this.

Dr. Mitchell Rothstein 43:19

And one of my favorite stories is when we were doing the vaccine trials during COVID, we had a participant and she was very happy. I walked into my doctor and I said, you know, why you laugh? What are you so happy about? She goes, I'm gonna be I'm gonna be part of history. She's gonna be contributing to history.

Narrator 43:35

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