408 GRO Bio aud
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Kevin Folta: [00:00:00] Hi everybody and welcome to this week's talking biotech podcast by Calabra. Now this week I'm going to shut up and let the technology do the talking and this is some pretty cool stuff. So small peptide therapeutics have incredible potential to treat disease. The problem is They're small peptides and the body readily recognizes them as foreign.

Now grow biosciences has new technologies that are truly game changers because they use some super cool molecular biology tricks to incorporate novel amino acids in the proteins and change how they're decorated with carbohydrate moieties to make them invisible to the immune system. It's essentially reeducating the immune system to be tolerant of the novel protein therapy being delivered.

These new therapies are being tested against a suite of disorders, but one of them being myasthenia gravis, uh, one that currently doesn't have a cure, just treatments that can help someone live with the disease. So [00:01:00] this is really good stuff. So this is technology I never thought of before. And I think of molecular biology a lot.

So, so this is super cool. Today's CEO and co founder of Gro Biosciences. Welcome to the podcast, Thanks, 

Dan Mandell: Kevin. It's great to be here with you. 

Kevin Folta: Yeah, this is really cool. I've enjoyed going through the materials and some of the papers associated with this work and have a lot of questions in my head, but I think it's something that the audience will really appreciate as two new ways of dealing with certain technologies.

And let's just start out with the idea of the development of protein based therapeutics and grow by taking a rather novel approach to development of these therapeutics. Thank you. What is exactly the grow platform and how does it enable protein based therapies? 

Dan Mandell: Yeah. So the grow platform is essentially a novel way to make proteins with new building blocks called [00:02:00] amino acids.

So really for the past three and a half billion years, All of life has used the same 20 amino acid building blocks. So everything that you see around us, from bacteria and viruses to trees and elephants, are composed of the same 20 building blocks. And each of these amino acid building blocks carries a special chemical property.

Um, and so when we're making therapeutics, We'd like to go beyond that limitation of only having these 20 building blocks to work with. So, with these organisms that we call genomically recoded organisms, or GROs as our name implies, we have the first organisms that can actually go beyond those 20 standard amino acids and bring in these powerful new chemistries that we can use to make Uh, novel therapeutics, um, to engineer this, uh, grow platform, um, it's, it's actually quite a bit of work.

So we had to radically change the organism's genetic code. Um, what that means is we took one of the codons from the [00:03:00] genetic code, um, which is any of the three consecutive nucleotides, uh, in the DNA alphabet. And we systematically changed it to what we call a synonymous codon. That is to say, we're changing the codon to another sequence that has the same meaning.

But, now that there are no instances of that codon in the genome, we can delete everything in the cell that would recognize or bind to that codon. So, effectively what we've done... Is reassign that codon to now specify the incorporation of a new amino acid, what we call a non standard amino acid. So these are really the first organisms that can go beyond the standard 20 amino acid building blocks and build completely novel proteins that nature could never consider before.

Kevin Folta: Okay, I think I got this. So this is all done in E. coli, right? 

Dan Mandell: That's right. So the first organism that we recoded is E. coli. Um, that's largely because it's a widely used and [00:04:00] relatively easy to use production platform. Um, it also happens to have one of the smaller genomes of all of the production organisms that are out there.

Um, and so that made the task of performing this systematic recoding. a little bit less, uh, daunting. Um, but, uh, efforts are underway to recode other organisms, uh, such as yeast and mammalian cells as well. 

Kevin Folta: And when you say a little less daunting, how many different edits did you have to make in those stop codons of E.

coli to do this across an entire genome? 

Dan Mandell: So there are hundreds of changes that had to be made for this first organism, um, but we're now finishing, uh, another organism, uh, which is going to have. multiple codons reassigned. That is to say now we can put in multiple different new chemistries simultaneously.

And that took tens of thousands of changes to the genome. So you can start to imagine how difficult the early work was on these projects. 

Kevin Folta: Okay, so this is coming together for me. So now you free [00:05:00] up this one code on that used to be assigned as a stop code on that now is available as a code on in the coding region of a transcript that now can Oh, thank you.

recruit a tRNA with a novel amino acid. But where does that tRNA come from? And where is that novel amino acid come from that is attached to it? 

Dan Mandell: Yeah, great question. So for every new amino acid that we want to add to the alphabet, We actually engineer a new tRNA and an enzyme called a synthetase that attaches that amino acid to the tRNA.

Um, so this is a process that's oftentimes taken years. So part of what we've built at Grobio is a computational and high throughput screening infrastructure, which we call our High Throughput BioFoundry, to bring roughly order of magnitude acceleration to that process. So what we do is... All of the [00:06:00] different templates that make and bring them into a design workflow that allows us to modify them to specifically react to this new amino acid.

And through that process, we can now relatively rapidly. Uh, engineer, what we call this translational machinery. That's the synthetase for each new amino acid. 

Kevin Folta: Okay. Now this is all starting to make even more sense because you have to have the tRNA attached to that amino acid. But what kind of amino acids are we talking about here?

I mean, I know there's a lot of naturally occurring ones that are not in the 20 that are used translationally. So are, are these just from that set, like towering and some of those, or are there Are they really kind of novel amino acids with unusual properties? 

Dan Mandell: Yeah, it's both. So we can take rarely used amino acids that are very difficult to encode genetically and now make them completely engineerable.

So there could be an amino acid, which has to be installed, uh, and then [00:07:00] modified through an enzymatic process, which is very slow and difficult to scale. We can now make that as trivial as popping that code on into the proteins coating, uh, proteins coating, excuse me, protein coding sequence. Um, but we can also put in totally novel amino acids, uh, and we've done that as well.

So different amino acids can confer different capabilities to proteins that can range from, uh, improving their stability, uh, allowing them to better penetrate inside cells, and even modulating the immune system. Um, and those are all totally novel capabilities which we can introduce with this expanded amino acid alphabet.

Kevin Folta: I see now this is really, really coming together. It gets better. We're sharpening this thing every step here. So now you can, uh, insert a, uh, your gene of interest that you want to generate this peptide or this protein and also recode that protein so that it has these, uh, amino acids that maybe confer better ability to, uh, be more [00:08:00] stable or maybe, you know, evade ubiquitination or whatever happens in its therapeutic context.

And so you're able to, uh, generate these in E. coli and now have a host of peptide based therapeutics that have potential roles in, uh, well, in treating some sort of disease. 

Dan Mandell: You nailed it. So now that codon, which we removed from the genome. Uh, only appears in the protein where you place it. So, for example, if you're a drug developer, all you have to do is put a plasmid, for example, encoding that gene into the grow, uh, and then place that code on anywhere in that protein coding sequence where you want that nonstandard amino acid to appear.

And so there's two really important features of the grow that make this, uh, what we call scalable. Um, one is your tRNA. Uh, that has the NSA on it will only go to the positions in your protein sequence where you've placed that code on. It will not travel to [00:09:00] other places in the genome, uh, and have what we call off target incorporation, which oftentimes makes the production cell sick.

You know, you can imagine a position where you're supposed to stop translation and now you stick in this novel amino acid. That's not very good for the fitness of the cell. Um, so that doesn't happen in our organism. It only goes to places where you place the codon. The second really important feature is in a wild type organism, every codon has associated translational machinery.

So, for example, if you take that recoded stop codon you mentioned earlier, um, there's a protein called release factor 1. that's trying to stop translation at that position. Well, we don't have any of those codons in the genome anymore. So now we can delete that release factor and there's no competition in the cell, uh, for your codon in your protein sequence.

So now whenever you put that codon in your therapeutic protein, uh, the tRNA will only associate at that position, and the tRNA doesn't have to compete with anything else in the, to associate at that [00:10:00] position. And this is a big part of why this is really the only scalable platform for making these NSCA bearing proteins.

Kevin Folta: Yeah, this is really good. So, so can you explain to me some of the advantages and disadvantages of using peptide based therapies? 

Dan Mandell: Sure. Yeah. So most drugs are typically going to be either small molecules, you know, these are things like ibuprofen and some of the statins, for example, that are made through chemical processes typically are sometimes extracted from.

Processes, um, protein therapies, which we're talking about today, uh, and, uh, gene therapies are really starting to push their way onto the scene. Um, now, there are small molecules have a whole suite of advantages and disadvantages relative to protein therapeutics. So, some of the advantages of proteins over small molecules is that proteins Uh, can assume many, many different shapes, and you can target them to almost anything.

Uh, antibodies, for example, are proteins. And, as you may know, antibodies can be trained to [00:11:00] recognize any, uh, chemical shape. Um, and so, that's a really big advantage of protein therapeutics. You can target, uh, pretty much any receptor or other protein in the body. Um, they're also much bigger than small molecules, as the name implies, and so they tend to have a longer half life.

So that can mean less frequent dosing, for example. Um, and they're also made using living cells, uh, like E. coli or yeast or sometimes even, uh, human or mammalian cells. And one advantage of that factor is because they're genetically encoded, we can actually use evolution to drive. The, uh, to drive better efficacy, uh, and activity, uh, of protein therapeutics.

So these are some of the things that make them really cool. Now, um, of course, that because we're making these, uh, proteins in living cells, they have to be purified from the cells, and that can make them more expensive, uh, than some small molecules. Um, and the fact that they're bigger also means it can be tougher for them to get inside of cells.

Uh, to target certain diseases. And so there [00:12:00] are some diseases that involve intracellular targets that at present are better suited for small molecules, but the field is making significant progress in developing cell penetrating peptides and proteins as well. Um, and finally, proteins typically won't survive passage through the stomach and the intestine.

Um, so they have to be administered typically by injection or administered through IV. Um, and so for that reason, uh, many protein therapeutics are used for more serious diseases. And then, as I mentioned, gene therapies, uh, this is where, uh, you typically are typically going to package, uh, a copy of a gene, a corrective gene, into a virus, is usually the common vector, and deliver that to the patient with the intent of correcting a mutation in the patient's genome that's causing a disease.

And so when it's done right, the corrected copy of the DNA in the virus can overwrite the mutation in the patient's genome, and there's even a possibility of a one dose cure for some diseases. And these are typically [00:13:00] used for some of the most devastating diseases, like spinal muscular atrophy or Duchenne's muscular dystrophy.

But the problem is really twofold. One is you may have off target. Uh, activity of that of that virus. And so if you edit the wrong spot, you can imagine that being devastating to a patient. The other is that, you know, you may not be surprised to hear that humans have evolved for a very long time to avoid viruses.

And so we typically have a powerful immune response to that viral delivery vector. That means that, first off, many people already have antibodies against the virus that we're trying to use to deliver the therapy, which means therapy won't be effective. Um, and secondly, once your body's seen that virus, uh, you can pretty much not no longer deliver it.

It's very difficult to re dose because if you didn't have antibodies against the virus before, well now you probably do. Um, and we are, in fact, as I mentioned, as we're developing these chemistries that allow us to modulate the immune system, [00:14:00] actually working on that problem to be able to reprogram the immune system to allow delivery of gene therapies, among other things.

Kevin Folta: This is all really good stuff. I mean, people don't realize, as you mentioned, antibodies are proteins, and then insulin is a great example of a small. Molecule therapeutic too for diabetes, for diabetics. So it's, it's, it's something that's very common, much more common than we think sometimes. And, um, grow bios platform really is one layer deeper because you have this pro gly concept, which uses the non standard amino acid library, but adding glycans to change how the immune system responds to that protein.

And so what are glycans and how do they interact with the immune system? 

Dan Mandell: Yeah. So glycans are the sugar molecule. That decorate most of the cells and proteins in your body. So, uh, you and I, uh, share the same glycan language, um, which is different than the language used by cows, which is different than the language used by, [00:15:00] uh, corn, uh, which is different than the language used by bacteria.

And so, for example, this is one of the key ways that your body distinguishes self from non self. Um, if you have a pathogenic bacteria in your body, it's going to recognize that foreign lake and sequence. Um, in fact, some pathogenic bacteria have gotten so clever, they've learned how to. Take hands off of your cells and put them on them to avoid immune surveillance, um, as an example of how powerful this language is as far as discriminating self, uh, from non self, um, and so, uh, the ability to engineer like oscillation, uh, on specific proteins has really evaded protein engineers.

For a long time. And so with ProGly, we're actually hoping to enable this for the first time. This ability to define that glycan signature on the surface of any protein and therein control how the immune system will respond to it. 

Kevin Folta: Okay. So are these just amino acids, which when you assemble the [00:16:00] protein are already somehow linked to that glycan or that come kind of a pre.

Uh, adorned with these Yes. Molecular. Yeah. So, so that's how that works. All right. That's pretty cool. So how does grow Bio's technology create these custom glycosylated proteins? 

Dan Mandell: Yeah, so, so pro Gly is one of, of several families of chemistries that we've enabled in the platform. So I mentioned, you know, there are chemistries for improving stability.

Uh, there are chemistries for enabling. Attachment of other things, and this is another family of chemistries, uh, which has glycans on it. And so you can really think of these as like any other amino acid building block in the alphabet. And that's part of what makes it so powerful. Um, wherever you place that target codon in your protein coding sequence, the organism will install this glycosylated amino acid.

And you can choose from a variety of effects on the immune system based on which glycan you use. [00:17:00] So, some of these glycans can cause a protein to be recognized as self. And so, for example, we could take an autoantigen and try to re educate, uh, the, uh, the patient's immune system to recognize it as a self protein to reverse an autoimmune disease.

Um, you could also imagine taking... A protein, which is on a cancer cell, um, and, uh, training the immune system to attack that by using a different light that would typically be used as a non self signal, like from bacteria. Um, so we can really go either way right now. The company is very focused on that 1st set of applications tolerance.

Because it's actually one of the more difficult problems faced in medicine. How do you train the immune system to recognize an arbitrary protein is safe? That it's a self protein. Um, and this is in our minds really, uh, the first way that's, uh, I think quite convincing to do it for any protein in a facile way.

Yeah, 

Kevin Folta: that's the real breakthrough solution. It sounds like, but [00:18:00] one of the barriers that I can imagine is that glycosylation is readily reversible. There's enzymes that put them on enzymes that take them off. And are these special proteins that you're creating resistant to those enzymes that remove glycosylation signals or just to make sure that these things have a longer half life or are not evading the mechanisms of the cell?

Dan Mandell: It's a great question. Um, and so In fact, uh, once a glycosylated protein is taken up by an immune cell, um, those enzymes we mentioned are actually inside the immune cell, and they remove the glycan. And the idea there is they want to present the underlying protein sequence to other immune cells to educate them about that antigen.

Um, and so in our case, uh, we actually want those glycans to get removed. So, for example, if we're trying to tolerize a patient to a protein that's causing an autoimmune disease, we want to tolerize them to the underlying sequence that's driving that disease. [00:19:00] And so we can take that exact same sequence.

But now we can use a glycosylated version of it. And what that does is when the glycosylated protein encounters that immune surveillance cell, that cell recognizes those glycans as self. It then removes the glycans and presents the antigen to other cells to say, Hey, this is a self protein, stand down.

And that's really the power of the approach. You can use that for any protein sequence. And you can educate the immune system to recognize that sequence as self. 

Kevin Folta: Yeah. So this would have tremendous application inside many autoimmune diseases. It sounds. Absolutely. Yeah. Yeah. So that's where we'll go next.

So we're speaking with Dr. Dan Mandel. He's the CEO and co founder of grow biosciences, and this is collaborators talking biotech podcast. And we'll be back in just a moment. And now we're back on collaborates talking biotech podcast. We're speaking with Dr. Dan Mandel. He's the CEO and co founder of grow [00:20:00] bio.

And we're talking about innovative strategies to change. E. coli and other organisms, making them genomically recoded organisms, organisms that can create new flavors of proteins, which can be helpful in therapeutics and then decorate those proteins with mechanisms that help them reeducate the immune system.

And where this gets exciting is when we start to talk about application because there's so many different diseases, especially autoimmune diseases, that Really a defy most, which, which defy many of the modern therapeutics that many of these are maintenance type, uh, drugs that don't cure the problem.

They just allow someone to live with it a little bit longer and more comfortably. And so let's talk about really the number one application in your pipeline is with myasthenia gravis. And, and so what is myasthenia gravis, how many people are affected, what kind of problem is it? 

Dan Mandell: Myasthenia gravis, or MG, is a serious [00:21:00] autoimmune disease that causes progressive muscle weakness in patients.

It often starts with ocular muscle weakness, so drooping of the eyes, and then it often progresses to more debilitating weakness, including difficulty breathing sometimes. So it's a very serious disease. Hundreds of thousands of people around the globe have this disease. And in the U. S. alone, thousands of patients are what we call refractory, meaning that they aren't responding to any of the first line therapies.

And so, uh, to your point, Kevin, you know, like many autoimmune diseases. These refractory MD patients are treated with harsh therapies that don't work very well. So these are broadly immunosuppressive therapies that are going to knock down the entire immune system. Um, and that's going to impair the patient's ability to fight, uh, infections.

It's going to increase your risk for cancer and, and and also, as you mentioned, they're, they're, they're simply symptom, uh, [00:22:00] management. They don't actually... cure the disease, or even in most cases, cause a very substantial improvement to symptoms. 

Kevin Folta: And so what is the actual therapeutic target in the case of mg?

How, how does that work? 

Dan Mandell: So, so one of the key reasons why we think we can really help here is that the auto antigen that drives MG is very well characterized. Uh, it's a muscle, uh, uh, protein called the acetylcholine receptor. Um, and, um, 85% of NG patients. are sick because they have an immune response to that one protein.

So, if we can make a pro gly version of that protein and administer it to the patient to, as you put it, re educate the immune system to recognize that autoantigen as a self protein, we can in fact cure the disease for 85% of these patients. and we can do it without having to repress the rest of the immune system.

This is what we call antigen specific tolerization, and there are [00:23:00] many diseases that could potentially be cured by an approach like this. Myasthenia gravis is one that happens to be quite well suited. 

Kevin Folta: That's really good stuff. And maybe I have to take a little bit of a step back because the two things that I'm not good at our immune systems and brains.

And so when we talk about the idea of reeducation, where the, it seems like the immune system has already made a decision, though, to identify this target as. Uh, foreign or non self and, uh, in initial, initialize this autoimmune response. So how does it override that first wave of the body's natural response against a self protein?

Dan Mandell: That's a great question. And it's all about restoring a balance or homeostasis in the immune cells of the patient. So in an autoimmune disease patient, oftentimes you have, uh, these, uh, certain what are called T cells, stimulatory T cells. that are causing inflammation, uh, those T cells also activate [00:24:00] other cells called B cells, which produce antibodies.

So in the case of myasthenia gravis, there are overactive T cells and B cells that are pumping out antibodies against that muscle, uh, uh, receptor. And that's what is ultimately driving the muscle weakness. It's those antibodies binding to that receptor. Um, and so the idea here is to deactivate or turn off.

Those overactive stimulatory T cells and B cells. So the way that Progly works, we talked about how, uh, the glycosylated antigen. Again, remember, this is the same protein that causes the disease, but it just has these Progly glycans on it. When that version of it now enters into an immune cell, and the immune cell has seen that self signature through those glycans, it's going to present that antigen sequence to the immune cell repertoire, um, as a self protein.

So what happens now is when new immune cells are made, they're educated to [00:25:00] understand that that is a self protein, and they differentiate into special T cells called T regulatory cells, or T regs. And Tregs are very special, very powerful cells, which actually will localize to the site of inflammation, uh, and deactivate in terms of causing energy or even clonal deletion of those overactive stimulatory T cells and ultimately suppressing the activity of the B cells that make the antibody.

So we're really turning off the faucet, as it were. Uh, that's driving the stimulatory immune response against that antigen and we're doing it by putting in powerful, uh, antigen specific immunosuppressive cells that are actually the result of administering the probe live version of the antigen. 

Kevin Folta: All right, this makes perfect sense now because immune cells are teas and your T and B cells have some sort of turnover.

So if you can re educate the. Foundation of the, of the, of the B cells. Now, all of a sudden you can, uh, build [00:26:00] a, as you say, a repertoire of reeducated, uh, immune cells. 

Dan Mandell: Exactly. Right. It's all about restoring equilibrium. 

Kevin Folta: All right. Well, this is really cool. So what have the results been so far in your models?

Because I believe you have a MG model. Um, uh, rodent that you can use and, uh, what are, what are we learning about how well this works? 

Dan Mandell: Yeah, so, uh, there, there is a, uh, rat model of myasthenia gravis. Uh, and it, it does happen to be, uh, one of the more translatable, uh, animal models, you know, no animal model, that's perfect.

But this happens to be one that pretty faithfully recapitulates the human disease. And where in, uh, treatments that work, uh, in, in human have worked in this rat model. And so, uh, it works the same way, you induce the disease with the same antigen that drives human disease, that acetylcholine receptor. And then over time, the animals develop, uh, progressive muscle weakness.

And so what we did, uh, was to, uh, go into this disease model, uh, split up the animals [00:27:00] and treat some, uh, with a, a vehicle, just with a, a, a, a, a, a pure solution without the therapeutic and then, uh, others with the Progly therapeutic. And what we found was that when we treated the animals with Progly, we could drive a profound improvement in disease progression in these animals.

And then furthermore, when we looked at the immune cells in these animals. We saw the mechanism that we hope to see, which was a multifold induction of those Treg cells. So we're able to put the antigen into the animals in this glycosylated form, drive the induction of those Treg cells. Those Treg cells are then quelling the immune response to the autoantigen.

And you're seeing this, uh, uh, this really great increase in the disease progression as muscle, excuse me, as measured by muscle strength in 

Kevin Folta: these animals. Well, it's all very exciting. Where does it sit in terms of the pipeline in terms of clinical testing, things like that? [00:28:00] 

Dan Mandell: Yeah, so now that we have compelling animal data, you know, the next steps are to move towards an IED filing.

Um, and, you know, you hope to be doing that next year and then getting into the clinic the year after that. 

Kevin Folta: Yeah, these things can never go fast enough and it's, and it's something that we talk about all the time here on the podcast is how, uh, it, how hearing these kinds of positive results in therapies that are novel, that look really good, uh, give hope to someone who's suffering from this disease, but the, uh, the process can never go quickly enough.

I guess the other thing I wanted to talk to you about was, uh, the concept of enzyme replacement and some of the work that's going on at Grow Bio in that area. So why is that relevant to human disease? 

Dan Mandell: Yeah, so, uh, oftentimes when a patient has a disease, um, it can be the result of a defective gene in their body, uh, that results in the gene's product, uh, of an enzyme, uh, being deficient.

Um, and there are many examples of, [00:29:00] of these diseases. And so oftentimes, the simplest way to cure that disease is to provide them with that enzyme. You can simply infuse it into the patient, and oftentimes it's very effective. The patient now has the right level of that enzyme, and they can go about their lives.

The problem is that oftentimes the sources of those enzymes are foreign, and as a result of that, um, you develop an immune reaction to it. So we just talked about how Progly can tolerate patients to proteins from within themselves, right, autoantigens. But we can just as easily tolerate patients to proteins from other sources, like enzymes that are from other species.

And so, uh, what we've done is we've taken an enzyme replacement therapy, which is very effective in refractory patients, but when you treat patients, it almost always generates a powerful inflammatory response in the form of antibodies. That bind that enzyme and stop it [00:30:00] from working. So we want to create a version of this enzyme, uh, which can be just as active, but which has a tolerization effect on the body, that is to say, it will not generate these neutralizing antibodies.

Um, so this is where our computational protein design, uh, uh, workflows have really come in handy again. Um, because now we can do is look at the surface of the enzyme, uh, in a computer, um, look at billions of possible places. We can put these different, uh, these different molecules, these like hands, uh, run that through a high throughput screening platform that we've built and ultimately identify variants that are highly tolerogenic, but also maintain all the activity of the wild type protein, right?

So here, uh, is an example of a protein where there's a marketed product. Um, it becomes ineffective in most patients very rapidly. And now we've been able to engineer a variant of it, which has many of these tolerogenic glycans, and which we can show has 100% of the activity [00:31:00] of the wild type enzyme in human blood serum, which is where this, uh, this therapeutic has a function.

Kevin Folta: Well, you mentioned the inflammation response coming from the addition of a therapeutic protein that isn't tolerated well that you now will make tolerated. But what's a couple examples, or maybe an example of a protein that's delivered therapeutically that maybe isn't, uh, received so well by the 

Dan Mandell: body.

Yeah, there are many. So, um, for example, you can look at the enzymes that are used for female ketonuria, um, Gaucher's disease. gout, um, and even some of the blood factors that are used for treating hemophilia. Um, all of these, you have, uh, observations of neutralizing antibodies that over time can render these, these therapies highly ineffective.

Kevin Folta: You also mentioned earlier how these technologies can be used to enhance the, uh, application of, uh, gene therapy because most of these are delivered or many of them are delivered by viruses. That the body begins to develop an immune response [00:32:00] towards really, really overriding the efficacy of the therapy itself.

And can you give us more ideas about how this technology can work in that context? 

Dan Mandell: Absolutely. So yeah, you hit the nail on the head. Uh, these immune responses to the gene therapy delivery vectors is really the primary impediment to expanding the access of gene therapy to more patients. So, just as we can tolerate patients to autoantigens and enzymes, we can also tolerate them to the proteins that comprise those gene therapy delivery vectors.

So the little twist here on what I described earlier, and I'll mention we have a couple of different approaches in the works, but one of the approaches that we pursue is to take those key immunogenic proteins from the virus, express them in our platform with those progly amino acids. And then basically create an empty viral delivery capsid, which is used prior to the gene [00:33:00] therapy treatment to educate the immune system to receive that treatment and not react to it.

So it's not itself a gene therapy. It's almost like a tolerogenic vaccine that you give prior to treatment. And this is actually well in line with the way you might treat a patient now, but it's done by hitting them with a corticosteroid or another immunosuppressive. I'm here again. We're trying to create an antigen specific polarization.

So you're only going to turn down the immune response to this one protein, leaving the rest of the immune system intact. And in principle, that can be done both to eliminate the pre existing antibodies that make some patients ineligible for treatment, as well as to, uh, eliminate or prevent the emergence of antibodies subsequent to treatment.

to enable redosing. And as I mentioned earlier, it's very hard to redose gene therapies right now. This is a way that for the first time we can potentially give multiple doses of these life saving therapies and perhaps at a safer and lower dose as well. 

Kevin Folta: Yeah, this is one of the major barriers that really keeps gene [00:34:00] therapy, well, some gene therapies from being effective.

And so what you're doing essentially is a pre treatment that says, Hey, body. Uh, pretty soon you're going to be seeing this and, and kind of, uh, you know, educating or reeducating the immune system to not respond to that particular new antigen. That's exactly right. Oh, wow. This, this is really cool stuff. So when you look at the current, um.

Pipeline of different products that you're talking about at grow bio. Uh, we, we, we talked about the potential therapy for myasthenia gravis. Where's everything else? 

Dan Mandell: Yeah, well, we're, we're hoping to bring, uh, our pipeline into clinical trials, uh, in 2025. Um, and as you said, it takes time to get through the clinic, but if you were to tack on sort of the typical five ish year development plan.

Um, that's, we'd be looking at to bring these to market. 

Kevin Folta: This is all super exciting stuff. And if people want to learn more about the technology or more about GrowBio, are there some [00:35:00] resources you can point them to online? 

Dan Mandell: Yeah, you can go to, uh, growbio. com that's G R O B I O. com. You can learn more about our Grow platform, uh, the ProGly approach.

We also have another. A set of chemistries called Dora logic that I alluded to earlier that can make proteins more stable to improve half life and dosing. Um, and we also have a lot of information there on ideas around future chemistries and basically how the company functions and works. We're also on Twitter, Instagram, Facebook.

So feel free to hit us up on social media. Um, we try to put out material pretty regularly and you can hear what we're up to 

Kevin Folta: now. Very good. And where do they find you on Twitter? 

Dan Mandell: Uh, we're GRO underscore BIO both for Twitter, uh, and for Instagram. And then we're also on LinkedIn. Ah, very 

Kevin Folta: good. Facebook. Yeah.

That's very helpful. Well, very good. Oh, Dr. Dan Mendel really appreciate your time today on this. This has been. For me, one of the most technology dense versions of [00:36:00] the podcast I've done in a very long time. And I'm going to have to really go back and scratch my head on this because it just is, it's amazing technology with really more applications that we probably haven't even thought of yet.

So thank you very much for your time today. 

Dan Mandell: Terrific speaking with you, Kevin. I'm looking forward to receiving my, my densest technology trophy from you this year, but these are fantastic questions. It's been a real pleasure chatting with 

Kevin Folta: you. And as always, thank you for listening to collaborators talking biotech podcast, think about how this company has now taken these new novel approaches to solve a really important problem of myasthenia gravis and how these may be applied to other immune disorders.

So many of which are really just diseases that have to be maintained because of lack of response to therapies. All very exciting and hopeful for the future of taking care of the folks who are ill now, and maybe never having the future experience these diseases. So thank you very much for listening to the talking biotech podcast.

And we'll talk to you again next [00:37:00] week.