Founder Stories: Keith Gottesdiener, CEO of Prime Medicine & The Promise of Gene Editing

Keith, really appreciate you taking some time with us today. We're so excited to talk to you about Prime Medicine. Tell us a little bit about how Prime Medicine got started. What's its origin? How did it get put together?

What really drove me to Prime Medicine were a couple of different things. So first, this is just really an incredible technology with incredible possibilities. You know, when you look at what prime editing can do, in many ways it just seems to me to be limitless. So first of all, prime medicine and prime editing grew out of the laboratory of David Liu at the Broad Institute of MIT and Harvard. And he's founded a whole variety of companies. He was a co-founder of Beam and of Editas, other gene editing companies. And he's really brought forward technologies that are incredible for patients. And I might add, often incredible for investors as well. He was one of the co-founders, obviously, of the company, but he was joined with that with a really brilliant postdoc called Andrew Andrew and Spallone, who really conceived the key steps of prime editing, really worked with David in the lab and developed it. And the two of them and many other folks who really helped to support that work released it to the world at the end of 2019 with a really remarkable Nature paper. You know, that paper was impressive both because of the originality of the work, but also because of the breadth of that work. What Andrew and David and their co-authors did is they really tried to look across prime editing and really see where it could be used. I think PRIME's role is really to help really translate genetic understanding into therapeutic reality to prevent or cure so many diseases. And I think the role that PRIME may play is to be, you know, really one of those critical technologies that really changes the way we look at genetic diseases, its breadth, its versatility, its precision, the fact that it really makes the corrections right in the genomic locus, essentially it changes things back to the way they should have been if we deliver on that promise. You know, we think this is really going to be just going to play an extraordinary role with our fixing a whole variety of different diseases. And I just can't tell you how excited I am to really be, you know, to be part of it.

So tell us a little bit about the vision for PRIME. You know, really what's the big picture problem that PRIME Medicine is trying to solve?

You know, what I like to say is, you know, our goal is to cure, halt, or prevent genetic diseases and really give lifelong benefits to patients. It's that simple. You know, the breadth and the power of this technique is really the op— you know, it's really the opportunity for a giant step towards a much wider range of diseases than many previously thought possible. And in that sense, I really feel this technology could become a cornerstone or potentially shape the future of gene editing. So I think part of our goal is take this— I may use this word often— this transformative therapy and really find places where we can show that it works and really make that difference to patients. And we feel this urge, this goal is just a really overpowering one that we really have to move forward as quickly as possible.

Yeah, it is a remarkable time. And I think as most people know, gene editing has the potential to really change medicine as we know it today, particularly for genetic diseases, but potentially for more common diseases. You know, when I talk to people who are not scientists about gene editing, I usually use a very simple analogy. I refer to version 1, which is known as CRISPR, as a pair of genetic scissors because it cuts the DNA. And I know you'll get into this, and then it puts a new sequence in there. And then came along version 2.0, which is called base editing, which was also created by David Liu. And I think of that as an eraser because it can just change one base. And when David Liu first presented to us at GV about Prime, he called it a word processor. In that it had the flexibility to insert, to delete, and replace. And so let's start from that. Maybe you can tell us a little bit more about, from your perspective, how prime editing works, what's so exciting about it, and how is it different from the ones that are already out there?

So the technology works by using a prime editor protein that has two parts. One part is a Cas nickase domain, which essentially finds or searches for a place in the DNA, and a reverse transcriptase domain. And those two protein domains are joined together with a guide RNA. We call it a prime editing guide RNA or PEG or PEG RNA. And that guide RNA has a part that's also for targeting and a part that's a template for replacement sequence for the actual correction that you do. So once you take this prime editor complex and you get it into cells, it searches for the very specific DNA sequence that needs to be edited. And once it's located there, the prime editor nicks the DNA, doesn't cut it, but only nicks one strand, and then uses the pegRNA's replace sequence to prime and then activate the reverse transcriptase domain. Now reverse transcriptases make new copies of DNA copying a template. And what happens in this case is they make a DNA copy of the template carried by the pegRNA, which is a corrected DNA sequence. So when you're done, you now have two forms of the DNA, the old mutated or inappropriate or wrong DNA and a new complete copy. And the corrected sequence then preferentially replaces the original genomic DNA, and it results in a permanent edit at the target location. So when you're done, you literally have gone to the spot where the problem has occurred, you fixed it, and you've left things right back the way you hope they would have been before you actually started. And that's why we call this in some ways like a word processor, a really true search and replace. We find a specific spot in the DNA, just like you would if you were trying to do a correction in a document, we go there and we replace it precisely at that native location. And we do it only at that location and return it to endogenous control. Now, of course, when this started out, you know, it was really just a laboratory phenomenon, a very exciting one, but still very preliminary. But, you know, about a year's gone by since the paper was published, and now it's being used and validated by study in thousands of laboratories, and there have already been dozens of papers published on this technique in all sorts of situations.

What kind of diseases or indications can prime editing potentially work on, and how does it address sort of the fundamental cause of the disease, and what could this potentially mean for patients with these genetic or other diseases?

Well, let me talk about it, but starting a little bit about why prime editing is different, because it really helps to frame the issue of why this is going to help patients the way it is. So, you know, it's a very versatile technique, and it has the potential to address more than 90% of known disease-causing mutations. And once you actually identify these disease-causing mutations, the technique itself can correct nearly all types of pathogenic gene mutations. So it's very broad in terms of what it can actually do. Not only that, it can correct multiple mutations all at once. So those can be multiple mutations in one patient or potentially multiple mutations across patients. So patient number 1 may have mutation number 1, patient number 2 may have mutation number 2. A single prime editor in many cases correct multiple mutations at once. Second of all, we've tested extensively where prime editing works, and it works in all types of cells, non-human cells, human cells, derived cells, and primary human cells across multiple organs. And more recently, it's been tested in a variety of animal models. This breadth really means it could be targeted to, as I mentioned, a very large group of genetic diseases. Third, it really has been shown to make genomic edits with what I call high fidelity. It makes very precise edits at the target, and it has minimal or no editing in other parts of the genome. And as I mentioned previously, it doesn't work at the native genetic location, which means it could potentially restore normal human gene function with a once-and-done permanent correction, really providing patients with a long-term cure. We've actually approached our diseases indications in four buckets, and they're not mutually exclusive, but they really give you an idea of how we've really approached these indications. So one bucket's kind of a practical one. We call it the immediate bucket. These are places where the primary purpose is to get prime editing into humans and show that it works, sort of technological proof of concept. And so there, what we've done is we've really looked for diseases where people really understand the genetics quite well. There are great animal models to test things out. Biomarkers are in place. In some cases, there are even regulatory paths. These aren't places where we may be the only person working in those diseases, though we do think in almost all cases, maybe all cases, we have some advantages about the way, you know, we're approaching it versus others. But the idea is to really go rapidly, get it into people and show it works. And as a result of that, we're looking at organs and places where people know how to get the editing machinery into those cells quite early. The second bucket is probably the one I'm most excited about, and that's what we call the differentiation bucket. And what's a differentiation bucket? It's a bucket where we're looking for places where prime editing does things that we think no other technique can do. And so we've made a long list of potential areas where we think prime editing is special or it has special advantages, and we've started a variety of programs in those areas in addition. There's a third bucket that's a little bit more long-term, and that's really moving beyond sort of rare diseases and other places where there's genomic diseases that need to be, you know, sort of attacked, but maybe a little bit more long-term, maybe a better choice when we understand really how to use prime editing better and we understand the safety profile of the drug and the regulatory path. And then the last bucket is kind of an overlapping bucket. We call it march up the chromosome. It's a bucket where we look and we say to ourselves, how could we set up prime editing in such a way that when we go into a gene, we're going to really be able to cure every single patient with that disease? We're not going to leave a single mutation behind. And that requires some really special extra work with, you know, manufacturing techniques and assays to show, you know, purity and approaches to things. And in many ways, it's going to require some real interaction in possibly some education of the regulatory agencies. But we think those are all different buckets that we work and need to work at, and we're trying to look quite broadly as we, as we work on that.

Well, you're certainly not going to be bored given that breadth. And, you know, as we talked about earlier, I do think, and we all think, that gene editing has the potential to really change the way we think about medicines. As you mentioned, it's potentially a one-and-done to actually completely correct the gene that is causing a disease. Because it's permanent, there's been a lot of focus and discussion among the different techniques about precision. And I know you mentioned a little bit about it, but I think it would be good to highlight again how you view prime editing from a precision perspective.

All the work we've done so far suggests that we can make the desired edits at the target sequence, the target gene. With incredible precision. So when you actually look to see what happens when we do a prime editing approach on a particular gene, we get an extraordinary degree of the desired edits actually occurring, in many cases well over 99%. Probably just as important, with all the tools we've looked at so far, we see minimal or no editing at other parts of the genome, which we think is a very important part of things. And We think part of the reason that occurs is in order for prime editing to occur, you need to match or line up pieces of DNA. It's kind of like putting a key in a lock and turning it. You need to actually do that 3 different times in the course of prime editing for the editing to occur. And so in a sense, it's kind of 3 edit checks along the way to make sure you're getting things right. Now, We also, we think some of that precision also comes because we only nick DNA and we don't break it. And I think there is a story to be told about double-stranded DNA breaks, which may be less desirable than one would wish. When you actually break through both strands of DNA, the net result is the DNA often tries to repair itself by filling in or deleting or trimming the piece that you're at, and the net result that is you get are what, what we refer to as indels. Indels are insertions and deletions at the particular site, but the important thing is to say is generally these are unwanted or random indels, things that occur to that DNA that are not precisely controllable. Now if your goal is to destroy a gene, for example, if there's a copy of a gene that really has a bad effect, it's a great way to do it. But we can go in and do the same thing precisely. We can make an edit that inactivates a gene, and we can be sure that a specific edit is the only one that occurs. And we can make sure that if we're correcting a gene, we can make that correction extremely precisely, and so only the edit that we desire, you know, happens as well.

And what kind of edits can prime editing actually make? And you mentioned a little bit, but what kind of cells or organs are open to this technology?

So it can really correct nearly all types of gene mutations. So any misswapped base pairs— now remember, there are 4 building blocks for DNA, and so if you do the math, there are 12 different ways building blocks can get messed up between a mutated sequence and the, what we call the wild type or the normal sequence. We can correct each and every one of them. In addition, if there are added base pairs, we can delete them and correct. And if there are deletions in the DNA, we can go in and we can add the pieces of DNA that are missing. So in a sense, we think we can do just about all types or fix nearly all types of gene mutations. So not only is there breadth, though, in the gene mutations, all the preliminary work we've done, and it's really quite extensive, show that we can work in essentially all types of cells. We can work in dividing cells and rapidly dividing cells, dividing cells, non-dividing cells, which sometimes differentiates us from other methods. We can work in every organ or every type of cell we've yet tested, and that's again, an extensive group of those cells. And we can work in what are called primary cells as well as cell lines. Those are literally the cells of your liver or your blood that come out and literally have come out of the body so that we can work with them there. So I think that part is important. And we also can show that we can work both ex vivo, which are those cells you take out and then modify, but we can also work in vivo by sending things into people or animals. At this point, only animal experiments have been done, of course. And more recently, we've been able to show that we can do that reasonably efficiently in animals, though the animal experiments are still at a very early stage. So again, you can see one of the themes of working with base, sorry, with prime editing is really the breadth of places where you can work.

Yeah, it's pretty remarkable. So before we end this section and move on to talk a little bit about your team, what are the risks and challenges with this technology that you're thinking about?

So let's talk about the risks first, okay? Conceptually, there are very, very few risks to the use of prime editing. You know, it's being studied and has been studied in many scientific settings, and its capabilities as a gene editor have been relatively well characterized in preclinical work, both in our hands and as well now in multiple, multiple independent settings. And these preliminary results raise very little concern about the possibility of risks of using prime editing. I think this because the editing is so precise, there's really minimal off-target editing. And, you know, we talked about this being once and done. There's really anticipated to be very short-term exposure to the prime editing technology. Now, those are the risks. There are challenging as well, challenges as well, excuse me. I think probably the challenge that I most focus on, like all gene editing approaches, we really must deliver the editing machinery to the proper location in the body to really do its actions. And I think we all know, those of us who are working in this field, that's not a trivial challenge. People have made extraordinary progress progress over the last decade or so, but there's still many challenges left to face.

So GV first invested in Prime in 2019, and the company's made a lot of progress since then. So maybe talk a little bit about how the science and the company have evolved since inception.

So probably the most important thing is in 2019, this was a one-laboratory phenomena. It was a very special laboratory, but still one laboratory. And I think what we've learned since, both for from the efforts of Prime Medicine, the company, as well as the literally hundreds, thousands of laboratories that potentially are working within the dozens of papers that have been published, the science is really validated. Now, the company's also grown. We've recruited much of our senior leadership. We've really grown the company to where we're approximately 50 people at this point, and we hope to be more than 100 this year and to continue growing. We've already actually expanded into our third space. So you can get some idea of how rapidly we're hoping to bring these things forward. We've made some very, very significant platform improvements, both in David Liu's lab and at Prime Medicine. And probably we'll see, stay tuned, you'll see some of that coming out during the course of the next 6 months. Also take great pride in the fact that we've had 2 very significant fundraisers. And at our heart, like every biotech company, getting funding to really advance this critical work is really important, and we've really developed an investor base that I think is second to none.

Obviously, prime editing is an incredible platform, but my assumption from our conversations is that you're building a therapeutic company. You want to make medicines that will bring to patients. Is that how you're approaching it?

It is, but there's a nuance to it, David, as I think you know. So in the end, The purpose of doing this isn't just to do science. It's to bring things and advance things to patients. So the therapeutic programs are by far the most important focus of the company. On the other hand, we've already learned just in this year just how much possibility there is at developing and expanding the prime editing technology. And so we're putting also a significant amount of time, effort, in resources to building out the technology as well. It's hard to put a number on it, but I think currently we're trying to spend 20 to 30% of our resources, our research resources, on really the platform and making it better, and the majority of the rest on developing things with patients. But, you know, to tell you the truth, you know, even in the first couple of months to year, we've seen a whole bunch of expansions that have come in Prime Medicine. And I think they're going to be paying dividends pretty soon. And so I think we can't put down that particular part of what we're doing as well and building the platform at the same time.

Let's dive in a little deeper on this incredible team that you've started to put together and talk a little bit about the culture that you're building at Prime Medicine.

Sure. Of course, I could talk about this all day, but I'll try not to. I told you already about Andrew and Stallone, who's just a wonderful recruit to the company and really, you know, brings that special understanding of prime editing. But I should point out, just mentioning the scientists, that we've been able to recruit, you know, both a number of Lou Lab graduates who have joined us, as well as star scientists from other local and more distant labs and some exceptional companies. So our scientific side has really grown rapidly. A lot of the credit for that goes to Jeremy Duffield, who we recruited as our CSO very early at the beginning of this year. Jeremy's an MD-PhD, was an academic, spent a number of years at Biogen, had a very successful career at Vertex, and he's really taken over the research organization. He's just done a fabulous job. We were able to recruit Meredith Goldwasser from Agios. I know you know her well, David, from your time there. She started as a status statistician, worked at multiple pharmas, Novartis, Genentech. And I think, you know, it's fair to say she helped build Ageos from the early days. And she now runs our strategy and corporate operations group. And frankly, she's the one who's really helping to keep that strategic view of how the company fits together to make sure all the pieces grow together as the company grows in size. We've recruited a great IP group led by Karen Brown as well, who was obviously, at Obsidian. So we've really started to put the core of a company in place. And there are many others that are either that I can't mention today, but I really feel like they've been an exceptional group of people. So what about our culture? So, you know, culture's in process. We're a year old, but I think there's some themes that I've stressed and frankly, you know, have really grown organically at Prime based on the kinds of people we've recruited. So the first is, as I think you heard me say before, We're in this for the patients. It's our lodestar. You know, when we have to make the hard decisions, the questions are, is this going to help patients and move things forward? Second, we're a very science-driven organization, really, you know, focused on scientific rigor, scientific excellence, scientific innovation. Third is, you know, we've inculcated a culture of transparency and trust and openness. We talk about all sorts of things in the company. We really We try to share all of the information with everybody. We want everybody to understand where we're going and why. And then last but not least, something I think is very important is we've really inculcated a sense of urgency that this is really important. Every day matters. There are people out there who are suffering. We need to really help. And I think, you know, many of those ideas have really become a cornerstone of the way we're building our culture today.

Keith, earlier in the conversation, you mentioned that Prime recently completed a B-round financing. Maybe tell us a little bit about the financing to date and where you hope that the current cash on hand will take you.

Well, our first initial Series A investors are a great bunch. So as you know, they included GV, F Prime, Arch, and New Path Partners. And they gave us a Series A of $115 million to jumpstart the company. About 9 months after we began operations, I was able to convince the board, or actually the board convinced me in some ways that, you know, we were making great strides and we really had to broaden out what we were doing, do everything a little faster, a little broader, a little more in parallel. And so our current investors really wanted to put in more capital to allow us to do that. And in the end, we were able to bring in 10 new investors as well as the 4 original investors and raised an additional $200 million. $315 million to date. And we've really put together an incredible high-caliber, you know, syndicate. Now we have a lot to do. As I mentioned, we gotta build the company, advance our clinical indications, really deliver on the promise of prime editing. You know, we can't let our guard down. It's not gonna be cheap, but I think, you know, we can look ahead and say it's gonna be an extraordinary journey. And I think we're lucky to have investors who really look at it that way.