RARE Daily

Changing What’s Possible with Cell and Gene Therapies

January 18, 2024

Genome editing technologies are rapidly evolving, but existing approaches have limited capabilities. Tome Biosciences, which emerged from stealth in December 2023, said its programmable genomic integration technology enables the insertion of any genetic sequence of any size at any location in the genome with precision. The technology overcomes barriers in existing approaches and can enable the development of a single therapy for a monogenic disease across a wide range of variants. We spoke to Rahul Kakkar, president and CEO of Tome, about the company’s genome editing technology, how it works, and its potential to change what is possible with gene and cell therapies.

Daniel Levine: Rahul, thanks for joining us.

Rahul Kakkar: Danny, thank you very much. Appreciate the interest.

Daniel Levine: We’re going to talk about gene editing, Tome Biosciences, and its editing technology that enables the insertion of any DNA sequence of any size into any program genomic location. Gene editing is quickly moving into the public mind. We’ve had the first CRISPR gene editing therapy approved in December. Where are we in our ability to edit the genome for therapeutic purposes?

Rahul Kakkar: Thanks, Danny. I think it’s an incredibly exciting time in human medicine. As you said, the first ever product that edits the genome to be approved is really a milestone, both scientifically and in terms of biopharma drug development. The field of genomic engineering for therapeutic purposes, I like to think of as cresting through different horizons. Really, the first horizon was established by the first three companies, Editas, CRISPR Therapeutics, and Intellia, using the CRISPR Cas9 enzyme, which is the enzyme that won the Nobel Prize to do what it does, which is it cuts DNA. And when you’re cutting DNA, you silence the gene that you’ve cut. That’s logical. If you think about it, most of human drug development to date has been about silencing pathways, either with a pill or with an injectable, or now with genome editing. But I think the real promise of CRISPR Cas9 as an enzyme and genomic editing as a field is not just to break genes, but to really correct them when nature has put an unfortunate bug in our software, which is our DNA—to actually be able to correct those bugs. I think the second horizon is really what we call base and prime editors, which are those modifications to that CRISPR Cas9 enzyme that allows the change of a single base pair or a few base pairs. And that’s certainly a leap in the technology, but as you can imagine, it’s limited. If you and I were both suffering from a genetic disease, for instance, [it’s] likely your genetic heritage and my genetic heritage would be different and therefore your mutation and my mutation would likely be different. And so, it creates this paradigm where if you’re going to correct a genetic defect, you’re almost creating a different drug for each individual person, which is, if you’re talking about supply chains and delivering drugs on an industrial level to a society, that’s very, very difficult. And so, I really think the maturation of this field is the ability to correct whole genes. And once you’re able to do that, then we can really think about genetic engineering coming into its own as a technology that can underwrite really the next horizon, the next phase of drug development in its most mature form, which is being able to correct entire genes for patients who have genetic defects and inserting genes and even logic circuits, gene circuits, into cells outside the body to reprogram those cells as therapeutics themselves. So, I really think this next area that we’re moving into, which is being able to edit the genome at the gene scale, not at the single base pair scale, really represents a quantum leap for the field.

Daniel Levine: Before we talk about your platform technology, can you explain to listeners what integrases are?

Rahul Kakkar: Sure. Integrases are a class of enzyme that occur in nature that do what their names suggest. They integrate, they integrate DNA into DNA, they integrate pieces of DNA into the genome. Those integrases that exist in the human body recognize certain areas in the genome to insert DNA into the genome. And these occur in multiple different animal systems, even viral systems, but they are very, very efficient at inserting DNA into a genome. And I think the two key characteristics of integrases is that they’re very efficient and they don’t care how big the piece of DNA going in is. So they can insert a few hundred base pairs, which is the size of an exon, which is that portion of a gene that encodes information. They can insert 50 to a hundred thousand base pairs, which is the size of multiple genes. So they become a very, very interesting tool if they can be used for therapeutic purposes to really modify the genome in a very flexible manner.

Daniel Levine: You’ve developed platform technology you call programmable genomic integration or PGI. What is this?

Rahul Kakkar: So PGI isn’t one technology. It’s more an approach or a philosophy. And what I mean by that is programmable genomic integration is the ability to place pieces of DNA into the genome in a user-defined manner. So, in other words, if a child is born with a defective gene, what we want to be able to do is to insert a healthy copy of the gene where it belongs, where nature has unfortunately provided this child with a defective gene. When we’re talking about creating cells that are therapeutics in their own right, we really want to be able to reprogram them in a way that represents our rewriting computer code. We want to be able to go into a cell’s genome and swap out components. And that philosophy or that idea is what programmable genomic integration is. Now the technology, the architecture of enzymes to actually do that PGI, there are many different. You can imagine different types of architectures to accomplish that, each of which will have its own advantages or disadvantages. Our company Tome is fully focused on the idea of PGI, and we actually have multiple different technologies that again, have different advantages and different disadvantages to be able to affect the ability to swap out, insert, and to change portions of the genome for a therapeutic benefit.

Daniel Levine: What’s the range of tools that might be used within a therapy, and are you limited at all by the size of the cargo or the ability to target specific tissue or cells within the body?

Rahul Kakkar: Yeah, great questions. I think the best analogy here is the world of computers. So when we think about the core of any computer, whether the computer is a desktop, a laptop, a tablet, a watch, the core is the central processing unit. It’s the CPU, but the CPU needs other components to do what it does. And if you combine the CPU with a GPU, a graphical processing unit, then you’re really talking about a machine that is optimized for graphics. If you then add an NPU, or a neural processing unit, now you’re talking about a computer that’s really optimized for AI, but the core of all of these devices is the same. It’s the CPU, it’s then augmented with the different architectures you place around it. So that’s how we can think about PGI. So PGI at its core is the CRISPR Cas9 enzyme, which is that enzyme that finds areas of the genome it’s programmed find. That’s the programmability part, the P in PGI. And then we can decorate or augment CRISPR Cas9 with different types of enzymes. Integrases would be one. If you decorate a Cas9 enzyme with an integrase plus another helper enzyme, you can insert very large pieces of DNA because that’s what integrases do. They’re very efficient and they don’t really care how big the insertion is. So we can routinely do 30,000 base pairs. That pretty much covers most genes in the human genome. We can also use an enzyme called a ligase instead of an integrase. We’ve just acquired a company that provides us with that technology that’s very good for smaller edits, tens to hundreds of base pairs. So, we really focus on augmenting that CPU, that CRISPR Cas9 enzyme, with various other enzymes to impart the programmable genomic integration functionality that we want. And it allows us to do something that I think has been limiting in the genomic engineering world. And what I mean by that, just to spend a minute on that, is if you’re a company that is focused on a single genomic engineering technology, then you approach every disease with that technology. In other words, you have a hammer. Every disease kind of has to look like a nail. Whereas if you’re a company that has various technologies under its belt, all of which can do different things, like I said, smaller edits, larger edits, then you can do what again, in my opinion as a practicing physician, you can do what patients want, which is give me the right technology for my disease, don’t make my disease fit in the technology you have. So that’s the real advantage that we have. We have numerous technologies, all of which fit within this concept of programmably editing the genome. But we do have our limitations and those limitations, as you acknowledge, are delivering these complex enzymatic components is not easy. These are some of the most complicated drug products that our industry has ever envisioned, and the current modalities we use to deliver them in the body, lipid nanoparticles, modified viruses, they do limit what we can do out of the gate. But over time, as the industry and we as a company, but the industry broadly, becomes better at developing these delivery technologies both lipid and viral, we foresee that we have the premier cargo for manipulating the genome regardless of the delivery vehicle used.

Daniel Levine: There have been efforts in the past to harness integrases for therapeutic ends, but they’ve been limited by the specificity of these enzymes. How has Tome been able to overcome this limitation?

Rahul Kakkar: Yeah, it’s a phenomenal question, and I will expand your question to say that there have been numerous approaches to modifying the genome or inserting genes into the genome that have been limited in some way or another. Integrases used in isolation are certainly limited. I’ll talk about how in a minute. But even using integrating viruses like lentiviruses have been used. Integrases have been utilized and they have their limitations. I’ll talk about that in a minute. Lentiviruses are integrating viruses that have been used and transposons are a third enzymatic class that have been used. But all of these suffer from somewhat similar limitations. Integrases in general recognize their native sites within the genome, so they’re not programmable. They will insert into the genome where nature has designed them to integrate into. Transposons are very similar. Lentiviruses are a bit different. They randomly integrate, and to me that’s a bit of Russian roulette. You put in a gene into the genome in a random location. How do you know you’re not putting something in a critical place within the genome? In fact, some of the lentiviral based gene therapies on the market currently do have a risk of secondary cancers. The difference that we have is the programmability. We insert genes where we program them to go, and this is where combining integrases with that Cas9 enzyme is the quantum leap forward. And so using Cas9 to direct the integrase to precisely the site in the genome and nowhere else where we want the gene to go is the leap forward that we’re bringing. So, all of the advantages of gene therapy in terms of durably inserting a gene into the genome without that risk of random integration or being forced to integrate in a site that the enzyme like an integrase would recognize on its own.

Daniel Levine: One of the benefits of your approach is the potential to insert large sequences. How does the size of the payload compare to existing editors and how large a gene might you be able to deliver?

Rahul Kakkar: It’s a great question. Integrases, as I said before, don’t really care how big the integrating piece is. And so from that standpoint, we’re really only limited by the payload capacity of the vector of the virus that we use to bring in the correct gene into place. And there are some limitations there, whether we’re using an adeno-associated virus, an AAV, or other types of vectors that we’re developing within Tome Biosciences. But by and large, because of how we use these viral vectors, there isn’t that much of a limitation. We can go after most human genetic diseases using the delivery vehicles that exist and operating within that two to 4,000 base pair arena. I think where the lack of a size limitation to our systems really shows its prowess is in programming cell therapies or cells outside the body. Because in our first cell therapy program for instance, we’re able to put in multiple genetic components and even logic circuits, which are 10,000 base pairs plus into those cells and integrate them exactly where we want them to go. In the future, we may want to be bringing very large 10, 20, 30,000 base pair segments into the gene therapy world. That’s not really a requirement for where we’re going first, but I think really those large component integration approaches really bring out the full potential of cell therapy where we can really fully reprogram cells for therapeutic benefit.

Daniel Levine: You talked about this early on, but the implication here is that if you have a genetic disease that can be driven by a range of variants that you can treat it with a single therapeutic here. So for instance, something like cystic fibrosis, which there may be 2000 variants for. I take it the idea is that Tome could develop a single gene editing solution.

Rahul Kakkar: Insightfully said, that’s exactly right. So our approach here is to make gene therapies look like traditional drug development. If you have cardiovascular disease, that’s my area of specialty, if you have an autoimmune disease, if you have a skin disorder, and you take a medicine, the drug companies are developing a single drug that really is for that entire disease. There is this concept of personalized medicine. However, in most situations, most individuals, when you’re talking about very efficacious drugs, derive tremendous benefit from the same drug, right? If you’re going to have high cholesterol and you’re going to take a cholesterol medicine, I don’t really need to know what’s driving your high cholesterol. I can give you a statin, and almost all patients react very, very well because these are very, very good drugs. We’re trying to bring that same scale to genomic diseases. Cystic fibrosis, as you mentioned right now, there’s a slew of drugs that are commercialized for anywhere between 70 and 90 percent of cystic fibrosis patients. Vertex as a company has been built off of launching these drugs, and there are about 10 to 30 percent of patients who are left behind without really any therapies because as you mentioned, they have one of a few hundred, if not a few thousand mutations that are not addressed by the current therapies. Our approach would be, let’s just replace the gene, one drug to create a cure for all patients with that disease, regardless of your genetic background and your genetic heterogeneity.

Daniel Levine: At the same time, it’s an argument against pursuing a gene therapy for that type of a condition, having such a large number of variants.

Rahul Kakkar: In current drug development, you’re absolutely right, and I think what we’re trying to do is say that our technology is able to actually bring those diseases that have numerous mutations scattered throughout their architecture into the realm of gene therapies. If you look at human monogenic diseases, less than 5 percent are driven by a single mutation for all patients. Sickle cell disease is an example. Some of the hemoglobin neuropathies are another example, but most diseases like cystic fibrosis, like muscular dystrophies, like some of the metabolic diseases of the liver, like some of the neurodegenerative diseases, these are driven by different diseases and are either very challenging or frankly out of the realm of traditional genomic editing technologies or gene therapies. Our approach is to say our technology is agnostic to the mutation that you have, and therefore all of these diseases come into the realm of potential drug development.

Daniel Levine: You mentioned that you’re only limited by the capacity of the vector in terms of the size of the cargo. I take it, this is true in terms of targeting delivery as well. You’re focused initially on liver and autoimmune diseases, which suggests you have the same delivery challenges as others in this field.

Rahul Kakkar: That’s exactly right. When we’re talking about delivering enzymatic components as well as nucleotide based components, which do the programming and integrating, we use vectors or delivery mechanisms like lipid nanoparticles and viral vectors as we mentioned before, and they have certain inherent technical limitations, both in terms of size and what we call tropism or where they go in the body, and we have those same limitations just as every other gene and genomic editing company out there. Our focus is really on the gene editing machinery and creating an industry defining gene editing machinery and to take advantage of advances in delivery as they occur in the industry.

Daniel Levine: Have you identified lead indications yet for either your gene therapy programs or your cell therapy programs?

Rahul Kakkar: We have for both. We’re not publicly discussing those as of yet, but in 2024 this year, it’s our intent to start talking more openly, particularly as we get later in the year, start openly about our data, the stage of development, the degree of maturation of our programs, and start talking about our pipeline. So, I look very much forward to having those conversations as the year moves on.

Daniel Levine: In terms of your cell therapies, your technology enables the creation of more complex approaches than existing technologies. What can you do with regards to cell therapies that may offer greater benefits than existing approaches?

Rahul Kakkar: Absolutely. I think there are several limitations that have prevented cell therapies from being broadly applied. Right now, cell therapies are largely relegated to the realm of relatively rare hematologic, or what’s called liquid cancers, and I harken back to the early days of biologic therapies. These are protein-based therapies, antibody-based therapies that are injected. I recall and slightly before my entry into the industry, there was skepticism as to whether antibody-based therapies would ever become mainstream because they were complicated to produce. They had certain limitations in terms of the body reacting to them, creating immune responses to them, and it took companies like Regeneron, like MedImmune, like Amgen, to really perfect those technologies to the point where now antibody-based therapies are present in almost every therapeutic area. As I look at cell therapies, they look very much like where biologic therapies were in their early days, very difficult to manufacture, very limited in how they can be used. And to me, the barrier to seeing cell therapies as being a broadly applied drug class in their own right is a technical one. We can’t edit those cells in a way that allows us to flexibly reprogram those cells to go after any target in a safe and tolerable manner. And that’s largely been an issue of our being able to edit those cells in a way that we want. We’re limited by our genomic editing technologies until now, and the PGI platform really allows us to only be limited by our imagination in terms of what we can do with those cells, program and go after any cell in the body we want, to be able to self-destruct when they’re done doing their job, to be able to be destroyed from the outside when a physician feels like the cell therapy has done its work, to really limit the ability for those cells to turn into cancer cells themselves. So all of those sorts of considerations that have limited our ability to really bring cell therapy in the mainstream, our technology allows us to overcome them.

Daniel Levine: Tome emerged from stealth in December. It announced that it completed $118 million series B round, which increased the total funding raised by the company to $213 million. Given the financing environment, what was the conversation with investors like? Particularly for a technology that will require significant additional investment to get to a product?

Rahul Kakkar: A very insightful question, and in short, the conversations were not easy over the course of our raising our second round of funding. As you said, much of the field, the industry, both investors and large strategic companies like the big pharma, really focused on clinical stage assets, particularly because the value that the price of those assets was coming down dramatically, and there was very, very little appetite for this sort of big idea, but also very expensive long-term investment thesis. And we were fortunate to be founded by investors who have that sort of long-term view, but also have large amounts of capital at their disposal to really be patient and invest for the long-term in what we all believe will be an industry defining company. And we were fortunate then to be joined in the course of our second fundraise, executed over the course of 2022 into 2023. Again, those investors that continue to see value in the long-term vision of Tome, I will say, say it’s an adage, and one that I think the data bears out, that some of the savviest investors and the greatest returns to those investors are made when they’re investing for the long-term during industry downturns, and we continue to execute with the capital we’ve raised and to be very humbled and appreciative of those investors who have that long-term vision that we share.

Daniel Levine: You touched on it towards the top of this discussion, but now that you have money in the bank, you recently did make an acquisition, you acquired Replace Therapeutics. I’m wondering what that suggests about your approach to building an expanding toolkit.

Rahul Kakkar: Yeah. The concept of Tome is not any one technology. Everything we do is focused on the CRISPR Cas9 core technology, then expanded in terms of its capability by these other enzymes, integrases, in the embodiment, what we call integrase mediated PGI, or IPGI as licensed from MIT, from our original founders, and now ligase-mediated PGI or LPGI in the acquisition of Replace. But it really, again, comes from that perspective, from that clinical perspective when you’re talking about trying to design a drug for a patient who either has a genetic mutation or could benefit from a cell therapy that could offer curative potential, we don’t want to be looking at their disease, this individual patient’s disease from the perspective of how do I go after that disease with the limited technology that I have? What we want to do is approach that disease from the standpoint of ‘I can modify the genome in multiple different ways depending on which technology I pull off the shelf, whether it’s LPGI or IPGI.’ And there are other PGI variants that we’re developing in-house in our discovery labs, and so I think our acquisition of Replace was quite strategic in that it allows us that flexibility to really take a clinical perspective to drug development rather than a technology-based perspective.

Daniel Levine: Prior to joining Tome, you were CEO of Pandion Therapeutics. Merck acquired Pandion for $1.9 billion in 2021. You joined Tome about five months after you left Pandion. I know some people don’t know what to do with themselves when they’re out of work, but why did you take the Tome job so soon after leaving Pantheon?

Rahul Kakkar: Yeah. I remember back to the summer of 2021 after the acquisition, it was a very enjoyable summer. I got to spend time with my three daughters, and of course, as you can imagine, there were many investors, recruiters, and people in my own network talking to me about what they were working on, and it was really quite thrilling being able to pick my head up from Pandion. Pandion was an 18 month adventure from series A to acquisition, so quite a whirlwind as you can imagine. But to be able to take a step back, take a deep breath, and really see what’s happening in the industry was quite a privilege. I actually did not initially have the intent to jump directly into a company. I was open to it for sure, but really wanted to see what was out there and do something at a larger scale. My first company, Corvidia Therapeutics, was a single asset company in an area that I’m quite passionate about—cardiovascular disease. Pandion was a multi-asset company, all focused on autoimmune disease. If I was going to do another company, I wanted it to be a few things. I want it to be larger in scale, and I really wanted to potentially be the last company I ever do, a long-term, build something that really defines human medicine in some meaningful way. And when I read the paper from Omar Abudayyeh Jonathan Gootenberg’s lab at MIT, which described integrase media PGI, they called it Paste. We’ve improved and industrialized their original inventions, which is why we now call it integrase mediated PGI. But I recognized from that preprint that this was a technology that really unlocked the full potential of genomic engineering for therapeutic purposes. It could be used to replace genes; it could be used to reprogram cells. It really was a quantum leap forward and [I] was at that point compelled, I think that’s probably the best word for it, compelled to join.

Daniel Levine: Rahul Kakkar, president and CEO of Tome Biosciences. Rahul, thanks so much for your time today,

Rahul Kakkar: Danny. Thank you very much. I appreciate it.

This transcript has been edited for clarity and readability.


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