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The Future of CRISPR/Genome Editing
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The Future of CRISPR/Genome Editing
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Language: EN.
Segment:0 .
KEVIN DAVIES: Welcome, everyone, to this exciting session. We couldn't convene The State of Biotech this year without inviting two very distinguished guests to discuss the future of CRISPR and genome editing. Dr. Rachel Haurwitz is the founding chief executive officer of Caribou Biosciences, which is developing off the shelf cell therapies. She co-founded Caribou with her former PhD supervisor, one Jennifer Doudna, who some of you have heard of, no doubt, and Martin Jinek, a former colleague.
KEVIN DAVIES: And our other guests today is Professor Rodolphe Barrangou from North Carolina State University, one of the original heroes of CRISPR in that legendary infamous cell article from Eric Lander a few years back. Co-founder of Intellia, a little startup that we'll get to a little bit later on in our discussion. And most importantly, of course, Rodolphe, the chief editor of The CRISPR Journal. We can't leave that out.
KEVIN DAVIES: So anyway, welcome to you both. Thank you so much for making the time.
RACHEL HAURWITZ: Thanks, Kevin.
RODOLPHE BARRANGOU: Kevin, good to be here.
KEVIN DAVIES: Great. So let me begin. We're into the second decade of the CRISPR revolution, I guess. Second decade AD, After Doudna. I think Rodolphe, you might have even coined that at some point. I dimly remember that phrase. But the Nobel celebrations of 2020 have now thankfully died down. The documentary films have had their glitzy premieres. The books chronicling the CRISPR revolution have sadly, in my case, slipped off the New York Times best seller list.
KEVIN DAVIES: So that all prompts me to ask, where is the field of genome editing in 2023? Rachel, would you like to start?
RACHEL HAURWITZ: I'd be happy to, Kevin. Thank you. I think we're at an incredibly exciting moment in CRISPRland. As I look back over the past decade, a huge amount of that time I think was focused on energy and work to figure out what some of the potential promise of CRISPR genome editing could be. And it's extraordinary to me how quickly we've moved from great ideas on the whiteboard to meaningful experiments in the laboratory.
RACHEL HAURWITZ: And now, quite a number of very exciting, promising clinical trials ongoing around the globe. I hope in the not too distant future later this year, we might see from some of our colleagues the very first approval for a CRISPR-based medicine. And so I think, to come back to the concept of an inflection point, we're at a real inflection point of proving out some of these initial use cases and demonstrating where CRISPR can be truly meaningful for solving challenging problems for patients.
RACHEL HAURWITZ: I know we'll have the opportunity to talk about applications outside of human therapeutics too. I think we're at an important inflection point in some of that work as well. So I'd say we're reaching a point where we really need to see the proof in the pudding.
KEVIN DAVIES: Right. Rodolphe.
RODOLPHE BARRANGOU: I would concur across the board. Obviously, I think we're at the end of the beginning in many ways, right? What sounded like a crazy idea just 10 years ago is now a reality. We have tens of thousands of papers published by tens of thousands of authors showing that we can use that technology and deploy it to change cells precisely, and accurately, and efficiently. And now that we have a roll up our sleeves to advance the toolbox, we're going to have to use it and implement it in the real world for real problems, in real patients with therapeutics, in real crops for agriculture, in real trees for forestry, and beyond.
RODOLPHE BARRANGOU: And we are ushering in a very important critical decade of taking that technology out of what can we do with it to what will we do with it in the real world to tackle grand challenges with grand technologies that are ready for prime time right now.
KEVIN DAVIES: Well, I want to come-- I will come to what you're both doing with it in just a few minutes. But you mentioned the toolbox, Rodolphe. I'm glad you brought that up. Obviously, the CRISPR toolbox has expanded dramatically over the past decade from Cas9 to now a slew of enzymes, precision editing platforms. Epigenetic editing is having a moment. Transposases are part of the ever expanding toolbox.
KEVIN DAVIES: Do you see this trend continuing? And Rachel, is Caribou investing resources in building its own toolbox?
RACHEL HAURWITZ: Very much so. So Caribou has actually invented its own next generation CRISPR technology. We call it the Chardonnay Technology. What we've done is actually invent new guides. They're part DNA, part RNA. We call it the CRISPR hybrid RNA DNA technology. You'll see that's a mouthful. That's why we call it by its little acronym, Chardonnay.
KEVIN DAVIES: Very tasty, yes.
RACHEL HAURWITZ: Indeed. It turns out the inclusion of DNA in those guides dramatically improves the specificity of genome editing. We see that benefit both with the Cas9 enzyme, as well as the Cas12a enzyme. In fact, our lead program today, which is an off the shelf CAR T for non-Hodgkin lymphoma, we manufacture it using Cas9 Chardonnay. All of the other programs we're working on today use Cas12a Chardonnay.
RACHEL HAURWITZ: So we have very much focused on technology development. But I think it has to be done in a context of to solve what problem. Not every hammer hits every nail, or maybe not every problem is a nail that needs to be hit by a hammer. I'm not sure how best to use that metaphor. Suffice to say, we think really hard about, in our case, what is the disease? What is the therapy we are trying to develop ?
RACHEL HAURWITZ: And what is the underlying technology we need to achieve that kind of therapeutic functionality? As I look across the field, I hope many others are doing the same things. Looking across many different diseases, many different areas for product development in agriculture, research, industrial, biotechnology, and other spaces, and really thinking product backwards, and how do you find the right tool to create the product you most desire.
KEVIN DAVIES: Rodolphe, do we have a big enough toolbox now, or do you think this is going to continue to expand?
RODOLPHE BARRANGOU: Well, we have a great set of tools, but we're going to continue to sharpen them and make them a little bit better and tweak them. So I think-- again, first, there was Cas9. And then now there's many Cas9's. And there was Cas12, and now there's many Cas12's. We have Cas13's. We've rediscovered appetite for Cascade Cas3, which is where a lot of things started in the first place. Of course, we have the ancestors thereof.
RODOLPHE BARRANGOU: ICB, TnpB. Fanzor as of late. And then of course, we can functionalize some deactivated versions of those effectors with other things that enable us, them and us not just to change the genome but alter the transcriptome and the epigenome. So we have CRISPR A and CRISPR I. Turn things on or off or up or down.
RODOLPHE BARRANGOU: Or change the epigenetic state and acetylation and methylation state of DNA. And then now we see and we continue to see increased enhancement of chimeras infusions of some of those CRISPR-associated effectors with deaminases, transcriptases, polymerases, reverse transcriptases, integrases, transposons, and the like, right? So we have a fairly sophisticated toolbox. It's fairly complete as far as I'm concerned.
RODOLPHE BARRANGOU: But we can make them better. And to Rachel's point, the key is to use the right tool for the right job. If you want a Cas3 chainsaw as an antimicrobial, you want to do a lot of damage. You certainly don't want to use that in a patient to do precision medicine in an individualized genotype. So I think the rationale of building, expanding, and sharpening the toolbox is here to stay.
RODOLPHE BARRANGOU: We're going to keep making those tools better, skinnier, safer, more efficient, more precise, and also multiflexible, right? Sometimes, there's going to be instances where we want to do more than one thing at the same time, concurrently, and/or iteratively, and that's great. And a lot of scientists have very creative ways to combine some of those constructs and molecular machines. But in the end, in the real world, again, we want the best tools to be used in the best case scenarios for the most needed therapies for patients.
RODOLPHE BARRANGOU: And oftentimes, we're going to use some of the good old, original, basic elements but make them better. Customize them. Chardonnay is a great example of that. Make them more efficient. Make them more precise. And formulate them ideally, so we can get not just to proof of concept, but we can get to drugs that will be approved.
RODOLPHE BARRANGOU:
KEVIN DAVIES: Before we talk about where things are currently progressing in the clinic, I would just like to get your thoughts on the state of the biotech market and particularly, this sector. Rachel, you took Caribou public a couple of years ago. And the markets have really not been terribly accommodating to the gene editing sector. Not specifically your company. Just it seems as a whole, it's been pretty bleak.
KEVIN DAVIES: I wonder if you can share any thoughts on why you think, despite the progress that we'll be talking about in the clinic and the driving forces at the bench, why the markets have been so down on the genome editing companies such as yours that are really making progress?
RACHEL HAURWITZ: Kevin, it's a great question. And I would say the answer is very broad, right? I think there's little that is specific to our collective corner of the universe and much that has to do with the macroeconomic environment. Wind the clock back a few years ago, interest rates were incredibly low. And so high risk, high reward markets, biotech probably being at the top of that list, was an incredibly attractive place for a wide swath of investors.
RACHEL HAURWITZ: Well, fast forward to today. Interest rates are at a near time record high. And so I think the broader appetite for biotech for drug development just isn't there in the same way. There are fantastic, long term healthcare-dedicated investors who I think are in an excellent position today. Many of them are incredibly well capitalized, and they are able to have their pick of the lot in terms of companies, technology platforms, and management teams who they can get excited about and back for the long term.
RACHEL HAURWITZ: As I bring it to our little corner of the universe, I think again, actually, Kevin, coming back to your very first question, we are at a really critical moment where a lot of companies are going to be judged not by the lofty promise of their technology platforms but by genuinely what they are able to demonstrate in the clinic in terms of potential for patients. I'm certainly pleased that our team earlier this year was able to share some quite positive data from our ongoing phase 1 clinical trial for our lead program, which gave us the opportunity to raise additional capital to continue investing in our programs and our platform.
KEVIN DAVIES: Has being public, has that hampered you? Have you had to adjust the company's trajectory or growth from how you envisioned it maybe two or three years ago, to adjusting to the current economic climate at all?
RACHEL HAURWITZ: I wouldn't say that's necessarily specific to being a publicly traded company. I see going public as a tool in the toolbox for how to finance what are very capital-intensive activities. I think most companies find at some point, they've raised as much as they can at meaningful valuations as private companies and ultimately tap the public markets to achieve access to the quantum of capital it takes to really meaningfully drive clinical programs forward and hopefully get to the point of approval of one or multiple therapies.
RACHEL HAURWITZ: Certainly, I think we have to constantly balance our capacity to fundraise, to capitalize the organization with what are the milestones we're trying to achieve, right? And so I think every company, private or public, is wrestling with the same need. To really map out what the path forward looks like for a technology platform, or more specifically, for given therapeutic programs. And then truly understanding what is the capital runway that you need to achieve key milestones that could then lead to the opportunity to raise additional capital to achieve future milestones.
KEVIN DAVIES: Rodolphe, what's your take?
RODOLPHE BARRANGOU: Yeah. So if you look back, and we look where we are now, and we look at the future. And again, I would concur fully, wholeheartedly with Rachel's assessment of the financial context over time in these dynamics, for sure. So that being said, I think it's management of risk and reward. And oftentimes, early on, people just looked at rewards, rewards, rewards, rewards at upside, right?
RODOLPHE BARRANGOU: And some of those evaluations were very colorful. The enthusiasm was real. There was hype. There was excitement. It was tangible, but it was promised, right? And I think as time went by, people understood the risk, some of the practical challenges inherent to turning what sounded like a crazy idea into a medicine, right?
RODOLPHE BARRANGOU: It takes time. It takes effort. It takes capital, and it takes patience. And I think people realize some of the timelines early on of translating CRISPR molecular tools into therapies sounded good, sounded feasible, sounded achievable. But some of those timelines were a little bit unrealistic or maybe a little bit aggressive. And there were some overpromising, and to some extent, some systemic underdelivery.
RODOLPHE BARRANGOU: But now, we find ourselves in a situation where critical milestones have been reached in the clinic by multiple people, multiple companies, in multiple indications, in multiple groups of patients with multiple diseases. And the path forward is clear. As a matter of fact, I would say the paths forward for different types of diseases, different types of dosages, different types of modalities of delivery, different types of targets, different types of patient populations are real, and investors are in a very enticing position right now, to Rachel's point, to place their bets in the second round of investments, in the second decade of genome editing that is CRISPR-fueled as we see it and as it beckons.
RODOLPHE BARRANGOU: And I think there's even more potential and less risk today than there was 10 years ago. So personally, I like the upside as we currently stand right now. We've made great progress. We've reached great milestones. We've derisked the technology in the clinic to a serious extent. But we also have a long ways to go. And now it becomes real.
RODOLPHE BARRANGOU: We're not just talking about phase 1. We're talking about phase 2. And before we know it, we're going to be talking about phase 3. So I think that reality in space and time and the financial rewards that come with it is more real in 2023 than it was in 2013.
KEVIN DAVIES: Well, speaking of milestones, Rachel, there's a big one I think looming in December of this year when the Vertex CRISPR Therapeutics exa-cel trial for sickle cell comes up for review at the FDA. How important is that potential-- I don't want to jinx it. But how important is that potential approval, not just for the sickle cell patients who've been so neglected for so long, but for the gene editing cell therapy field as a whole?
RACHEL HAURWITZ: I mean, I think it's incredibly exciting to be here 11 years after that initial science paper and to be talking about the anticipated first approval of a CRISPR-based medicine. I think we have to give tremendous credit to many colleagues in other fields who have facilitated this, right? There's so much work that was done by gene therapy, cell therapy, RNAI, LNP pioneers that has been co-opted, borrowed, used in the CRISPR field to allow some of these trials or programs that exist today to have been developed on incredibly rapid timelines.
RACHEL HAURWITZ: So as I look specifically at that PDUFA date later this year, I think it's really exciting for the field to see this turn from great idea on the whiteboard, to great clinical data, to hopefully first approved medicine. And maybe, Kevin I'll look a further five to 10 years in the future. I personally believe that we are on the cusp of a world where patients have access to three fundamental modalities of medicines.
RACHEL HAURWITZ: Today, it's really there are two legs to that stool, right? Small molecule medicines and antibodies or other recombinant proteins. I believe we're very close to the third leg of the stool, which I'll call genetic medicines writ large. And I think CRISPR is absolutely at the vanguard of that to unlock quite a number of these different kinds of therapeutic approaches for patients.
KEVIN DAVIES: Yeah. Rodolphe, how important is that December date and verdict do you think?
RODOLPHE BARRANGOU: I think it's very important. So firstly, it does take a village, let's just be honest here. I mean, the CRISPR community by and large has certainly done its job, but it's also building and expanding on and sometimes repurposing earlier effort by armies of people. And the scientific collective at its best arguably of iterating and combining different ingredients, different modalities, different technologies, and different versions thereof over time to culminate to a combination that is a masterpiece.
RODOLPHE BARRANGOU: So I think we are at a very promising and exciting point in time right now. But it's not just CRISPR. CRISPR has enabled it, accelerated it, fueled it to some extent, and hopefully will democratize it in due time. But we are at a very important point in time. That being said, we need the FDA to get it right. So to me, it's not just about approval or non-approval, green light and thumbs up per se.
RODOLPHE BARRANGOU: I think there is so much at stake that we have to have the wisdom. We have to have the patience. We have to have the fortitude to ensure that to the best of our knowledge, collectively, we do justice to the technology that lies before us. And that's why maybe to some extent, some people think the FDA has been a little bit slow, a little bit overly cautious.
RODOLPHE BARRANGOU: I'm not going to say paranoid because it'd be out of line. But there's been some careful considerations in play, and lots of discussions, and lots of education, and lots of interactions, lots of dialogue exactly because we have to collectively get it right and ensure we do justice to the technology. So I see that question of when rather than if we're going to get there as the right question and the right answer.
RODOLPHE BARRANGOU: And I have the utmost confidence in our ability and the ability of the FDA. Sometimes more D than we need F, but we'll get to that later. The FDA to make the right call. And endorse confidently technologies and therapies that will be successful in the clinic for large patient populations because we know they can do things in smaller patient cohorts right now. And we have to get it right more than they have to get it soon as far as I'm concerned.
KEVIN DAVIES: Right. Well, Rachel, you're not quite at that stage yet, but your team is working towards that goal. How is Caribou's own journey into the clinic progressing, and are you laser focused on immunotherapy as the central goal field of the company, or are you still considering opportunities to potentially diversify into other types of therapy as well?
RACHEL HAURWITZ: Yeah. So several years ago, we really pivoted our business model into human therapeutic product development and laser-focused on off the shelf cell therapies for a variety of oncology indications. As we're now starting to get our feet underneath us, and I look forward to sharing a little bit about those programs, I hope we reach a point where we can start to think about deploying these technologies for additional therapeutic applications.
RACHEL HAURWITZ: There are so many potential uses for off the shelf cell therapies not only much more broadly in oncology than where we are today but outside of oncology, thinking about immunology and other spaces. And of course, the other side of the coin is to take some of these technologies and deliver them directly in vivo to patients. We have a technology platform, the Chardonnay Technology that, as I mentioned, is really quite specific and I think could be quite compelling in terms of some of these in vivo applications where specificity is incredibly important given the likely permanent nature of the changes that you can make inside a patient's body.
RACHEL HAURWITZ: So today, our energy and effort is focused on our wholly owned pipeline of off the shelf cell therapies. We're working on off the shelf CAR T's with a focus on blood cancers and off the shelf CAR and Cas with a focus on solid tumors. Our first two programs, both off the shelf CAR T's, are in the clinic today in ongoing phase 1 trials. And our third program is on track for an IND later this year.
RACHEL HAURWITZ: So for us, quite a lot of excitement as we continue to translate these great research ideas into the clinic. Not that long ago, we shared positive data from the dose escalation portion of our ongoing phase 1 trial for the lead program. The trial is called ANTLER in true Caribou fashion, and it's evaluating CB-010, which is an off the shelf CAR T for non-Hodgkin lymphoma.
RACHEL HAURWITZ: What we wanted to do was provide an update that had enough patients to tell us something meaningful about CB-010's activity. And perhaps even more importantly, enough followup on those patients to really understand how durable the response that this could be driven by CB-010. And so we were so excited to see that CB-010 can drive meaningfully durable responses that really rival those of the autologous CAR Ts.
RACHEL HAURWITZ: Very exciting to see these data. I think it throws more fuel on the fire and certainly creates enhanced urgency for us internally as we continue to expeditiously move this program forward, as well as the rest of our pipeline.
KEVIN DAVIES: Excellent. That was a fantastic update. Thank you so much. Another critical aspect of genome editing, it's been the subject of editorials and many talks, is the delivery question. Rodolphe, one of the many companies that you're intimately familiar with, Intellia, is of course one of the pioneers of in vivo genome editing using lipid nanoparticles.
KEVIN DAVIES: Can you bring us up to speed on the significance of this as a delivery vehicle, and are you excited by other types of non-viral delivery systems that might be in development?
RODOLPHE BARRANGOU: I mean, absolutely. So to Rachel's point, ex vivo therapies can do a lot for a lot of patients, a lot of diseases with large numbers and large markets that are addressable. So that's fantastic and exciting. And it's becoming a reality every day. But I think there's a lot of excitement and potential for in vivo delivery of CRISPR-based medicines and gene therapies.
RODOLPHE BARRANGOU: And the landmark study published a couple of years ago in the New England Journal of Medicine by Intellia, and colleagues, and others speaks volumes, right? Being able to do it in patients with the safety, the efficacy, the longevity, and the lowering of TGR challenges to the extent that they did was a milestone, you know? And a clinical milestone and a proof of concept that really got a lot of people excited for the right reasons. Delivery is sometimes the hard part, right?
RODOLPHE BARRANGOU: That's where LNPs, DNA-free versions of genome editing. Going to the liver, of course, is easier. Going to the blood is easier. Injecting to the muscle sometimes easier. Injecting to an eye for retinal disease is a practical delivery modality that people can use on an ongoing basis that's unknown. And of course, the advent and the development of RNA-based technologies, and the advances that we have with Moderna and others, and some of the Moderna founders or founders of Intellia as well for full disclosure here, opens up a whole new set of avenues for in-vivo delivery of DNA-free gene therapies that will alter our DNA.
RODOLPHE BARRANGOU: So I think that's exciting. It's ushering in a new era of medicines per se. Very promising modalities. And they don't just have to work. They have to be affordable. They don't just have to be affordable. They have to be scalable. So at a time of individualized medicine, affordable health care, scalable health care, and individualized health care, those are modalities that are going to enable MDs to those patients and address diseases in ways that are important not just now but for the future.
RODOLPHE BARRANGOU: And the affordability of RNA is not today where we would like it to be ideally. But scaling up the operation, scaling down the cost is important. Scaling down the dose is important as well, and that's important. Another item of interest I think that is technically very important is the longevity and durability of the editing. So being able to show that it works is one thing.
RODOLPHE BARRANGOU: Being able to show that it works in a cohort of patients for more than one disease is great. But being able to establish unequivocally that even with those lower dose modalities, we can edit DNA and enough cells in enough masses, enough level to have a sustainable over time, a reduction of clinical symptoms is very important. And I think that milestone sometimes has been missed by some people and is very important because it sets the stage for managing the doses and not just the first installment or the first therapy and the first cohort of patients, but having more practical set of drugs that we can implement in patients with durability, and the affordability that comes with it, and the clinical benefits that come with it.
RODOLPHE BARRANGOU: So I think, again, we have a few technical enhancements and advances that we have to make to manage the dosage. How much RNA do we deliver? How much LNP do we deliver? How many doses do we need to deliver? And what are the targets that we need to achieve? But we're getting there. The milestone study from two years ago was great, and there's more to come.
KEVIN DAVIES: Rachel, we were just talking off air before we started this session about the recent meeting at Cold Spring Harbor where Fyodor Urnov gave the keynote. I know you were too busy to watch it. But you're familiar with these arguments because they're all, its subject du jour at your former home at IGI, the Innovative Genomics Institute, and Jennifer and the team there. Similar themes that he expressed in an op ed in the New York Times several months ago.
KEVIN DAVIES: The unrealized or potentially unrealized promise of CRISPR if we don't really make some important fixes to the regulatory structure that would allow simple tweaks to guide RNAs to be more platformed and readily applied to potentially hundreds or thousands of genetic diseases and shorten the time frame to get these things into the clinic and potentially to the approval stage.
KEVIN DAVIES: Is that something you think about a lot? Do you feel there's important work that needs a bigger voice to help the community at large?
RACHEL HAURWITZ: Yeah. Thank you for that question. I'll take an opportunity to highlight that what we get to do at Caribou today using our CRISPR technology to make off the shelf versions of CAR T's I think is a really important way of trying to broaden the number of patients who can have access to these therapies, right? Today's approved CAR T's, so-called autologous CAR T's, they are patient-specific.
RACHEL HAURWITZ: It is an n of 1 strategy. So for a patient to receive that product, they actually have to go to a clinic, have quite a lot of their blood removed. It gets shipped to a laboratory. Product is manufactured. They ultimately get one dose of their therapy. And hopefully, it is impactful for them, and it is for some patients.
RACHEL HAURWITZ: That doesn't scale particularly well, right? That n of 1 strategy. And so that's really motivated why we are doing what we're doing. Using genome editing to turn this into an off the shelf approach, where we can manufacture products with healthy donor material instead of the patient's own T cells. And that means, one, manufacturing run results in dozens of doses instead of one dose.
RACHEL HAURWITZ: And so I think this is a great example of where CRISPR genome editing is unlocking some of the scale that Rodolphe just highlighted.
KEVIN DAVIES: Yeah.
RACHEL HAURWITZ: I'll also note the FDA is learning right along with the rest of us, right? And I have to say at least our experience has been incredibly positive. We have had the opportunity to engage with them now across multiple programs in our pipeline. And we can certainly see that they are learning a tremendous amount from the many sponsors who they work with who are developing similar, sometimes different approaches using genome editing in the cell therapy space.
RACHEL HAURWITZ: And I think that's great. And no doubt, some of these learnings are going to impact broadly how they approach some of these different regulatory questions. Caribou today is not living in the world that think Fyodor has described in some of these discussions of trying to develop n of 1 or end of small strategies. In fact, we're almost intentionally on the other side of that equation right now, where they're n of many.
RACHEL HAURWITZ: I love the challenge that he has posed to the field of how do we use some of these reagents in an n of 1 or n of small way. And clearly, the field has some work to do there.
KEVIN DAVIES: Yeah. Rodolphe, that journal proudly hanging behind you, does it not have a special issue on this theme coming out to be announced?
RODOLPHE BARRANGOU: We sure do indeed. So as we know, there's a lot of things we can do with CRISPR. But evidently, CRISPR trials is going to be the name of our forthcoming 2024 themed issue on updates on clinical trials and where CRISPR is going to the clinic, how fast and how far it's getting into the clinic. Absolutely. And to add one point to the question you just asked Rachel about Fyodor and the IGI and the aspirational pursuit of accessible medicines.
RODOLPHE BARRANGOU: I think part of Fyodor's focus is also on orphan diseases. And if we keep a bar that's unreasonably high for orphan diseases that cannot afford to do a lot of research, that cannot afford to do a lot of scalability, that cannot afford to do a lot of studies, I think that the challenge posed is how are we going to address those patient populations? Ab n of 1's or n of few as opposed to an end of many. And we're compelled to find creative ways, safe ways, responsible ways, affordable ways to target all those patient populations.
RODOLPHE BARRANGOU: And it'd be unfortunate if not tragic if we were unable to deploy the most promising technologies for patients that need them. So I think that balancing act, if I dare put my own spin on it, is a challenge. And again, to Rachel's point, we're collectively working on it. And FDA is receptive, is engaging in the dialogue. And we're all learning together of how the next chapter, how's the next process, how's the next approval pipeline, how's the next framework under which we can grandfather some of the approaches in or not, what gets changed, what gets tweaked when you formulate those drugs.
RODOLPHE BARRANGOU: And what can we build off of in the dossier that's already been pre-established and pre-approved, as opposed to something that's new and it's a different drug? What is a different drug? What is not a different drug? And how does a new guide fit into the technicality of approving something that's a new formulation? So I think those are challenges. Those are technical details that are very important that have to be figured out.
RODOLPHE BARRANGOU: And collectively, we need to wrap our minds, and our heads, and our creative thoughts around that to address what Fyodor and IGI and others are bringing up.
KEVIN DAVIES: Yeah. That's a fantastic note to end on. It's been a really enjoyable conversation. Thanks so much to Rachel Haurwitz from Caribou, Rodolphe Barrangou from North Carolina State University and the CRISPR Journal. And we look forward to moving on to the next session. Thank you both very much.
RACHEL HAURWITZ: Thanks, Kevin. Appreciate it.
RODOLPHE BARRANGOU: Thank you, Kevin.
Segment:0 .
KEVIN DAVIES: Welcome, everyone, to this exciting session. We couldn't convene The State of Biotech this year without inviting two very distinguished guests to discuss the future of CRISPR and genome editing. Dr. Rachel Haurwitz is the founding chief executive officer of Caribou Biosciences, which is developing off the shelf cell therapies. She co-founded Caribou with her former PhD supervisor, one Jennifer Doudna, who some of you have heard of, no doubt, and Martin Jinek, a former colleague.
KEVIN DAVIES: And our other guests today is Professor Rodolphe Barrangou from North Carolina State University, one of the original heroes of CRISPR in that legendary infamous cell article from Eric Lander a few years back. Co-founder of Intellia, a little startup that we'll get to a little bit later on in our discussion. And most importantly, of course, Rodolphe, the chief editor of The CRISPR Journal. We can't leave that out.
KEVIN DAVIES: So anyway, welcome to you both. Thank you so much for making the time.
RACHEL HAURWITZ: Thanks, Kevin.
RODOLPHE BARRANGOU: Kevin, good to be here.
KEVIN DAVIES: Great. So let me begin. We're into the second decade of the CRISPR revolution, I guess. Second decade AD, After Doudna. I think Rodolphe, you might have even coined that at some point. I dimly remember that phrase. But the Nobel celebrations of 2020 have now thankfully died down. The documentary films have had their glitzy premieres. The books chronicling the CRISPR revolution have sadly, in my case, slipped off the New York Times best seller list.
KEVIN DAVIES: So that all prompts me to ask, where is the field of genome editing in 2023? Rachel, would you like to start?
RACHEL HAURWITZ: I'd be happy to, Kevin. Thank you. I think we're at an incredibly exciting moment in CRISPRland. As I look back over the past decade, a huge amount of that time I think was focused on energy and work to figure out what some of the potential promise of CRISPR genome editing could be. And it's extraordinary to me how quickly we've moved from great ideas on the whiteboard to meaningful experiments in the laboratory.
RACHEL HAURWITZ: And now, quite a number of very exciting, promising clinical trials ongoing around the globe. I hope in the not too distant future later this year, we might see from some of our colleagues the very first approval for a CRISPR-based medicine. And so I think, to come back to the concept of an inflection point, we're at a real inflection point of proving out some of these initial use cases and demonstrating where CRISPR can be truly meaningful for solving challenging problems for patients.
RACHEL HAURWITZ: I know we'll have the opportunity to talk about applications outside of human therapeutics too. I think we're at an important inflection point in some of that work as well. So I'd say we're reaching a point where we really need to see the proof in the pudding.
KEVIN DAVIES: Right. Rodolphe.
RODOLPHE BARRANGOU: I would concur across the board. Obviously, I think we're at the end of the beginning in many ways, right? What sounded like a crazy idea just 10 years ago is now a reality. We have tens of thousands of papers published by tens of thousands of authors showing that we can use that technology and deploy it to change cells precisely, and accurately, and efficiently. And now that we have a roll up our sleeves to advance the toolbox, we're going to have to use it and implement it in the real world for real problems, in real patients with therapeutics, in real crops for agriculture, in real trees for forestry, and beyond.
RODOLPHE BARRANGOU: And we are ushering in a very important critical decade of taking that technology out of what can we do with it to what will we do with it in the real world to tackle grand challenges with grand technologies that are ready for prime time right now.
KEVIN DAVIES: Well, I want to come-- I will come to what you're both doing with it in just a few minutes. But you mentioned the toolbox, Rodolphe. I'm glad you brought that up. Obviously, the CRISPR toolbox has expanded dramatically over the past decade from Cas9 to now a slew of enzymes, precision editing platforms. Epigenetic editing is having a moment. Transposases are part of the ever expanding toolbox.
KEVIN DAVIES: Do you see this trend continuing? And Rachel, is Caribou investing resources in building its own toolbox?
RACHEL HAURWITZ: Very much so. So Caribou has actually invented its own next generation CRISPR technology. We call it the Chardonnay Technology. What we've done is actually invent new guides. They're part DNA, part RNA. We call it the CRISPR hybrid RNA DNA technology. You'll see that's a mouthful. That's why we call it by its little acronym, Chardonnay.
KEVIN DAVIES: Very tasty, yes.
RACHEL HAURWITZ: Indeed. It turns out the inclusion of DNA in those guides dramatically improves the specificity of genome editing. We see that benefit both with the Cas9 enzyme, as well as the Cas12a enzyme. In fact, our lead program today, which is an off the shelf CAR T for non-Hodgkin lymphoma, we manufacture it using Cas9 Chardonnay. All of the other programs we're working on today use Cas12a Chardonnay.
RACHEL HAURWITZ: So we have very much focused on technology development. But I think it has to be done in a context of to solve what problem. Not every hammer hits every nail, or maybe not every problem is a nail that needs to be hit by a hammer. I'm not sure how best to use that metaphor. Suffice to say, we think really hard about, in our case, what is the disease? What is the therapy we are trying to develop ?
RACHEL HAURWITZ: And what is the underlying technology we need to achieve that kind of therapeutic functionality? As I look across the field, I hope many others are doing the same things. Looking across many different diseases, many different areas for product development in agriculture, research, industrial, biotechnology, and other spaces, and really thinking product backwards, and how do you find the right tool to create the product you most desire.
KEVIN DAVIES: Rodolphe, do we have a big enough toolbox now, or do you think this is going to continue to expand?
RODOLPHE BARRANGOU: Well, we have a great set of tools, but we're going to continue to sharpen them and make them a little bit better and tweak them. So I think-- again, first, there was Cas9. And then now there's many Cas9's. And there was Cas12, and now there's many Cas12's. We have Cas13's. We've rediscovered appetite for Cascade Cas3, which is where a lot of things started in the first place. Of course, we have the ancestors thereof.
RODOLPHE BARRANGOU: ICB, TnpB. Fanzor as of late. And then of course, we can functionalize some deactivated versions of those effectors with other things that enable us, them and us not just to change the genome but alter the transcriptome and the epigenome. So we have CRISPR A and CRISPR I. Turn things on or off or up or down.
RODOLPHE BARRANGOU: Or change the epigenetic state and acetylation and methylation state of DNA. And then now we see and we continue to see increased enhancement of chimeras infusions of some of those CRISPR-associated effectors with deaminases, transcriptases, polymerases, reverse transcriptases, integrases, transposons, and the like, right? So we have a fairly sophisticated toolbox. It's fairly complete as far as I'm concerned.
RODOLPHE BARRANGOU: But we can make them better. And to Rachel's point, the key is to use the right tool for the right job. If you want a Cas3 chainsaw as an antimicrobial, you want to do a lot of damage. You certainly don't want to use that in a patient to do precision medicine in an individualized genotype. So I think the rationale of building, expanding, and sharpening the toolbox is here to stay.
RODOLPHE BARRANGOU: We're going to keep making those tools better, skinnier, safer, more efficient, more precise, and also multiflexible, right? Sometimes, there's going to be instances where we want to do more than one thing at the same time, concurrently, and/or iteratively, and that's great. And a lot of scientists have very creative ways to combine some of those constructs and molecular machines. But in the end, in the real world, again, we want the best tools to be used in the best case scenarios for the most needed therapies for patients.
RODOLPHE BARRANGOU: And oftentimes, we're going to use some of the good old, original, basic elements but make them better. Customize them. Chardonnay is a great example of that. Make them more efficient. Make them more precise. And formulate them ideally, so we can get not just to proof of concept, but we can get to drugs that will be approved.
RODOLPHE BARRANGOU:
KEVIN DAVIES: Before we talk about where things are currently progressing in the clinic, I would just like to get your thoughts on the state of the biotech market and particularly, this sector. Rachel, you took Caribou public a couple of years ago. And the markets have really not been terribly accommodating to the gene editing sector. Not specifically your company. Just it seems as a whole, it's been pretty bleak.
KEVIN DAVIES: I wonder if you can share any thoughts on why you think, despite the progress that we'll be talking about in the clinic and the driving forces at the bench, why the markets have been so down on the genome editing companies such as yours that are really making progress?
RACHEL HAURWITZ: Kevin, it's a great question. And I would say the answer is very broad, right? I think there's little that is specific to our collective corner of the universe and much that has to do with the macroeconomic environment. Wind the clock back a few years ago, interest rates were incredibly low. And so high risk, high reward markets, biotech probably being at the top of that list, was an incredibly attractive place for a wide swath of investors.
RACHEL HAURWITZ: Well, fast forward to today. Interest rates are at a near time record high. And so I think the broader appetite for biotech for drug development just isn't there in the same way. There are fantastic, long term healthcare-dedicated investors who I think are in an excellent position today. Many of them are incredibly well capitalized, and they are able to have their pick of the lot in terms of companies, technology platforms, and management teams who they can get excited about and back for the long term.
RACHEL HAURWITZ: As I bring it to our little corner of the universe, I think again, actually, Kevin, coming back to your very first question, we are at a really critical moment where a lot of companies are going to be judged not by the lofty promise of their technology platforms but by genuinely what they are able to demonstrate in the clinic in terms of potential for patients. I'm certainly pleased that our team earlier this year was able to share some quite positive data from our ongoing phase 1 clinical trial for our lead program, which gave us the opportunity to raise additional capital to continue investing in our programs and our platform.
KEVIN DAVIES: Has being public, has that hampered you? Have you had to adjust the company's trajectory or growth from how you envisioned it maybe two or three years ago, to adjusting to the current economic climate at all?
RACHEL HAURWITZ: I wouldn't say that's necessarily specific to being a publicly traded company. I see going public as a tool in the toolbox for how to finance what are very capital-intensive activities. I think most companies find at some point, they've raised as much as they can at meaningful valuations as private companies and ultimately tap the public markets to achieve access to the quantum of capital it takes to really meaningfully drive clinical programs forward and hopefully get to the point of approval of one or multiple therapies.
RACHEL HAURWITZ: Certainly, I think we have to constantly balance our capacity to fundraise, to capitalize the organization with what are the milestones we're trying to achieve, right? And so I think every company, private or public, is wrestling with the same need. To really map out what the path forward looks like for a technology platform, or more specifically, for given therapeutic programs. And then truly understanding what is the capital runway that you need to achieve key milestones that could then lead to the opportunity to raise additional capital to achieve future milestones.
KEVIN DAVIES: Rodolphe, what's your take?
RODOLPHE BARRANGOU: Yeah. So if you look back, and we look where we are now, and we look at the future. And again, I would concur fully, wholeheartedly with Rachel's assessment of the financial context over time in these dynamics, for sure. So that being said, I think it's management of risk and reward. And oftentimes, early on, people just looked at rewards, rewards, rewards, rewards at upside, right?
RODOLPHE BARRANGOU: And some of those evaluations were very colorful. The enthusiasm was real. There was hype. There was excitement. It was tangible, but it was promised, right? And I think as time went by, people understood the risk, some of the practical challenges inherent to turning what sounded like a crazy idea into a medicine, right?
RODOLPHE BARRANGOU: It takes time. It takes effort. It takes capital, and it takes patience. And I think people realize some of the timelines early on of translating CRISPR molecular tools into therapies sounded good, sounded feasible, sounded achievable. But some of those timelines were a little bit unrealistic or maybe a little bit aggressive. And there were some overpromising, and to some extent, some systemic underdelivery.
RODOLPHE BARRANGOU: But now, we find ourselves in a situation where critical milestones have been reached in the clinic by multiple people, multiple companies, in multiple indications, in multiple groups of patients with multiple diseases. And the path forward is clear. As a matter of fact, I would say the paths forward for different types of diseases, different types of dosages, different types of modalities of delivery, different types of targets, different types of patient populations are real, and investors are in a very enticing position right now, to Rachel's point, to place their bets in the second round of investments, in the second decade of genome editing that is CRISPR-fueled as we see it and as it beckons.
RODOLPHE BARRANGOU: And I think there's even more potential and less risk today than there was 10 years ago. So personally, I like the upside as we currently stand right now. We've made great progress. We've reached great milestones. We've derisked the technology in the clinic to a serious extent. But we also have a long ways to go. And now it becomes real.
RODOLPHE BARRANGOU: We're not just talking about phase 1. We're talking about phase 2. And before we know it, we're going to be talking about phase 3. So I think that reality in space and time and the financial rewards that come with it is more real in 2023 than it was in 2013.
KEVIN DAVIES: Well, speaking of milestones, Rachel, there's a big one I think looming in December of this year when the Vertex CRISPR Therapeutics exa-cel trial for sickle cell comes up for review at the FDA. How important is that potential-- I don't want to jinx it. But how important is that potential approval, not just for the sickle cell patients who've been so neglected for so long, but for the gene editing cell therapy field as a whole?
RACHEL HAURWITZ: I mean, I think it's incredibly exciting to be here 11 years after that initial science paper and to be talking about the anticipated first approval of a CRISPR-based medicine. I think we have to give tremendous credit to many colleagues in other fields who have facilitated this, right? There's so much work that was done by gene therapy, cell therapy, RNAI, LNP pioneers that has been co-opted, borrowed, used in the CRISPR field to allow some of these trials or programs that exist today to have been developed on incredibly rapid timelines.
RACHEL HAURWITZ: So as I look specifically at that PDUFA date later this year, I think it's really exciting for the field to see this turn from great idea on the whiteboard, to great clinical data, to hopefully first approved medicine. And maybe, Kevin I'll look a further five to 10 years in the future. I personally believe that we are on the cusp of a world where patients have access to three fundamental modalities of medicines.
RACHEL HAURWITZ: Today, it's really there are two legs to that stool, right? Small molecule medicines and antibodies or other recombinant proteins. I believe we're very close to the third leg of the stool, which I'll call genetic medicines writ large. And I think CRISPR is absolutely at the vanguard of that to unlock quite a number of these different kinds of therapeutic approaches for patients.
KEVIN DAVIES: Yeah. Rodolphe, how important is that December date and verdict do you think?
RODOLPHE BARRANGOU: I think it's very important. So firstly, it does take a village, let's just be honest here. I mean, the CRISPR community by and large has certainly done its job, but it's also building and expanding on and sometimes repurposing earlier effort by armies of people. And the scientific collective at its best arguably of iterating and combining different ingredients, different modalities, different technologies, and different versions thereof over time to culminate to a combination that is a masterpiece.
RODOLPHE BARRANGOU: So I think we are at a very promising and exciting point in time right now. But it's not just CRISPR. CRISPR has enabled it, accelerated it, fueled it to some extent, and hopefully will democratize it in due time. But we are at a very important point in time. That being said, we need the FDA to get it right. So to me, it's not just about approval or non-approval, green light and thumbs up per se.
RODOLPHE BARRANGOU: I think there is so much at stake that we have to have the wisdom. We have to have the patience. We have to have the fortitude to ensure that to the best of our knowledge, collectively, we do justice to the technology that lies before us. And that's why maybe to some extent, some people think the FDA has been a little bit slow, a little bit overly cautious.
RODOLPHE BARRANGOU: I'm not going to say paranoid because it'd be out of line. But there's been some careful considerations in play, and lots of discussions, and lots of education, and lots of interactions, lots of dialogue exactly because we have to collectively get it right and ensure we do justice to the technology. So I see that question of when rather than if we're going to get there as the right question and the right answer.
RODOLPHE BARRANGOU: And I have the utmost confidence in our ability and the ability of the FDA. Sometimes more D than we need F, but we'll get to that later. The FDA to make the right call. And endorse confidently technologies and therapies that will be successful in the clinic for large patient populations because we know they can do things in smaller patient cohorts right now. And we have to get it right more than they have to get it soon as far as I'm concerned.
KEVIN DAVIES: Right. Well, Rachel, you're not quite at that stage yet, but your team is working towards that goal. How is Caribou's own journey into the clinic progressing, and are you laser focused on immunotherapy as the central goal field of the company, or are you still considering opportunities to potentially diversify into other types of therapy as well?
RACHEL HAURWITZ: Yeah. So several years ago, we really pivoted our business model into human therapeutic product development and laser-focused on off the shelf cell therapies for a variety of oncology indications. As we're now starting to get our feet underneath us, and I look forward to sharing a little bit about those programs, I hope we reach a point where we can start to think about deploying these technologies for additional therapeutic applications.
RACHEL HAURWITZ: There are so many potential uses for off the shelf cell therapies not only much more broadly in oncology than where we are today but outside of oncology, thinking about immunology and other spaces. And of course, the other side of the coin is to take some of these technologies and deliver them directly in vivo to patients. We have a technology platform, the Chardonnay Technology that, as I mentioned, is really quite specific and I think could be quite compelling in terms of some of these in vivo applications where specificity is incredibly important given the likely permanent nature of the changes that you can make inside a patient's body.
RACHEL HAURWITZ: So today, our energy and effort is focused on our wholly owned pipeline of off the shelf cell therapies. We're working on off the shelf CAR T's with a focus on blood cancers and off the shelf CAR and Cas with a focus on solid tumors. Our first two programs, both off the shelf CAR T's, are in the clinic today in ongoing phase 1 trials. And our third program is on track for an IND later this year.
RACHEL HAURWITZ: So for us, quite a lot of excitement as we continue to translate these great research ideas into the clinic. Not that long ago, we shared positive data from the dose escalation portion of our ongoing phase 1 trial for the lead program. The trial is called ANTLER in true Caribou fashion, and it's evaluating CB-010, which is an off the shelf CAR T for non-Hodgkin lymphoma.
RACHEL HAURWITZ: What we wanted to do was provide an update that had enough patients to tell us something meaningful about CB-010's activity. And perhaps even more importantly, enough followup on those patients to really understand how durable the response that this could be driven by CB-010. And so we were so excited to see that CB-010 can drive meaningfully durable responses that really rival those of the autologous CAR Ts.
RACHEL HAURWITZ: Very exciting to see these data. I think it throws more fuel on the fire and certainly creates enhanced urgency for us internally as we continue to expeditiously move this program forward, as well as the rest of our pipeline.
KEVIN DAVIES: Excellent. That was a fantastic update. Thank you so much. Another critical aspect of genome editing, it's been the subject of editorials and many talks, is the delivery question. Rodolphe, one of the many companies that you're intimately familiar with, Intellia, is of course one of the pioneers of in vivo genome editing using lipid nanoparticles.
KEVIN DAVIES: Can you bring us up to speed on the significance of this as a delivery vehicle, and are you excited by other types of non-viral delivery systems that might be in development?
RODOLPHE BARRANGOU: I mean, absolutely. So to Rachel's point, ex vivo therapies can do a lot for a lot of patients, a lot of diseases with large numbers and large markets that are addressable. So that's fantastic and exciting. And it's becoming a reality every day. But I think there's a lot of excitement and potential for in vivo delivery of CRISPR-based medicines and gene therapies.
RODOLPHE BARRANGOU: And the landmark study published a couple of years ago in the New England Journal of Medicine by Intellia, and colleagues, and others speaks volumes, right? Being able to do it in patients with the safety, the efficacy, the longevity, and the lowering of TGR challenges to the extent that they did was a milestone, you know? And a clinical milestone and a proof of concept that really got a lot of people excited for the right reasons. Delivery is sometimes the hard part, right?
RODOLPHE BARRANGOU: That's where LNPs, DNA-free versions of genome editing. Going to the liver, of course, is easier. Going to the blood is easier. Injecting to the muscle sometimes easier. Injecting to an eye for retinal disease is a practical delivery modality that people can use on an ongoing basis that's unknown. And of course, the advent and the development of RNA-based technologies, and the advances that we have with Moderna and others, and some of the Moderna founders or founders of Intellia as well for full disclosure here, opens up a whole new set of avenues for in-vivo delivery of DNA-free gene therapies that will alter our DNA.
RODOLPHE BARRANGOU: So I think that's exciting. It's ushering in a new era of medicines per se. Very promising modalities. And they don't just have to work. They have to be affordable. They don't just have to be affordable. They have to be scalable. So at a time of individualized medicine, affordable health care, scalable health care, and individualized health care, those are modalities that are going to enable MDs to those patients and address diseases in ways that are important not just now but for the future.
RODOLPHE BARRANGOU: And the affordability of RNA is not today where we would like it to be ideally. But scaling up the operation, scaling down the cost is important. Scaling down the dose is important as well, and that's important. Another item of interest I think that is technically very important is the longevity and durability of the editing. So being able to show that it works is one thing.
RODOLPHE BARRANGOU: Being able to show that it works in a cohort of patients for more than one disease is great. But being able to establish unequivocally that even with those lower dose modalities, we can edit DNA and enough cells in enough masses, enough level to have a sustainable over time, a reduction of clinical symptoms is very important. And I think that milestone sometimes has been missed by some people and is very important because it sets the stage for managing the doses and not just the first installment or the first therapy and the first cohort of patients, but having more practical set of drugs that we can implement in patients with durability, and the affordability that comes with it, and the clinical benefits that come with it.
RODOLPHE BARRANGOU: So I think, again, we have a few technical enhancements and advances that we have to make to manage the dosage. How much RNA do we deliver? How much LNP do we deliver? How many doses do we need to deliver? And what are the targets that we need to achieve? But we're getting there. The milestone study from two years ago was great, and there's more to come.
KEVIN DAVIES: Rachel, we were just talking off air before we started this session about the recent meeting at Cold Spring Harbor where Fyodor Urnov gave the keynote. I know you were too busy to watch it. But you're familiar with these arguments because they're all, its subject du jour at your former home at IGI, the Innovative Genomics Institute, and Jennifer and the team there. Similar themes that he expressed in an op ed in the New York Times several months ago.
KEVIN DAVIES: The unrealized or potentially unrealized promise of CRISPR if we don't really make some important fixes to the regulatory structure that would allow simple tweaks to guide RNAs to be more platformed and readily applied to potentially hundreds or thousands of genetic diseases and shorten the time frame to get these things into the clinic and potentially to the approval stage.
KEVIN DAVIES: Is that something you think about a lot? Do you feel there's important work that needs a bigger voice to help the community at large?
RACHEL HAURWITZ: Yeah. Thank you for that question. I'll take an opportunity to highlight that what we get to do at Caribou today using our CRISPR technology to make off the shelf versions of CAR T's I think is a really important way of trying to broaden the number of patients who can have access to these therapies, right? Today's approved CAR T's, so-called autologous CAR T's, they are patient-specific.
RACHEL HAURWITZ: It is an n of 1 strategy. So for a patient to receive that product, they actually have to go to a clinic, have quite a lot of their blood removed. It gets shipped to a laboratory. Product is manufactured. They ultimately get one dose of their therapy. And hopefully, it is impactful for them, and it is for some patients.
RACHEL HAURWITZ: That doesn't scale particularly well, right? That n of 1 strategy. And so that's really motivated why we are doing what we're doing. Using genome editing to turn this into an off the shelf approach, where we can manufacture products with healthy donor material instead of the patient's own T cells. And that means, one, manufacturing run results in dozens of doses instead of one dose.
RACHEL HAURWITZ: And so I think this is a great example of where CRISPR genome editing is unlocking some of the scale that Rodolphe just highlighted.
KEVIN DAVIES: Yeah.
RACHEL HAURWITZ: I'll also note the FDA is learning right along with the rest of us, right? And I have to say at least our experience has been incredibly positive. We have had the opportunity to engage with them now across multiple programs in our pipeline. And we can certainly see that they are learning a tremendous amount from the many sponsors who they work with who are developing similar, sometimes different approaches using genome editing in the cell therapy space.
RACHEL HAURWITZ: And I think that's great. And no doubt, some of these learnings are going to impact broadly how they approach some of these different regulatory questions. Caribou today is not living in the world that think Fyodor has described in some of these discussions of trying to develop n of 1 or end of small strategies. In fact, we're almost intentionally on the other side of that equation right now, where they're n of many.
RACHEL HAURWITZ: I love the challenge that he has posed to the field of how do we use some of these reagents in an n of 1 or n of small way. And clearly, the field has some work to do there.
KEVIN DAVIES: Yeah. Rodolphe, that journal proudly hanging behind you, does it not have a special issue on this theme coming out to be announced?
RODOLPHE BARRANGOU: We sure do indeed. So as we know, there's a lot of things we can do with CRISPR. But evidently, CRISPR trials is going to be the name of our forthcoming 2024 themed issue on updates on clinical trials and where CRISPR is going to the clinic, how fast and how far it's getting into the clinic. Absolutely. And to add one point to the question you just asked Rachel about Fyodor and the IGI and the aspirational pursuit of accessible medicines.
RODOLPHE BARRANGOU: I think part of Fyodor's focus is also on orphan diseases. And if we keep a bar that's unreasonably high for orphan diseases that cannot afford to do a lot of research, that cannot afford to do a lot of scalability, that cannot afford to do a lot of studies, I think that the challenge posed is how are we going to address those patient populations? Ab n of 1's or n of few as opposed to an end of many. And we're compelled to find creative ways, safe ways, responsible ways, affordable ways to target all those patient populations.
RODOLPHE BARRANGOU: And it'd be unfortunate if not tragic if we were unable to deploy the most promising technologies for patients that need them. So I think that balancing act, if I dare put my own spin on it, is a challenge. And again, to Rachel's point, we're collectively working on it. And FDA is receptive, is engaging in the dialogue. And we're all learning together of how the next chapter, how's the next process, how's the next approval pipeline, how's the next framework under which we can grandfather some of the approaches in or not, what gets changed, what gets tweaked when you formulate those drugs.
RODOLPHE BARRANGOU: And what can we build off of in the dossier that's already been pre-established and pre-approved, as opposed to something that's new and it's a different drug? What is a different drug? What is not a different drug? And how does a new guide fit into the technicality of approving something that's a new formulation? So I think those are challenges. Those are technical details that are very important that have to be figured out.
RODOLPHE BARRANGOU: And collectively, we need to wrap our minds, and our heads, and our creative thoughts around that to address what Fyodor and IGI and others are bringing up.
KEVIN DAVIES: Yeah. That's a fantastic note to end on. It's been a really enjoyable conversation. Thanks so much to Rachel Haurwitz from Caribou, Rodolphe Barrangou from North Carolina State University and the CRISPR Journal. And we look forward to moving on to the next session. Thank you both very much.
RACHEL HAURWITZ: Thanks, Kevin. Appreciate it.
RODOLPHE BARRANGOU: Thank you, Kevin.
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You have requested to see a portion of the video outside of the clip.
Click OK to switch to the full video or click if you would like to stay inside the clip. You can always go back to the clip with Tools and Clip Mode