Hey everyone, I'm Erin Harris, host of Cell and Gene the Podcast, and I'm kicking off an in vivo focused special series that will feature four SMEs from four different companies, all of whom are making strides in the in vivo space. So, why an in vivo focused special series and why now? Well, as cell and gene therapy enters its next phase, one theme is becoming really impossible to ignore, and you guessed it, it's in vivo. For years, much of the industry's focus centered on ex vivo approaches, which of course are engineering cells outside the body and re-infusing them into patients, but increasingly, the conversation is shifting toward therapies designed to work directly inside the patient using advanced delivery systems and gene editing technologies to target disease at its source.
And right now feels like a genuine inflection point for the field. The science is maturing, clinical programs are advancing rapidly, and for the first time, the industry is beginning to seriously envision what widespread in vivo therapeutic adoption could look like over the next several years. But alongside that excitement are still very real questions around delivery, safety, off-target effects, translational predictability, manufacturing, long-term durability, and a lot more. So, in this series, we're talking with leaders across the space about where in vivo technology stands today, the challenges that remain, and what it will take to turn early promise into routine clinical reality.
And case in point, the shift was impossible to miss at the 2026 ASGCT annual meeting in Boston, which as of this recording has already ended. In vivo gene editing, non-viral delivery with lipid nanoparticles, capsid engineering, precision editing, all really dominated the scientific sessions and industry discussions alike. And in this episode, I'm joined by Dr. Cassie Gorsuch, CSO at Precision Biosciences. I learned so much from Cassie in this episode, and she shares her perspective on the evolution of in vivo gene editing and the growing importance of delivery strategy and specificity, and how Precision Biosciences is approaching clinical translation through its Arcus platform and programs in hepatitis B and Duchenne muscular dystrophy. And so I'm thrilled to kick off this special series with my discussion with Cassie, and I'm sure you'll find her insight just as valuable as I do. And without further ado, here's my conversation with Precision Biosciences' Dr. Cassie Gorsuch, and enjoy.
Hi Cassie, welcome to Cell & Gene the podcast in this special series on in vivo technologies, and I'm so happy you're here to talk through with us your role at Precision Biosciences and what you're working on. So thanks for being here. I'm happy you're sharing your time with us.
Yeah, thanks Erin for having me. It's really a pleasure to be here with you.
Good, good. Well, for us at Cell & Gene, we work in, and me specifically, we've worked with Precision Biosciences many times over the years, but for the listener who may not be up to speed on what Precision Biosciences is doing and working on, tell us a little bit about the company and then specifically your role as CSO.
Sure. So Precision is an in vivo gene editing company. We actually just celebrated our 20th birthday. So we predate the vast majority of gene editing companies that are out there. We have a history of working in a lot of different types of technologies between agriculture, ex vivo CAR-T applications, and now we're really singularly focused on in vivo gene editing therapies. We were really founded by a couple of really brilliant scientists who had previously worked in the gene editing space, primarily on zinc finger nucleases. And I think, you know, their perspective was that they could see the limitations in the technology and they wanted to identify a better editing tool that could be utilized therapeutically to improve people's lives. And that's, if you know our company motto, dedicated to improving life. And so, that's really the origin of where Precision came from.
Those original founders, really, what they were able to do was to crack the code on taking a naturally occurring protein. It's a protein that occurs in a eukaryotic algae for the purposes of gene editing in nature. And they were able to take that protein and engineer it in a way that allows us, now at Precision, to select a 22 base pair target sequence that we can now program that nuclease to target. And so, that's the foundation of our technology. We call these Arcus nucleases. It's the Arcus editing platform. And it's very distinct, actually, from any other editing platform that's out there. I'm sure we'll get into some of those differences. So really where we are today at Precision is we've utilized our Arcus gene editing technology in a couple indications where we think we can really take advantage of the differences of the platform. We're big believers in know your technology well and apply it where it can really shine. So, I think there's a place for a lot of different types of editors. It's really about knowing what your technology does and leveraging its advantages.
And so today Precision has two lead programs, internally owned lead programs. The first one is for chronic hepatitis B. So we're using our Arcus nucleases with the goal of eradicating cccDNA and providing a cure for people with chronic hepatitis B, which affects over 300 million people in the world. So huge, huge opportunity to improve people's lives. The second wholly owned program is utilizing our Arcus technology for Duchenne muscular dystrophy. I think a lot of people are familiar with how devastating of a disorder Duchenne is, and we think our technology is really well suited to provide a first-in-class gene editing approach for DMD, leveraging again some of those differences that make our platform different from other editing platforms. That program, we can get into that a little bit more too, but we just recently received IND clearance from FDA for that program and are moving as fast as we can towards that major milestone of dosing our first patient, hoping to achieve that in this quarter, so first half of this year. So that's really where we are today at Precision, singularly focused on in vivo gene editing utilizing our Arcus gene editing platform.
My role at Precision, so I've been with the company about 10 years now. My role has evolved a lot over those 10 years. Today I oversee our preclinical research group, looking for our next applications for utilizing our Arcus editing platform, as well as early translational sciences. So helping to interpret the early clinical data from our clinical stage programs now. I do a lot of external communication with the scientific communities, with our investigators, and of course with investors and media like yourself. And it's always fun to get to talk about Precision and tell the Precision story and share just, you know, our perspective on what we think is really exciting going on at Precision.
Great. Well, thank you for that. I'm sure glad you're here talking to us today. We're going to definitely get into Arcus later on in our discussion, DMD, HBV, all of that. Before we do, I kind of want to have a broader discussion about in vivo gene editing. And so, it's seemingly because it is all over the media today about how, you know, it's the next major thing, major leap in cell and gene therapy. From your perspective and what you're seeing at Precision, what technical or biological barriers do you think still stand between where we are today and where we're trying to get to with routine clinical success?
Yeah, from my perspective, I think it's been really incredible to see the momentum and the progress that the editing field has really demonstrated over the last several years. It's very exciting to see clinical stage programs move into later phase development. I think that's been a major achievement for the editing field as a whole. And of course, I think it's exciting now to start to see editing programs enter populations that have huge numbers of patients, whether those are cardiovascular indications or like our program for hep B, as I just mentioned. One of the big challenges that I think still persists is on the delivery side. The vast majority of editing programs utilize lipid nanoparticles for liver delivery, and we're using lipid nanoparticles for our chronic hep B program as well.
I think really there's a challenge when you think about delivery, it really comes down to two components. The first is the limitation on the delivery side, and then the second I'd say is more of a limitation on the editing side or the cargo side. On the delivery side, I think LNPs, we have good options for liver delivery around different LNP formulations. That field has made quite a bit of stride, you know, from the early LNP days to where we are today, and now there are good LNP options for liver delivery. Unfortunately, if you want to deliver outside of the liver, your options are more limited. There's a lot of work going on for non-viral delivery ex liver, but I think the reality today is if you are trying to target an indication that affects tissues outside of the liver, like Duchenne muscular dystrophy and a muscle targeting program, really the delivery of choice is adeno-associated viruses or AAV. And those are good delivery options, but they are limited in that they can't be redosed, and so there's still some work to be done on delivery technologies outside of the liver.
I mentioned the second challenge really comes down to the cargo, and that's the fact that most editing technologies are too large to fit into adeno-associated viral packaging capacities, and so that really limits taking the editing technology outside of the liver. This is something that again, going back to our philosophy of know your technology, know what its advantages are, Arcus nucleases are extremely small, so they're encoded by about a thousand bases of sequence, fitting comfortably into an AAV vector. And so, that really I think is a major advantage in the face of a major limitation. Where delivery is a challenge, I think that Arcus technology is well suited to have more flexibility than a lot of the other technologies in terms of delivery modalities. And that's what we're using. We are using an AAV vector for our Duchenne muscular dystrophy program. And so, really kind of diversifying our ability to deliver by LNPs or AAV. But I think generally speaking, delivery remains a challenge for really thinking about taking gene editing beyond the liver utilizing other types of gene editing technologies.
Got you. Well, we know obviously off-target effects and long-term safety continue to be big problems for in vivo editing. So, what strategies are you prioritizing to characterize and mitigate these risks as your programs move into and through the clinic?
Yeah, specificity is certainly a top concern, a top priority for any gene editing company. At Precision, we've built a really robust pipeline for how we approach analyzing the specificity of our nucleases. It's a very comprehensive package that utilizes multiple orthogonal methods for both identification of potential off-target sites as well as then confirmation of off-target sites and functional consequences of potential off-target sites. I think it's exciting actually, very recently within the last week or two, FDA has put out an additional draft guidance on utilizing next generation sequencing technology specifically for off-target analysis. What I was really encouraged by when I read the draft guidance is it's very much in line with what we've already assembled as our specificity analysis pipeline. And that makes sense to me because at Precision we now have three programs actually that have gone through FDA review. Our two internally owned programs for hep B and DMD, but also a partnered program that has an open IND through a company called E-A-Cure utilizing Arcus nucleases for in vivo gene editing for severe OTC deficiency. And so the FDA has seen our specificity package, has seen our approach for specificity. And I was very encouraged to see that their draft guidance is very much in line with how we think about characterizing the safety of nucleases.
And I think the other thing that I'll say is I'm also encouraged by, you know, the approach FDA's taken for thinking about what's an acceptable specificity profile. Where it really comes down to not just the potential for off-target edits, but what are the consequences of those off-target edits? Off-target editing in the view of FDA, as they've shared at scientific meetings, isn't a deal breaker. But the consequence of the off-target edit needs to be characterized and understood. And so is any risk that you could change the function of that cell or change the function of a gene within the cell that could have significant safety risks for patients. And so going to that next level of not just characterizing where off-targeting may happen, but what is the functional consequence of that off-target editing, I think it's really important as we all continue to advance gene editing programs clinically.
Sure. Okay. More on the topic of specificity, you know, how are you evaluating the tradeoffs between efficiency, specificity, and durability when you're designing an in vivo editing therapy today?
Yeah, this is a question I think that's going to be probably specific to each editing technology because you have different levers available to you depending on your technology for how you can tinker with specificity or how you can tinker with activity of your nuclease. One of the things I really love about Arcus nucleases is that they are what we call single-component editors. What I mean by that is that it's one protein. We engineer the protein to recognize a 22-base pair target sequence, and that same protein also has catalytic activity. So, it is also the same component that binds the DNA and cuts the DNA. And that's in contrast to like a CRISPR-based system where guide RNA is the GPS, it recognizes the target site, and then the Cas nuclease is what cuts the target site. So, two components that have to work together in order to confer specificity and activity versus Arcus nucleases, it's all built into one protein.
What that allows us to do is utilize iterative protein engineering to play with both components at the same time because it's integrated into that one protein. And so, we use an iterative protein engineering process that we've developed at Precision where we can read out for activity and specificity together, and we can evaluate those in the context of optimization of these nucleases and find the ideal candidate that gives you the activity level you need for the therapeutic edit that you're looking to achieve and the specificity profile necessary to ensure safety of that type of therapeutic edit. And so, that's how we think about it at Precision, in the context of our technology, it's really protein engineering to achieve that desirable profile where you've got the activity that you need as well as the specificity of that same nuclease.
All right, okay. I want to talk a little bit about the translational gaps that are existing. You know, when we're promising preclinical in vivo data and clinical success, like where do you actually see those really big translational gaps today? Are there any? What are they?
