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Close to the Edge: Episode 16 – Andrew Anzalone
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Close to the Edge: Episode 16 – Andrew Anzalone
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[MUSIC PLAYING]
ALEX PHILIPPIDIS: Howdy, and welcome to Close to the Edge, the show from GEN Edge where we invite leading executives, scientists, and innovators from groundbreaking biotech and pharma companies to discuss their science, technology, and their business strategy. I'm Alex Philippidis, a Senior Business Editor with Genetic Engineering and Biotechnology news. The world's first biotech publication proudly covering the industry for more than 40 years.
KEVIN DAVIES: And I'm Kevin Davies, Executive Editor of GEN's new marquee peer review journal GEN Biotechnology, and the author of Editing Humanity-- The CRISPR Revolution and the New Era of Genome Editing. On today's episode, our guest is someone who plays a cameo role in my book and someone we've been eagerly looking forward to hosting on the show for quite some time. Andrew Anzalone from Prime Medicine that's coming right up.
ALEX PHILIPPIDIS: Close to the Edge is the flagship video program from GEN Edge, our premium subscription channel providing exclusive in-depth news, interviews, and analysis of key trends in the biotech industry. Coupled with a range of multimedia offerings such as this one, details of personal and group rate subscriptions are at www.genengnews.com/genedge. And don't miss GEN's blockbuster virtual event coming up on February 28, the State of Genomics and NGS.
ALEX PHILIPPIDIS: Four hours of conversation and presentations featuring NHGRI Director Eric Green, Pardis Sabeti and Niall Lennon from the Broad Institute. Karen Miga on the Completion of the Human Genome Sequence, Chris Mason on Space Genomics and much more. Google the state of genomics for more information.
KEVIN DAVIES: Thanks, Alex. Andrew Anzalone is the lead developer of Prime Editing and the scientific co-founder and head of the Prime Editing platform at Prime Medicine-- the company that is in pole position to commercially develop and bring this technology into the clinic. Prime Editing is an incredibly exciting technology for precision genome editing, because it can, in principle, engineer any potential base change by performing a truly ingenious molecular choreography on the double helix itself.
KEVIN DAVIES: So in the month that the double helix turns 70 years of age, it's great to have the architect of Prime Editing on the show. Andrew, thanks so much for joining us on Close to the Edge.
ANDREW ANZALONE: Yes. Thanks so much, Kevin, for the opportunity to talk to you guys today.
KEVIN DAVIES: So let's start shockingly at the beginning. Can you take us back-- I think it was only about five years or so, to your time at Columbia University where you got your MD and PhD and the inception of this gene editing technology.
ANDREW ANZALONE: Yeah. I could, probably, talk to you all day about that. But I'll try to keep it short. So yeah. I guess it all started back in my days as a trainee where I was focused on chemistry and molecular engineering. Also very interested in medicine and seeing how we can push science forward to help people with diseases and treat their diseases. So as I went through my training, I had such an enthusiasm for the science and working in the lab and this desire to, again, develop therapies.
ANDREW ANZALONE: And as I ended towards-- that was towards the end of my training. I wanted to look for a position in research that would allow me to really translate this science into something, potentially, meaningful. In the backdrop of all of this, of course, was this CRISPR revolution that had begun. That had started around 2012, 2013 with some really landmark publications from people you've researched and talked about numerous times.
ANDREW ANZALONE: Jennifer Doudna, Emmanuelle Charpentier, Feng Zhang, George Church, the list goes on and on. And as I looked for new opportunities in my research and new directions, I came across some really interesting work that was being done in this gene editing field using these CRISPR technologies. And David Loo really quickly rose up on my list of people of interest.
ANDREW ANZALONE: Recently, he had just developed a base editing system which we can discuss a little more later. But this was a system that could precisely make single-base bare changes to DNA. And not only did he develop one base editor, but he had actually just published a second base editor, really just about a year apart from each other. And I looked at this and I just thought, wow.
ANDREW ANZALONE: This is really exploding. This is something that I could have never imagined would be possible 10 years ago when I had started medical school and learning about all these different genetic diseases. So I saw that as an opportunity to build on what was done, what had been done prior. We have this incredible, natural system. These CRISPR enzymes that can target, in a programmable way, a DNA sequence.
ANDREW ANZALONE: To go and find it in this vast sea of, otherwise, other similar-looking DNA sequences. And we can start making more sophisticated machines that could edit the DNA in different ways. And of course, a big challenge was still, we have this CRISPR system that can target and find sequences in the genome, but how to change them to exactly what you want was still a little bit of a challenge.
ANDREW ANZALONE: There was still something to be done there to address this second half of what was required for gene editing. And that's where the idea came from for how we might develop a new system, which eventually became prime editing.
KEVIN DAVIES: Right. I've read in earlier reporting that the idea can be traced back to an evening stroll around your New York neighborhood. It's not exactly Kary Mullis popping LSD on a midnight drive- through Napa Valley en route to discovering PCR. But perhaps, you can paint a picture for us of how you think the real breakthrough came about.
ANDREW ANZALONE: Yeah, happy to. And there was no LSD involved. I think the only substance involved was caffeine. But I do like to do my thinking on walks, that's definitely a place in time where I can do some real hard thinking. And I think at some point, a notion just occurred to me. That these CRISPR systems, so elegant, they have these RNA molecules that are almost like instructions and give them an address for where to go in the genome to bind to DNA and to change that DNA.
ANDREW ANZALONE: And what a nice opportunity now for that programmability to now not just be used to say where to go but also what to do. And in fact, we've already got this RNA sequence that has information in it bound at the target site of the genome where you want to make a change. Why not just add some instructions on what that change might be? So this is really the notion of, OK, we've got programmability for targeting, what about the programmability for editing or making that change?
ANDREW ANZALONE: And the system is already poised to do that. It already has the right molecules in place. And so that was the conception. And obviously, that's just an idea. That's not worth a whole lot on its own. It wasn't really until I entered the Broad Institute that I really started to get into the details of this and think about how this might be possible. And it took quite a few steps to actually make that a reality.
KEVIN DAVIES: Before you got to the Broad, which is, of course, where David Liu runs his lab and where base editing was developed in these two seminal papers in Nature that you just mentioned, Andrew, work led by Alexis Como and Nicole [? Gordelli, ?] former postdocs in David's lab. How did you approach David? Did he, immediately-- kind of you were you on the same wavelength straightaway, or did you have to twist his arm a little bit?
ANDREW ANZALONE: In some ways, I think, many people saw the promise in the idea, including David, but also a lot of the challenges that we would face. And there are a lot of questions that any one of them, if things didn't go as planned, the system wouldn't work. So while I think there was some optimism, I think there was a healthy amount of skepticism as well as any, I think, scientists naturally would have. It was little bit of a funny story.
ANDREW ANZALONE: I had discussed the idea on my actual post-doc interview with David and many members of the group. And it was quite a colorful discussion as you could imagine but a really nice one. And a few weeks after my interview, I followed up with David about it, and he agreed to allow me to join the lab and pursue this project and then hit the ground running when I got there on this.
KEVIN DAVIES: Yeah. So when you joined the lab, were you working in isolation? As most postdocs, it's a pretty solitary experience or did-- was there a feeling that there's so much potential in this approach that it became a bit more of a team effort?
ANDREW ANZALONE: Yeah. Like a lot of others in academia, initially, it started as a project that only I worked on. That being said, I can't emphasize enough how great of an environment David had developed at the Broad in his laboratory in terms of learning all the techniques from people. These were all things I hadn't done before. I had never done genome editing in a human cell or getting to David Liu's lab.
ANDREW ANZALONE: So I'd never done high throughput sequencing using all these next generation technologies, which were all at our disposal there. So I definitely credit all of my lab mates there for showing me these things and helping me talk through ideas and how to make this work. And as the project showed more and more promise, that's when others started to join in with me on the project.
ANDREW ANZALONE: I think, ultimately, the paper that we published had 12 or so co-authors on it, all of whom make very important contributions. So I really do credit the environment that was cultivated there to a lot of the success. And especially, the speed of the success.
KEVIN DAVIES: Yeah. It wasn't smooth sailing, that first year, but you overcome whatever stumbling blocks that they were.
ANDREW ANZALONE: Yeah. Yeah. There were at least four challenges that laid in front of us in terms of we have to get this to work, we have to get then this to work. David likes to refer to it as four little miracles that needed to happen Prime Editing to actually work. And I [INAUDIBLE] one little stumbling block, tweaked some things, worked on some new designs, and got past each one of them one at a time until, ultimately, getting into human cells and making it work there.
KEVIN DAVIES: And was the main driver, as again you touched on a few minutes ago, the idea that base editing is excellent at making certain categories of base substitution but prime editing in principle could give you the full repertoire?
ANDREW ANZALONE: That's exactly right. So exploiting all there is to offer from having a nucleic acid sequence template, that sequence change. So the RNA and DNA, they share pretty much the same letters. That information is easily exchanged in both directions. The direction that we needed to exchange it was from RNA into DNA. That's a process that is performed, that's called reverse transcription.
ANDREW ANZALONE: There's a whole category of enzymes that do this. They synthesize DNA from an RNA template. And because this template sequence could be changed very simply by changing one base here, another base there, deleting some bases, adding some bases, that template will then dictate what sequence goes into the DNA. So it's very easy to just swap out one for another and make any edit, in principle, that you really want in a pretty confined but substantial region of DNA.
KEVIN DAVIES: I think your paper which is published in Nature was impressed when David presented the work for the first time, I believe, at the Cold Spring Harbor CRISPR Conference. I was in the audience with a 500 other scientists pretty much on the edge of their seat, because the abstract had been deliberately vague, I think, as you were sweating the fate of the manuscript. Do you recall what he said at the end of his talk in his little acknowledgment slide?
ANDREW ANZALONE: I do. And I recall a lot of the things that happened at that conference. It was a very meaningful experience for me. But David said something along the lines of, he's excited to see what I do in the second year of my postdoc. It was partially set back by the pandemic, unfortunately. But I think we still got a bit more done in the prime editing space then.
KEVIN DAVIES: Yeah. And how-- to the paper, I know the two base editing papers had very different fates during the review process at Nature. The first one, Alexis's paper was a bit of a struggle. The second one sail through. Do you recall what the process was like for your paper?
ANDREW ANZALONE: Yeah I think it was a very reasonable process. We were asked to do some very reasonable follow-up experiments, some of which we anticipated and had already begun doing. I'd say, on the whole, it was not a very challenging process. I've had far more challenging review process--
KEVIN DAVIES: The lesser papers, yeah.
ANDREW ANZALONE: Yeah. So this was not as difficult, but there were some very critical experiments that we had to do and were asked to do. And I think they were the right ones.
KEVIN DAVIES: Yeah. Now, by the time the paper was published, we're talking towards the close of 2019, were you and David already thinking that this technology would be commercially developed as an independent company?
ANDREW ANZALONE: Yeah, absolutely. I mean, I think there was a lot of recognition of that pretty early on, I would say, a few months before we published the paper, because we were trying all these different things and they were all working. Once we finally developed the system, getting it to the state where it was working in human cells, again, like I said, we could swap out the RNA with a new sequence and make an edit somewhere else in the genome.
ANDREW ANZALONE: And we just saw the potential for that. And it doesn't take a lot of effort to go look through the types of mutations that cause genetic disease and just tally up what percentage of these could we potentially fix with prime editing? And it's a pretty large number. Probably somewhere close to 90%, at least, of the mutations in certain databases like ClinVar.
ANDREW ANZALONE: So we immediately recognized the opportunity there and the potential. And David, obviously, has a lot of experience founding companies and was able to get that going pretty efficiently.
KEVIN DAVIES: Yeah. And before I pass it over to Alex, we've touched on some of the advantages, the repertoire of prime editing as one big attraction for developing the technology. Of course, in common with base editing, it only nicks the double helix. I wonder if you could talk a little bit more about that and some of the other potential advantages and the expanded range of edits that Prime Editing not just in theory, but I think increasingly in practice can give researchers.
ANDREW ANZALONE: Yeah. No. I mean, maybe I'll try to set it up a little bit with what an ideal gene editing system look like. I think there's probably five factors that a lot of us have discussed and arrived on as being really critical. The first is programmability. I think I've already discussed this a little bit. Essentially what this means is you can go one place in the genome and then the next day change that location and go somewhere else and do that with a lot of ease and do it really quickly.
ANDREW ANZALONE: So that's one key factor, the programmability. The second would be specificity. You only want to go to the place you want to go. The one place, not the other places. That has implications for things like off target editing, which I think I can get into related to an earlier question a little bit. I would say, the third one is versatility. When you get to that place in the genome, can you make all the different types of changes that you might want to make?
ANDREW ANZALONE: So how broad can that genome editing system be in terms of making a point mutation, deletion, insertion, et cetera? And then how precisely will it do it? So at that location, are you making just that change or are you making other changes as well? And finally, how efficient is that system? Ideally, every cell that gets treated with these editing systems would make an edit, so this is five different principles that I think really you would look for in a perfect or ideal gene editing system.
ANDREW ANZALONE: So Prime Editing in a lot of ways, and all CRISPR systems, I would say, are very programmable. It's very straightforward to give a new set of instructions to these CRISPR systems, these guide RNAs to tell it to go to a new place in the genome. And that makes it really easy to go say, on one day I want to fix this mutation and CFTR that causes cystic fibrosis. On another day, I want to fix this mutation in sickle cell disease.
ANDREW ANZALONE: And so that's a real powerful principle for CRISPR technology. Now, once you get there though, you want to minimize the other things you do besides making the precise edit that you're intending to make. So that's-- in a prime editing system, we're using this RNA template to make a change. In principle, the fidelity of copying that sequence is very high.
ANDREW ANZALONE: And so you're very likely to only incorporate that one change. And you only make a single break in the DNA. And that's really important. When a cell has a double strand break, and this is what the more traditional CRISPR nucleases or CRISPR scissors do, so it sets off a lot of alarm bells. It quickly identifies that broken DNA and stitches it together as fast as possible and without a lot of care for what happens to the sequence when it does that.
ANDREW ANZALONE: So you can imagine these two pieces coming together, but little errors happening in that process that lead to these small changes, insertions or deletions of a few bases that often will disrupt a gene. And that's just an intrinsic thing the cells will do. Now, if you make only one break in the DNA double helix, you avoid a lot of these responses in the cell. And that's exactly what prime editing does. It makes just a single nick to copy DNA sequence onto that one strand of DNA.
ANDREW ANZALONE: And then other DNA repair mechanisms can incorporate that edit to both strands eventually. But you avoid this alternative DNA repair pathways that tend to lead to a lot of undesirable outcomes. Another advantage to that is that at any potential off target sites in the genome, so places where you didn't intend that prime editor system or CRISPR system to go to, you're also not going to be making double strand breaks.So it's much less likely to cause damage at those other places in the genome.
KEVIN DAVIES: Great. Let me pass it over to Alex.
ALEX PHILIPPIDIS: Here. Thanks, Kevin. Now, Andrew, when Prime Medicine launched around 2019, as I recall, did you have any doubts about being an active part of building the company? Because presumably, you could have had your pick of any faculty position or, maybe, return a medicine.
ANDREW ANZALONE: Yeah. That's a very-- I think I thought very hard about but actually not that long about. As I said, I had always been really motivated from early days in research. Actually, my first research experiences were in medicinal chemistry at a small pharmaceutical company. So I was always really interested in developing therapeutics.
ANDREW ANZALONE: In David's lab, I had obviously had a lot of success doing science that had the ability to translate into therapeutics in the past. And that was one of the reasons I was very, very attracted to going to his group. So when the opportunity arose, I didn't really have to think too long about why this would be a great opportunity for me. Now, I love the science, it's a science that I'm really committed to.
ANDREW ANZALONE: I was there when it started. I can't think of anything better than being able to carry that forward to the point of using it for human therapeutics. And that's really what drove me to join the company, also joined by a grade group of people fro that Liu lab that joined the company with me. So great colleagues and I really didn't have to think hard about whether or not to do that.
ALEX PHILIPPIDIS: Now, how did the company grow, and what, if any, challenges did you have finding talent to join the company?
ANDREW ANZALONE: First six months or so it was a little slow. This was the earlier days of the pandemic. Obviously, those presented some challenges. But I would say in the next year and a half to two years that followed, we've had a really amazing growth period I've hired up to almost 200 people now at Prime Medicine, and I think we've been able to tap into the excitement that the community feels about gene editing and about prime editing in particular and its potential.
ANDREW ANZALONE: Many of the folks that have joined Prime Medicine have worked on gene editing in the past and have experienced using Prime Editing. They've seen the potential there and want to contribute to making it into medicine. So I would say that despite the obstacles that the pandemic and competition and other things presented, we still were able to have a pretty rapid growth trajectory and really bring in the people that would get the job done.
ANDREW ANZALONE: I really am proud about the company that we've built and the team that we've built.
ALEX PHILIPPIDIS: Now, who are some of the key members of your executive team? For example, is David Liu still actively involved?
ANDREW ANZALONE: So David Liu is involved. He does touch base with us, I think, on a weekly basis or so. And definitely, gives us a lot of feedback on what we're doing. Also his lab is actively working on Prime Editing technology development. So things that his group develops and improvements to the technology often come over to us and we have the ability to use those and capitalize on those developments.
ANDREW ANZALONE: So we still have quite a strong relationship with David Liu.
ALEX PHILIPPIDIS: And then as far as the team goes?
ANDREW ANZALONE: So the team-- I mean, we have an excellent leadership team in my opinion. Keith Gottesdiener, is our CEO, a very experienced CEO who's been in biotech and pharma for several decades. And Jeremy Duffield is our chief scientific officer, similarly, very experienced and really an expert in the disease biology. So I think we put together a grade group, and we have a lot of internal expertise. I think there's now six other people from David Liu's lab at Prime Medicine that have all been there from the very beginning.
ANDREW ANZALONE: I think almost every-- yeah. Every one of them was an author on a Prime Editing publication. So this expertise, I think, has really helped us accelerate moving things forward.
ALEX PHILIPPIDIS: Now, the company remained in stealth for a couple of years. But last year, you filed a successful IPO and released details of the pipeline. Why such an early IPO given how challenging the financial climate was in the market declines that happened back then?
ANDREW ANZALONE: Yeah. I guess I'm not the type of person that could answer a lot of those questions in terms of the financials of things. This is all pretty new to me I have to say, but I think our ability to do the IPO probably does signify one thing and that's the excitement for the technology and the potential that it has. And it was just an amazing experience to be part of that process to go public.
ANDREW ANZALONE: I had to pinch myself a few times when I went to in Times Square in New York City. I mean, I'd walk through there so many times earlier in my life I never thought I would be in the NASDAQ building. So it was quite the experience, and I'm really proud of the team for getting us there. We released our pipeline as you referenced, and we have a lot of areas that we're looking to work in.
ANDREW ANZALONE: We weren't sure when we started where Prime Editing was going to work or where it would work the best. And maybe there would be some places where it just wouldn't work and we wouldn't be able to do anything in that area. But the more things we tried, we just kept finding that we can find things that work through all the optimizations and enhancements to the technology that have been developed.
ANDREW ANZALONE: And most of the areas where we're trying to do something, we've had a lot of success. So we've got a lot of decisions to make, but there's the good type of decisions, I think.
ALEX PHILIPPIDIS: Now, Prime's pipeline is pretty ambitious. It features, at least, a half dozen targets, including almost a who's who of well-known Mendelian diseases, including DMD, Duchenne muscular dystrophy, fragile X, et cetera. What are some of the initial clinical priorities at Prime?
ANDREW ANZALONE: Yeah. So that's a very nuanced question in the sense that, again, we have the potential to address some of these really well known diseases that have affected so many people and for many of them, there hasn't been a really great therapeutic option available. And so Prime Editing offers this really exciting opportunity. But in some cases, there's also challenges associated with delivery of the gene editing systems to the right cells in the body.
ANDREW ANZALONE: And so we've taken an approach where we've looked at the landscape and said, OK, there are certain places where we think we could be really successful early on because there are some of these challenges have been addressed, such as delivery. In other places where we think the technology does something really special, we probably need some other areas to catch up before they really can become a possibility.
ANDREW ANZALONE: So we've tried to develop a pipeline that has some examples from each of these categories. And certainly, there will be places where we can move a lot quicker, ex vivo programs, for example, are a lot easier to do in the sense that the delivery challenges is not as prominent. And then certain in vivo programs where delivery has also been established previously.
ALEX PHILIPPIDIS: Now, is Prime trying to pursue all these itself, or will you be seeking partners to develop some of these programs?
ANDREW ANZALONE: Yes. So I guess it would be a little unrealistic to say that we're going to take 18 programs forward in the next few years and be able to develop them into medicines for people. So I assume there are a lot of solutions to those challenges, whether that be through partnering with other companies or by prioritization internally. And that's something, I think, we'll have to be deciding in the next couple of years.
ALEX PHILIPPIDIS: And which of these programs is furthest advanced? And what's going to determine which targets Prime prioritizes?
ANDREW ANZALONE: Yeah. Those are questions that are still being worked through. Again, I think the targets where we've had a lot of ability to deliver the gene editing systems to the cells of interest, again, the ex vivo programs have the ability to get past that a little bit more quickly. Those, we can make pretty rapid progress in. And likewise, delivery into systems by lipid nanoparticles to the liver, these are also areas where we can move a little faster.
ANDREW ANZALONE: That being said, we still have a lot of-- paying a lot of attention to those other programs where there's so much potential. So they may require other delivery solutions, but we're actively pursuing those two.
ALEX PHILIPPIDIS: Now, is Prime just focusing on medical applications of the technology? What about, for example, Prime Editing applications in plants or other organisms?
ANDREW ANZALONE: Yeah. We focus on therapeutic applications or applications for human therapeutics. So we haven't been pursuing any applications in plants and I don't think we intend to in the near future. But that's, obviously, an area of genome editing that's had a lot of-- beared a lot of fruit, no pun intended in the sense that the ability to modify the genes of these plants has really been very useful for these folks.
ALEX PHILIPPIDIS: Now, I remember earlier, you spoke of Prime having grown to about 200 people. What kind of growth is Prime looking at for this year?
ANDREW ANZALONE: Oh, yeah. That's, I think, challenging for me to ask or to answer that question specifically. I think we want to grow in a way that meets the demands of what we're trying to do. So as we move closer and closer to the clinic, we need to establish parts of the company that can do the CMC and the manufacturing, we need to establish a clinical group and regulatory group. So I would say, we're growing in the right areas where we can address the next stage of what our company will be doing.
ALEX PHILIPPIDIS: Given those challenges and the need to address those areas, is this year realistic enough for Prime's first product to go into the clinic, or is that more of a longer term plan?
ANDREW ANZALONE: Yeah. I don't think I can speak to one exactly. We would go into the clinic. I think that's hard to predict from this stage. But I don't think we want to-- I think we'd like to get into the clinic and demonstrate proof of concept to people and show that really Prime Editing can work and it can be used in a therapeutic context, it's not just a research tool.
ANDREW ANZALONE: So that's something we're eager to do, but I can't say specifically when exactly that will happen.
ALEX PHILIPPIDIS: Kevin, over to you.
KEVIN DAVIES: Thank you, Alex. Andrew, I want to talk about patents and IP for a couple of minutes, if we can. The development of CRISPR, of course, as you referenced 10, 11 years ago, led to a protracted patent dispute between the Broad and the University of California and other entities allied with [? Dowden's ?] group. Is there a danger at all that something similar could happen in the world of prime editing? Perhaps, you could just update us on what the state of the patent landscape is regarding this technology.
ANDREW ANZALONE: I guess, I'm certainly not a patent attorney so I don't want to speculate on any of that. But you know what I will say is, I think, Prime has a very strong position in prime editing. We filed patents at the Broad Institute, very early on, that I believe cover the prime editing system. We've been awarded some of those patents, and we continue to file more patents on both our technology and our therapeutic applications as does David Liu's group at the Broad Institute, which we enlicense.
ANDREW ANZALONE: So I feel very good about our IP position and the work that we did to establish that position.
KEVIN DAVIES: Andrew, there's a lot of increase-- an exciting increase, I think, of gene editing technology, new waves of gene editing technologies. We can go through the acronyms. [INAUDIBLE],, [? transposase ?] have had a lot of attention in the last few years. More and more companies are getting involved in this space. Many of them are your neighbors in the Kendall Square Cambridge area.
KEVIN DAVIES: Do you anticipate increased competition in developing these precision editing tools?
ANDREW ANZALONE: Yeah. So I would say that the CRISPR space has always been competitive and genome editing in general has been a very competitive space, even from the beginning. When the first CRISPR systems were described, there was races to find new CRISPR effector proteins, new CRISPR systems that could be translated into therapeutics, whether those be smaller CAS systems or other beneficial properties. And similarly, competitions in developing the next generation approaches to do genome editing.
ANDREW ANZALONE: I would say, all of that, again, has been very healthy in making this technology more effective and ultimately more useful for the development of therapeutics and who will, ultimately, benefit from that, I believe, are the patients who could be treated with these systems. So I think that's a really exciting thing to witness as a scientist and as a member of the community. And from the standpoint of prime medicine, we're also really interested in continuing to do that development and contributing to that innovation and moving things forward just like others are.
ANDREW ANZALONE: So I think it's a really good feature of a scientific community. It's, by no means, stagnant, and I think that's a good sign of a healthy functioning scientific field.
KEVIN DAVIES: Yeah. A few minutes ago, Alex referenced a who's who of Mendelian genetic disorders that Prime has expressed interest in researching. Not all of them will make it to the clinic presumably, but it's interesting that you're tackling such a wide array of disorders. And some of these fragile X and Huntington's are not the simple base substitution. Some of these are much more complicated genetic mechanisms.
KEVIN DAVIES: And that was always, I think, one of the potential advantages of the Prime Editing platform. Can we go back to the technology for a second and talk a little bit about what is it about you the platform that allows you to, potentially, tackle some of these more complicated genetic mechanisms?
ANDREW ANZALONE: Yeah, absolutely. So you referenced earlier, some of these sort of developments to the primitive technology that I haven't actually talked about yet. One of those is dual flap prime editing or twin prime editing, gone by a few different names. But essentially, this is an approach to prime editing that allows you to replace or delete much larger pieces of DNA. And one of the real exciting applications for that, in my opinion, is the ability to delete expanded repeats in DNA that are known to cause some of these diseases that you mentioned.
ANDREW ANZALONE: Huntington's disease, fragile X, Friedreich's ataxia. There's a long list of these. And they're really quite devastating and very challenging to treat. So Prime Editing has this other second generation version a dual flap version that can really be harnessed, in my opinion, to address some of these. And I'll just take the opportunity to also mention that beyond that, we're very interested in other larger changes that you could make to a genome, including the insertion of large DNA sequences.
ANDREW ANZALONE: So with this twin prime editing approach, we showed when I was still in David's Liu's lab, that you could use it to very efficiently insert short DNA sequences of 30 to 50 bases that are called recombinase attachment sites. These can be paired up with a class of enzymes called integrases or recombinases. Many scientists have used versions of these like [INAUDIBLE] combinase.
ANDREW ANZALONE: And once that very specific attachment site has been prime edited into a specific location in the genome, these recombinase enzymes can then take new DNA pieces and insert them there. So now, we've developed a mechanism for targeted integration of large pieces of DNA. We did the proof of concept of that in the Liu lab and since then, in Prime medicine, we've been able to develop it and actually just recently, a few weeks ago at the JPM conference, showed an example of this in T cells where we showed we could do targeted integration of 3.5 kb of DNA at a 60% efficiency, 60% of the cells receiving this integration.
ANDREW ANZALONE: So I think all of these additional developments on that prime editing technology platform are enabling so many new things and really allows us to address new exciting areas that the initial Prime Editing system, maybe, wouldn't have been able to do.
ALEX PHILIPPIDIS: All right. There are many other factors, of course, in successfully developing a gene editing technology besides optimizing the chemistry of the technology itself. One thinks of delivery, how are you're going to deliver these constructs into the cells where they need to go, conditioning for ex vivo applications. To what extent is Prime Medicine-- now that you have 200 employees and growing, to what extent do you have the resources to, potentially, explore some of these other, in some ways, more peripheral but, perhaps, no less important aspects of building a truly successful medical, clinical gene editing platform?
ANDREW ANZALONE: No. We're very invested in that from the standpoint of-- we're here to develop, medicines not to do science projects that can only be demonstrated in a tissue culture experiment where, of course, that's the beginning but that's not the endpoint. So as you've already mentioned, the delivery approaches that we need to develop to get these therapeutics into the right cells are very important.
ANDREW ANZALONE: And all the accessory things that happen that are required to deliver these therapeutics like conditioning and other associated processes, these are all part of making the medicine. So we're very much thinking about that. On the delivery front, we've been thinking a lot about how do we get our gene editing system into cells in vivo using transient delivery systems that are based on RNA.
ANDREW ANZALONE: These are lipid nanoparticle formulations, the same way that a lot of the COVID vaccines have been delivered and now are formulated. Thinking of ways that we can get these into other cell types beyond the liver, which is where primarily, they've been able to be effective. And then also thinking of, likewise, viral delivery solutions that can get our genetic components into even broader set of cell types, such as the central nervous system.
ANDREW ANZALONE: So we're very much thinking about this and developing a full medicine, not just a gene editing system.
KEVIN DAVIES: I think one of my-- that's my closing question is to reference a recent op Ed that I'm sure you read in The New York Times from Theodore [INAUDIBLE] who was raising I think a very important-- some very important issues about the practical realities and the cost of turning these breakthrough technologies into affordable medicines. And I'm going to try and take this question away from Prime Medicine, because this is some way down the future. But I'm curious to just hear your personal thoughts, these therapies-- that some of the gene editing therapies and genetic therapies that have been recently approved are coming with really exorbitant price tags of $2 to $3 million in some cases.
KEVIN DAVIES: You went into-- you're a trained doctor, you went into medicine. How do you balance the need for these companies such as yours to get a return on their huge investments in developing these drugs with pricing them in a way that this can become a truly affordable therapy, not just for the wealthy in the United States, but for potentially millions of patients around the world? It's almost an existential question, but it's one that, I think, everybody in the industry is having to wrestle with.
ANDREW ANZALONE: Yeah. It really is. And it's an important question. As you mentioned, there are these therapies that could be developed for the Western world. And genetic diseases affect everybody and not in the same way. Obviously, these are inherited from family members in a large percentage of patients. So the certain regions of the world have their own sets of genetic mutations that you might have to fix.
ANDREW ANZALONE: So developing treatments for everybody, it's going to, I think, take a lot. And we're going to have to figure out ways to pay for it and make it accessible to folks. Now, in the near term, my personal view of this, which is not maybe the most sophisticated, is that that's going to require-- just based on the amount of investment and time that it takes to make one of these the first time, that's going to, potentially, require that the cost be proportional so that we can support the growth of this new therapeutic area.
ANDREW ANZALONE: My hope would be that over time, as we learn how to do this with more ease, with less upfront investment, with more of an ability to swap out a guide RNA, for example, and not have to do an entirely new clinical trial and be able to move from one patient in their mutation to another patient and their mutation with very minimal extra cost. I think as this, maybe, world comes into reality, I think the possibility of making these genetic systems for more folks at a very affordable price, it would make sense.
ANDREW ANZALONE: And I will also say, I can't tell you how many times I saw patients come into the hospital for the same problem over and over again because of their genetic disease. And from a cost standpoint, it might even make sense to treat that patient and prevent all of those recurrent costs and not to mention, the quality of their life that would be affected. And most importantly, how much of a benefit that would have to them.
ANDREW ANZALONE: So I think there's a good reason to invest here from my personal perspective. And like anything else, I would hope that costs can be minimized in the future so that this isn't a major restriction.
KEVIN DAVIES: Yeah. Well, Andrew. I just want to end on a personal note, I did my PhD in the 1980s with Bob Williamson at St. Mary's Hospital in London and during the heyday of the Gold Rush of mapping Mendelian disease genes before the Human Genome Project, so dating myself. And despite the early hopes of gene therapy, I don't even think it was science fiction to think that we might, one day, develop a technology to literally perform this single base chemistry on the genome.
KEVIN DAVIES: And I know prime editing isn't the first such technology. But it, certainly, would appear to have the most flexibility and promise. So congratulations on all of your success so far, and we hope that Prime Medicine continues to enjoy the momentum and can really make a difference in the clinic. Time will tell. But keeping our fingers crossed for you. Alex, over to you.
ALEX PHILIPPIDIS: Here. Thanks, Kevin. And thanks for joining us on Close to the Edge. Thanks, Andrew, thanks, Kevin. We'll have many more exciting interviews in the weeks and months ahead. For Kevin Davies, I'm Alex Philippidis. Take care, stay safe. [MUSIC PLAYING]
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ALEX PHILIPPIDIS: Howdy, and welcome to Close to the Edge, the show from GEN Edge where we invite leading executives, scientists, and innovators from groundbreaking biotech and pharma companies to discuss their science, technology, and their business strategy. I'm Alex Philippidis, a Senior Business Editor with Genetic Engineering and Biotechnology news. The world's first biotech publication proudly covering the industry for more than 40 years.
KEVIN DAVIES: And I'm Kevin Davies, Executive Editor of GEN's new marquee peer review journal GEN Biotechnology, and the author of Editing Humanity-- The CRISPR Revolution and the New Era of Genome Editing. On today's episode, our guest is someone who plays a cameo role in my book and someone we've been eagerly looking forward to hosting on the show for quite some time. Andrew Anzalone from Prime Medicine that's coming right up.
ALEX PHILIPPIDIS: Close to the Edge is the flagship video program from GEN Edge, our premium subscription channel providing exclusive in-depth news, interviews, and analysis of key trends in the biotech industry. Coupled with a range of multimedia offerings such as this one, details of personal and group rate subscriptions are at www.genengnews.com/genedge. And don't miss GEN's blockbuster virtual event coming up on February 28, the State of Genomics and NGS.
ALEX PHILIPPIDIS: Four hours of conversation and presentations featuring NHGRI Director Eric Green, Pardis Sabeti and Niall Lennon from the Broad Institute. Karen Miga on the Completion of the Human Genome Sequence, Chris Mason on Space Genomics and much more. Google the state of genomics for more information.
KEVIN DAVIES: Thanks, Alex. Andrew Anzalone is the lead developer of Prime Editing and the scientific co-founder and head of the Prime Editing platform at Prime Medicine-- the company that is in pole position to commercially develop and bring this technology into the clinic. Prime Editing is an incredibly exciting technology for precision genome editing, because it can, in principle, engineer any potential base change by performing a truly ingenious molecular choreography on the double helix itself.
KEVIN DAVIES: So in the month that the double helix turns 70 years of age, it's great to have the architect of Prime Editing on the show. Andrew, thanks so much for joining us on Close to the Edge.
ANDREW ANZALONE: Yes. Thanks so much, Kevin, for the opportunity to talk to you guys today.
KEVIN DAVIES: So let's start shockingly at the beginning. Can you take us back-- I think it was only about five years or so, to your time at Columbia University where you got your MD and PhD and the inception of this gene editing technology.
ANDREW ANZALONE: Yeah. I could, probably, talk to you all day about that. But I'll try to keep it short. So yeah. I guess it all started back in my days as a trainee where I was focused on chemistry and molecular engineering. Also very interested in medicine and seeing how we can push science forward to help people with diseases and treat their diseases. So as I went through my training, I had such an enthusiasm for the science and working in the lab and this desire to, again, develop therapies.
ANDREW ANZALONE: And as I ended towards-- that was towards the end of my training. I wanted to look for a position in research that would allow me to really translate this science into something, potentially, meaningful. In the backdrop of all of this, of course, was this CRISPR revolution that had begun. That had started around 2012, 2013 with some really landmark publications from people you've researched and talked about numerous times.
ANDREW ANZALONE: Jennifer Doudna, Emmanuelle Charpentier, Feng Zhang, George Church, the list goes on and on. And as I looked for new opportunities in my research and new directions, I came across some really interesting work that was being done in this gene editing field using these CRISPR technologies. And David Loo really quickly rose up on my list of people of interest.
ANDREW ANZALONE: Recently, he had just developed a base editing system which we can discuss a little more later. But this was a system that could precisely make single-base bare changes to DNA. And not only did he develop one base editor, but he had actually just published a second base editor, really just about a year apart from each other. And I looked at this and I just thought, wow.
ANDREW ANZALONE: This is really exploding. This is something that I could have never imagined would be possible 10 years ago when I had started medical school and learning about all these different genetic diseases. So I saw that as an opportunity to build on what was done, what had been done prior. We have this incredible, natural system. These CRISPR enzymes that can target, in a programmable way, a DNA sequence.
ANDREW ANZALONE: To go and find it in this vast sea of, otherwise, other similar-looking DNA sequences. And we can start making more sophisticated machines that could edit the DNA in different ways. And of course, a big challenge was still, we have this CRISPR system that can target and find sequences in the genome, but how to change them to exactly what you want was still a little bit of a challenge.
ANDREW ANZALONE: There was still something to be done there to address this second half of what was required for gene editing. And that's where the idea came from for how we might develop a new system, which eventually became prime editing.
KEVIN DAVIES: Right. I've read in earlier reporting that the idea can be traced back to an evening stroll around your New York neighborhood. It's not exactly Kary Mullis popping LSD on a midnight drive- through Napa Valley en route to discovering PCR. But perhaps, you can paint a picture for us of how you think the real breakthrough came about.
ANDREW ANZALONE: Yeah, happy to. And there was no LSD involved. I think the only substance involved was caffeine. But I do like to do my thinking on walks, that's definitely a place in time where I can do some real hard thinking. And I think at some point, a notion just occurred to me. That these CRISPR systems, so elegant, they have these RNA molecules that are almost like instructions and give them an address for where to go in the genome to bind to DNA and to change that DNA.
ANDREW ANZALONE: And what a nice opportunity now for that programmability to now not just be used to say where to go but also what to do. And in fact, we've already got this RNA sequence that has information in it bound at the target site of the genome where you want to make a change. Why not just add some instructions on what that change might be? So this is really the notion of, OK, we've got programmability for targeting, what about the programmability for editing or making that change?
ANDREW ANZALONE: And the system is already poised to do that. It already has the right molecules in place. And so that was the conception. And obviously, that's just an idea. That's not worth a whole lot on its own. It wasn't really until I entered the Broad Institute that I really started to get into the details of this and think about how this might be possible. And it took quite a few steps to actually make that a reality.
KEVIN DAVIES: Before you got to the Broad, which is, of course, where David Liu runs his lab and where base editing was developed in these two seminal papers in Nature that you just mentioned, Andrew, work led by Alexis Como and Nicole [? Gordelli, ?] former postdocs in David's lab. How did you approach David? Did he, immediately-- kind of you were you on the same wavelength straightaway, or did you have to twist his arm a little bit?
ANDREW ANZALONE: In some ways, I think, many people saw the promise in the idea, including David, but also a lot of the challenges that we would face. And there are a lot of questions that any one of them, if things didn't go as planned, the system wouldn't work. So while I think there was some optimism, I think there was a healthy amount of skepticism as well as any, I think, scientists naturally would have. It was little bit of a funny story.
ANDREW ANZALONE: I had discussed the idea on my actual post-doc interview with David and many members of the group. And it was quite a colorful discussion as you could imagine but a really nice one. And a few weeks after my interview, I followed up with David about it, and he agreed to allow me to join the lab and pursue this project and then hit the ground running when I got there on this.
KEVIN DAVIES: Yeah. So when you joined the lab, were you working in isolation? As most postdocs, it's a pretty solitary experience or did-- was there a feeling that there's so much potential in this approach that it became a bit more of a team effort?
ANDREW ANZALONE: Yeah. Like a lot of others in academia, initially, it started as a project that only I worked on. That being said, I can't emphasize enough how great of an environment David had developed at the Broad in his laboratory in terms of learning all the techniques from people. These were all things I hadn't done before. I had never done genome editing in a human cell or getting to David Liu's lab.
ANDREW ANZALONE: So I'd never done high throughput sequencing using all these next generation technologies, which were all at our disposal there. So I definitely credit all of my lab mates there for showing me these things and helping me talk through ideas and how to make this work. And as the project showed more and more promise, that's when others started to join in with me on the project.
ANDREW ANZALONE: I think, ultimately, the paper that we published had 12 or so co-authors on it, all of whom make very important contributions. So I really do credit the environment that was cultivated there to a lot of the success. And especially, the speed of the success.
KEVIN DAVIES: Yeah. It wasn't smooth sailing, that first year, but you overcome whatever stumbling blocks that they were.
ANDREW ANZALONE: Yeah. Yeah. There were at least four challenges that laid in front of us in terms of we have to get this to work, we have to get then this to work. David likes to refer to it as four little miracles that needed to happen Prime Editing to actually work. And I [INAUDIBLE] one little stumbling block, tweaked some things, worked on some new designs, and got past each one of them one at a time until, ultimately, getting into human cells and making it work there.
KEVIN DAVIES: And was the main driver, as again you touched on a few minutes ago, the idea that base editing is excellent at making certain categories of base substitution but prime editing in principle could give you the full repertoire?
ANDREW ANZALONE: That's exactly right. So exploiting all there is to offer from having a nucleic acid sequence template, that sequence change. So the RNA and DNA, they share pretty much the same letters. That information is easily exchanged in both directions. The direction that we needed to exchange it was from RNA into DNA. That's a process that is performed, that's called reverse transcription.
ANDREW ANZALONE: There's a whole category of enzymes that do this. They synthesize DNA from an RNA template. And because this template sequence could be changed very simply by changing one base here, another base there, deleting some bases, adding some bases, that template will then dictate what sequence goes into the DNA. So it's very easy to just swap out one for another and make any edit, in principle, that you really want in a pretty confined but substantial region of DNA.
KEVIN DAVIES: I think your paper which is published in Nature was impressed when David presented the work for the first time, I believe, at the Cold Spring Harbor CRISPR Conference. I was in the audience with a 500 other scientists pretty much on the edge of their seat, because the abstract had been deliberately vague, I think, as you were sweating the fate of the manuscript. Do you recall what he said at the end of his talk in his little acknowledgment slide?
ANDREW ANZALONE: I do. And I recall a lot of the things that happened at that conference. It was a very meaningful experience for me. But David said something along the lines of, he's excited to see what I do in the second year of my postdoc. It was partially set back by the pandemic, unfortunately. But I think we still got a bit more done in the prime editing space then.
KEVIN DAVIES: Yeah. And how-- to the paper, I know the two base editing papers had very different fates during the review process at Nature. The first one, Alexis's paper was a bit of a struggle. The second one sail through. Do you recall what the process was like for your paper?
ANDREW ANZALONE: Yeah I think it was a very reasonable process. We were asked to do some very reasonable follow-up experiments, some of which we anticipated and had already begun doing. I'd say, on the whole, it was not a very challenging process. I've had far more challenging review process--
KEVIN DAVIES: The lesser papers, yeah.
ANDREW ANZALONE: Yeah. So this was not as difficult, but there were some very critical experiments that we had to do and were asked to do. And I think they were the right ones.
KEVIN DAVIES: Yeah. Now, by the time the paper was published, we're talking towards the close of 2019, were you and David already thinking that this technology would be commercially developed as an independent company?
ANDREW ANZALONE: Yeah, absolutely. I mean, I think there was a lot of recognition of that pretty early on, I would say, a few months before we published the paper, because we were trying all these different things and they were all working. Once we finally developed the system, getting it to the state where it was working in human cells, again, like I said, we could swap out the RNA with a new sequence and make an edit somewhere else in the genome.
ANDREW ANZALONE: And we just saw the potential for that. And it doesn't take a lot of effort to go look through the types of mutations that cause genetic disease and just tally up what percentage of these could we potentially fix with prime editing? And it's a pretty large number. Probably somewhere close to 90%, at least, of the mutations in certain databases like ClinVar.
ANDREW ANZALONE: So we immediately recognized the opportunity there and the potential. And David, obviously, has a lot of experience founding companies and was able to get that going pretty efficiently.
KEVIN DAVIES: Yeah. And before I pass it over to Alex, we've touched on some of the advantages, the repertoire of prime editing as one big attraction for developing the technology. Of course, in common with base editing, it only nicks the double helix. I wonder if you could talk a little bit more about that and some of the other potential advantages and the expanded range of edits that Prime Editing not just in theory, but I think increasingly in practice can give researchers.
ANDREW ANZALONE: Yeah. No. I mean, maybe I'll try to set it up a little bit with what an ideal gene editing system look like. I think there's probably five factors that a lot of us have discussed and arrived on as being really critical. The first is programmability. I think I've already discussed this a little bit. Essentially what this means is you can go one place in the genome and then the next day change that location and go somewhere else and do that with a lot of ease and do it really quickly.
ANDREW ANZALONE: So that's one key factor, the programmability. The second would be specificity. You only want to go to the place you want to go. The one place, not the other places. That has implications for things like off target editing, which I think I can get into related to an earlier question a little bit. I would say, the third one is versatility. When you get to that place in the genome, can you make all the different types of changes that you might want to make?
ANDREW ANZALONE: So how broad can that genome editing system be in terms of making a point mutation, deletion, insertion, et cetera? And then how precisely will it do it? So at that location, are you making just that change or are you making other changes as well? And finally, how efficient is that system? Ideally, every cell that gets treated with these editing systems would make an edit, so this is five different principles that I think really you would look for in a perfect or ideal gene editing system.
ANDREW ANZALONE: So Prime Editing in a lot of ways, and all CRISPR systems, I would say, are very programmable. It's very straightforward to give a new set of instructions to these CRISPR systems, these guide RNAs to tell it to go to a new place in the genome. And that makes it really easy to go say, on one day I want to fix this mutation and CFTR that causes cystic fibrosis. On another day, I want to fix this mutation in sickle cell disease.
ANDREW ANZALONE: And so that's a real powerful principle for CRISPR technology. Now, once you get there though, you want to minimize the other things you do besides making the precise edit that you're intending to make. So that's-- in a prime editing system, we're using this RNA template to make a change. In principle, the fidelity of copying that sequence is very high.
ANDREW ANZALONE: And so you're very likely to only incorporate that one change. And you only make a single break in the DNA. And that's really important. When a cell has a double strand break, and this is what the more traditional CRISPR nucleases or CRISPR scissors do, so it sets off a lot of alarm bells. It quickly identifies that broken DNA and stitches it together as fast as possible and without a lot of care for what happens to the sequence when it does that.
ANDREW ANZALONE: So you can imagine these two pieces coming together, but little errors happening in that process that lead to these small changes, insertions or deletions of a few bases that often will disrupt a gene. And that's just an intrinsic thing the cells will do. Now, if you make only one break in the DNA double helix, you avoid a lot of these responses in the cell. And that's exactly what prime editing does. It makes just a single nick to copy DNA sequence onto that one strand of DNA.
ANDREW ANZALONE: And then other DNA repair mechanisms can incorporate that edit to both strands eventually. But you avoid this alternative DNA repair pathways that tend to lead to a lot of undesirable outcomes. Another advantage to that is that at any potential off target sites in the genome, so places where you didn't intend that prime editor system or CRISPR system to go to, you're also not going to be making double strand breaks.So it's much less likely to cause damage at those other places in the genome.
KEVIN DAVIES: Great. Let me pass it over to Alex.
ALEX PHILIPPIDIS: Here. Thanks, Kevin. Now, Andrew, when Prime Medicine launched around 2019, as I recall, did you have any doubts about being an active part of building the company? Because presumably, you could have had your pick of any faculty position or, maybe, return a medicine.
ANDREW ANZALONE: Yeah. That's a very-- I think I thought very hard about but actually not that long about. As I said, I had always been really motivated from early days in research. Actually, my first research experiences were in medicinal chemistry at a small pharmaceutical company. So I was always really interested in developing therapeutics.
ANDREW ANZALONE: In David's lab, I had obviously had a lot of success doing science that had the ability to translate into therapeutics in the past. And that was one of the reasons I was very, very attracted to going to his group. So when the opportunity arose, I didn't really have to think too long about why this would be a great opportunity for me. Now, I love the science, it's a science that I'm really committed to.
ANDREW ANZALONE: I was there when it started. I can't think of anything better than being able to carry that forward to the point of using it for human therapeutics. And that's really what drove me to join the company, also joined by a grade group of people fro that Liu lab that joined the company with me. So great colleagues and I really didn't have to think hard about whether or not to do that.
ALEX PHILIPPIDIS: Now, how did the company grow, and what, if any, challenges did you have finding talent to join the company?
ANDREW ANZALONE: First six months or so it was a little slow. This was the earlier days of the pandemic. Obviously, those presented some challenges. But I would say in the next year and a half to two years that followed, we've had a really amazing growth period I've hired up to almost 200 people now at Prime Medicine, and I think we've been able to tap into the excitement that the community feels about gene editing and about prime editing in particular and its potential.
ANDREW ANZALONE: Many of the folks that have joined Prime Medicine have worked on gene editing in the past and have experienced using Prime Editing. They've seen the potential there and want to contribute to making it into medicine. So I would say that despite the obstacles that the pandemic and competition and other things presented, we still were able to have a pretty rapid growth trajectory and really bring in the people that would get the job done.
ANDREW ANZALONE: I really am proud about the company that we've built and the team that we've built.
ALEX PHILIPPIDIS: Now, who are some of the key members of your executive team? For example, is David Liu still actively involved?
ANDREW ANZALONE: So David Liu is involved. He does touch base with us, I think, on a weekly basis or so. And definitely, gives us a lot of feedback on what we're doing. Also his lab is actively working on Prime Editing technology development. So things that his group develops and improvements to the technology often come over to us and we have the ability to use those and capitalize on those developments.
ANDREW ANZALONE: So we still have quite a strong relationship with David Liu.
ALEX PHILIPPIDIS: And then as far as the team goes?
ANDREW ANZALONE: So the team-- I mean, we have an excellent leadership team in my opinion. Keith Gottesdiener, is our CEO, a very experienced CEO who's been in biotech and pharma for several decades. And Jeremy Duffield is our chief scientific officer, similarly, very experienced and really an expert in the disease biology. So I think we put together a grade group, and we have a lot of internal expertise. I think there's now six other people from David Liu's lab at Prime Medicine that have all been there from the very beginning.
ANDREW ANZALONE: I think almost every-- yeah. Every one of them was an author on a Prime Editing publication. So this expertise, I think, has really helped us accelerate moving things forward.
ALEX PHILIPPIDIS: Now, the company remained in stealth for a couple of years. But last year, you filed a successful IPO and released details of the pipeline. Why such an early IPO given how challenging the financial climate was in the market declines that happened back then?
ANDREW ANZALONE: Yeah. I guess I'm not the type of person that could answer a lot of those questions in terms of the financials of things. This is all pretty new to me I have to say, but I think our ability to do the IPO probably does signify one thing and that's the excitement for the technology and the potential that it has. And it was just an amazing experience to be part of that process to go public.
ANDREW ANZALONE: I had to pinch myself a few times when I went to in Times Square in New York City. I mean, I'd walk through there so many times earlier in my life I never thought I would be in the NASDAQ building. So it was quite the experience, and I'm really proud of the team for getting us there. We released our pipeline as you referenced, and we have a lot of areas that we're looking to work in.
ANDREW ANZALONE: We weren't sure when we started where Prime Editing was going to work or where it would work the best. And maybe there would be some places where it just wouldn't work and we wouldn't be able to do anything in that area. But the more things we tried, we just kept finding that we can find things that work through all the optimizations and enhancements to the technology that have been developed.
ANDREW ANZALONE: And most of the areas where we're trying to do something, we've had a lot of success. So we've got a lot of decisions to make, but there's the good type of decisions, I think.
ALEX PHILIPPIDIS: Now, Prime's pipeline is pretty ambitious. It features, at least, a half dozen targets, including almost a who's who of well-known Mendelian diseases, including DMD, Duchenne muscular dystrophy, fragile X, et cetera. What are some of the initial clinical priorities at Prime?
ANDREW ANZALONE: Yeah. So that's a very nuanced question in the sense that, again, we have the potential to address some of these really well known diseases that have affected so many people and for many of them, there hasn't been a really great therapeutic option available. And so Prime Editing offers this really exciting opportunity. But in some cases, there's also challenges associated with delivery of the gene editing systems to the right cells in the body.
ANDREW ANZALONE: And so we've taken an approach where we've looked at the landscape and said, OK, there are certain places where we think we could be really successful early on because there are some of these challenges have been addressed, such as delivery. In other places where we think the technology does something really special, we probably need some other areas to catch up before they really can become a possibility.
ANDREW ANZALONE: So we've tried to develop a pipeline that has some examples from each of these categories. And certainly, there will be places where we can move a lot quicker, ex vivo programs, for example, are a lot easier to do in the sense that the delivery challenges is not as prominent. And then certain in vivo programs where delivery has also been established previously.
ALEX PHILIPPIDIS: Now, is Prime trying to pursue all these itself, or will you be seeking partners to develop some of these programs?
ANDREW ANZALONE: Yes. So I guess it would be a little unrealistic to say that we're going to take 18 programs forward in the next few years and be able to develop them into medicines for people. So I assume there are a lot of solutions to those challenges, whether that be through partnering with other companies or by prioritization internally. And that's something, I think, we'll have to be deciding in the next couple of years.
ALEX PHILIPPIDIS: And which of these programs is furthest advanced? And what's going to determine which targets Prime prioritizes?
ANDREW ANZALONE: Yeah. Those are questions that are still being worked through. Again, I think the targets where we've had a lot of ability to deliver the gene editing systems to the cells of interest, again, the ex vivo programs have the ability to get past that a little bit more quickly. Those, we can make pretty rapid progress in. And likewise, delivery into systems by lipid nanoparticles to the liver, these are also areas where we can move a little faster.
ANDREW ANZALONE: That being said, we still have a lot of-- paying a lot of attention to those other programs where there's so much potential. So they may require other delivery solutions, but we're actively pursuing those two.
ALEX PHILIPPIDIS: Now, is Prime just focusing on medical applications of the technology? What about, for example, Prime Editing applications in plants or other organisms?
ANDREW ANZALONE: Yeah. We focus on therapeutic applications or applications for human therapeutics. So we haven't been pursuing any applications in plants and I don't think we intend to in the near future. But that's, obviously, an area of genome editing that's had a lot of-- beared a lot of fruit, no pun intended in the sense that the ability to modify the genes of these plants has really been very useful for these folks.
ALEX PHILIPPIDIS: Now, I remember earlier, you spoke of Prime having grown to about 200 people. What kind of growth is Prime looking at for this year?
ANDREW ANZALONE: Oh, yeah. That's, I think, challenging for me to ask or to answer that question specifically. I think we want to grow in a way that meets the demands of what we're trying to do. So as we move closer and closer to the clinic, we need to establish parts of the company that can do the CMC and the manufacturing, we need to establish a clinical group and regulatory group. So I would say, we're growing in the right areas where we can address the next stage of what our company will be doing.
ALEX PHILIPPIDIS: Given those challenges and the need to address those areas, is this year realistic enough for Prime's first product to go into the clinic, or is that more of a longer term plan?
ANDREW ANZALONE: Yeah. I don't think I can speak to one exactly. We would go into the clinic. I think that's hard to predict from this stage. But I don't think we want to-- I think we'd like to get into the clinic and demonstrate proof of concept to people and show that really Prime Editing can work and it can be used in a therapeutic context, it's not just a research tool.
ANDREW ANZALONE: So that's something we're eager to do, but I can't say specifically when exactly that will happen.
ALEX PHILIPPIDIS: Kevin, over to you.
KEVIN DAVIES: Thank you, Alex. Andrew, I want to talk about patents and IP for a couple of minutes, if we can. The development of CRISPR, of course, as you referenced 10, 11 years ago, led to a protracted patent dispute between the Broad and the University of California and other entities allied with [? Dowden's ?] group. Is there a danger at all that something similar could happen in the world of prime editing? Perhaps, you could just update us on what the state of the patent landscape is regarding this technology.
ANDREW ANZALONE: I guess, I'm certainly not a patent attorney so I don't want to speculate on any of that. But you know what I will say is, I think, Prime has a very strong position in prime editing. We filed patents at the Broad Institute, very early on, that I believe cover the prime editing system. We've been awarded some of those patents, and we continue to file more patents on both our technology and our therapeutic applications as does David Liu's group at the Broad Institute, which we enlicense.
ANDREW ANZALONE: So I feel very good about our IP position and the work that we did to establish that position.
KEVIN DAVIES: Andrew, there's a lot of increase-- an exciting increase, I think, of gene editing technology, new waves of gene editing technologies. We can go through the acronyms. [INAUDIBLE],, [? transposase ?] have had a lot of attention in the last few years. More and more companies are getting involved in this space. Many of them are your neighbors in the Kendall Square Cambridge area.
KEVIN DAVIES: Do you anticipate increased competition in developing these precision editing tools?
ANDREW ANZALONE: Yeah. So I would say that the CRISPR space has always been competitive and genome editing in general has been a very competitive space, even from the beginning. When the first CRISPR systems were described, there was races to find new CRISPR effector proteins, new CRISPR systems that could be translated into therapeutics, whether those be smaller CAS systems or other beneficial properties. And similarly, competitions in developing the next generation approaches to do genome editing.
ANDREW ANZALONE: I would say, all of that, again, has been very healthy in making this technology more effective and ultimately more useful for the development of therapeutics and who will, ultimately, benefit from that, I believe, are the patients who could be treated with these systems. So I think that's a really exciting thing to witness as a scientist and as a member of the community. And from the standpoint of prime medicine, we're also really interested in continuing to do that development and contributing to that innovation and moving things forward just like others are.
ANDREW ANZALONE: So I think it's a really good feature of a scientific community. It's, by no means, stagnant, and I think that's a good sign of a healthy functioning scientific field.
KEVIN DAVIES: Yeah. A few minutes ago, Alex referenced a who's who of Mendelian genetic disorders that Prime has expressed interest in researching. Not all of them will make it to the clinic presumably, but it's interesting that you're tackling such a wide array of disorders. And some of these fragile X and Huntington's are not the simple base substitution. Some of these are much more complicated genetic mechanisms.
KEVIN DAVIES: And that was always, I think, one of the potential advantages of the Prime Editing platform. Can we go back to the technology for a second and talk a little bit about what is it about you the platform that allows you to, potentially, tackle some of these more complicated genetic mechanisms?
ANDREW ANZALONE: Yeah, absolutely. So you referenced earlier, some of these sort of developments to the primitive technology that I haven't actually talked about yet. One of those is dual flap prime editing or twin prime editing, gone by a few different names. But essentially, this is an approach to prime editing that allows you to replace or delete much larger pieces of DNA. And one of the real exciting applications for that, in my opinion, is the ability to delete expanded repeats in DNA that are known to cause some of these diseases that you mentioned.
ANDREW ANZALONE: Huntington's disease, fragile X, Friedreich's ataxia. There's a long list of these. And they're really quite devastating and very challenging to treat. So Prime Editing has this other second generation version a dual flap version that can really be harnessed, in my opinion, to address some of these. And I'll just take the opportunity to also mention that beyond that, we're very interested in other larger changes that you could make to a genome, including the insertion of large DNA sequences.
ANDREW ANZALONE: So with this twin prime editing approach, we showed when I was still in David's Liu's lab, that you could use it to very efficiently insert short DNA sequences of 30 to 50 bases that are called recombinase attachment sites. These can be paired up with a class of enzymes called integrases or recombinases. Many scientists have used versions of these like [INAUDIBLE] combinase.
ANDREW ANZALONE: And once that very specific attachment site has been prime edited into a specific location in the genome, these recombinase enzymes can then take new DNA pieces and insert them there. So now, we've developed a mechanism for targeted integration of large pieces of DNA. We did the proof of concept of that in the Liu lab and since then, in Prime medicine, we've been able to develop it and actually just recently, a few weeks ago at the JPM conference, showed an example of this in T cells where we showed we could do targeted integration of 3.5 kb of DNA at a 60% efficiency, 60% of the cells receiving this integration.
ANDREW ANZALONE: So I think all of these additional developments on that prime editing technology platform are enabling so many new things and really allows us to address new exciting areas that the initial Prime Editing system, maybe, wouldn't have been able to do.
ALEX PHILIPPIDIS: All right. There are many other factors, of course, in successfully developing a gene editing technology besides optimizing the chemistry of the technology itself. One thinks of delivery, how are you're going to deliver these constructs into the cells where they need to go, conditioning for ex vivo applications. To what extent is Prime Medicine-- now that you have 200 employees and growing, to what extent do you have the resources to, potentially, explore some of these other, in some ways, more peripheral but, perhaps, no less important aspects of building a truly successful medical, clinical gene editing platform?
ANDREW ANZALONE: No. We're very invested in that from the standpoint of-- we're here to develop, medicines not to do science projects that can only be demonstrated in a tissue culture experiment where, of course, that's the beginning but that's not the endpoint. So as you've already mentioned, the delivery approaches that we need to develop to get these therapeutics into the right cells are very important.
ANDREW ANZALONE: And all the accessory things that happen that are required to deliver these therapeutics like conditioning and other associated processes, these are all part of making the medicine. So we're very much thinking about that. On the delivery front, we've been thinking a lot about how do we get our gene editing system into cells in vivo using transient delivery systems that are based on RNA.
ANDREW ANZALONE: These are lipid nanoparticle formulations, the same way that a lot of the COVID vaccines have been delivered and now are formulated. Thinking of ways that we can get these into other cell types beyond the liver, which is where primarily, they've been able to be effective. And then also thinking of, likewise, viral delivery solutions that can get our genetic components into even broader set of cell types, such as the central nervous system.
ANDREW ANZALONE: So we're very much thinking about this and developing a full medicine, not just a gene editing system.
KEVIN DAVIES: I think one of my-- that's my closing question is to reference a recent op Ed that I'm sure you read in The New York Times from Theodore [INAUDIBLE] who was raising I think a very important-- some very important issues about the practical realities and the cost of turning these breakthrough technologies into affordable medicines. And I'm going to try and take this question away from Prime Medicine, because this is some way down the future. But I'm curious to just hear your personal thoughts, these therapies-- that some of the gene editing therapies and genetic therapies that have been recently approved are coming with really exorbitant price tags of $2 to $3 million in some cases.
KEVIN DAVIES: You went into-- you're a trained doctor, you went into medicine. How do you balance the need for these companies such as yours to get a return on their huge investments in developing these drugs with pricing them in a way that this can become a truly affordable therapy, not just for the wealthy in the United States, but for potentially millions of patients around the world? It's almost an existential question, but it's one that, I think, everybody in the industry is having to wrestle with.
ANDREW ANZALONE: Yeah. It really is. And it's an important question. As you mentioned, there are these therapies that could be developed for the Western world. And genetic diseases affect everybody and not in the same way. Obviously, these are inherited from family members in a large percentage of patients. So the certain regions of the world have their own sets of genetic mutations that you might have to fix.
ANDREW ANZALONE: So developing treatments for everybody, it's going to, I think, take a lot. And we're going to have to figure out ways to pay for it and make it accessible to folks. Now, in the near term, my personal view of this, which is not maybe the most sophisticated, is that that's going to require-- just based on the amount of investment and time that it takes to make one of these the first time, that's going to, potentially, require that the cost be proportional so that we can support the growth of this new therapeutic area.
ANDREW ANZALONE: My hope would be that over time, as we learn how to do this with more ease, with less upfront investment, with more of an ability to swap out a guide RNA, for example, and not have to do an entirely new clinical trial and be able to move from one patient in their mutation to another patient and their mutation with very minimal extra cost. I think as this, maybe, world comes into reality, I think the possibility of making these genetic systems for more folks at a very affordable price, it would make sense.
ANDREW ANZALONE: And I will also say, I can't tell you how many times I saw patients come into the hospital for the same problem over and over again because of their genetic disease. And from a cost standpoint, it might even make sense to treat that patient and prevent all of those recurrent costs and not to mention, the quality of their life that would be affected. And most importantly, how much of a benefit that would have to them.
ANDREW ANZALONE: So I think there's a good reason to invest here from my personal perspective. And like anything else, I would hope that costs can be minimized in the future so that this isn't a major restriction.
KEVIN DAVIES: Yeah. Well, Andrew. I just want to end on a personal note, I did my PhD in the 1980s with Bob Williamson at St. Mary's Hospital in London and during the heyday of the Gold Rush of mapping Mendelian disease genes before the Human Genome Project, so dating myself. And despite the early hopes of gene therapy, I don't even think it was science fiction to think that we might, one day, develop a technology to literally perform this single base chemistry on the genome.
KEVIN DAVIES: And I know prime editing isn't the first such technology. But it, certainly, would appear to have the most flexibility and promise. So congratulations on all of your success so far, and we hope that Prime Medicine continues to enjoy the momentum and can really make a difference in the clinic. Time will tell. But keeping our fingers crossed for you. Alex, over to you.
ALEX PHILIPPIDIS: Here. Thanks, Kevin. And thanks for joining us on Close to the Edge. Thanks, Andrew, thanks, Kevin. We'll have many more exciting interviews in the weeks and months ahead. For Kevin Davies, I'm Alex Philippidis. Take care, stay safe. [MUSIC PLAYING]
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