RNA is having a moment thanks to the emergence of RNA vaccines against COVID-19 and its critical role in the CRISPR genome editing machinery. But over the past few years, there has been growing interest in correcting disease-causing mutations at the RNA level, which is emerging as a promising therapeutic strategy.
In nature, RNA molecules undergo multiple post-transcriptional processes such as splicing, editing, modification, translation, and degradation. A defect, mis-regulation, or malfunction of these processes often results in diseases in humans, sometimes referred to as “RNA diseases.”
In recent years, research on RNA therapeutics has made important scientific and clinical advances. RNA-targeted therapies based on antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) have emerged with clinical success, proving that messenger RNA (mRNA) can be a valid target for treating genetic diseases.
These first-generation RNA-targeted therapeutics act by either destroying RNA or modifying its splicing. Yet, there are significant improvements possible for these approaches and many more genetic diseases that could be treated if there were more effective and adaptable systems to modify disease-causing RNA.
Based in San Diego, Locanabio is built on the concept that gene therapy can deliver RNA-directed proteins to prevent or treat disease by targeting and modifying dysfunctional RNA. The company’s technology comprises an RNA targeting-effector approach using Cas9—the original nuclease used in CRISPR genome editing—to address the root cause of genetic disease, creating therapeutic candidates that are distinct from DNA-targeted approaches and nucleic acid-based RNA targeting.
Locanabio, named after the Sanskrit word for illuminating (in reference to their proof-of-concept experiments fluorescently tagging RNA), is developing therapies to treat multiple genetic diseases with no approved therapeutic alternatives. They are developing potentially life-changing therapies for patients with severe neurodegenerative, neuromuscular, and retinal diseases.
GEN Edge sat down with James Burns, PhD, CEO of Locanabio, to discuss the different ways that disease-causing RNA can be targeted and manipulated as well as how his team is building a company based on a completely new type of medicine. (This interview has been lightly edited for length and clarity.)
GEN Edge: What is the Locanabio’s vision?
Burns: Our vision for the organization is to create a major new advance in medicine based on targeting disease-causing RNA. There’s been so much progress made in the RNA space that has validated that this is a viable target. We believe our approach is unique, and it potentially could be a new platform for genetic medicines.
Our mission is to transform this early-stage research to find ways of engineering RNA binding proteins to manipulate dysfunctional RNA to treat disease. That’s what we’ve been doing since the founding of the company—to take some genes early work with the RNA-targeted Cas9 and to show that this can work in vivo in disease models.
We then want to take it to the next step, which is to expand that platform to do more than just what the initial work was doing, which was to destroy dysfunctional RNA, but also to do other things with it by engineering this platform. That includes splicing modifications, translational enhancement, RNA editing, and what we call “destruction and replacement.” Our vision is to develop a transformative new platform for medicine via development of this novel way of approaching RNA targeting with RNA-binding proteins that are delivered by gene therapy.
GEN Edge: Has there been pushback for proposing a new genetic medicine?
Burns: No, I think the attraction is that people now see that it’s possible to use RNA as a therapeutic itself, which we’re not doing but also target RNA to manipulate and treat disease. People also see that gene therapy is working and a therapeutic modality. We’re using it as a means to an end to deliver our tool for manipulating RNA.
Investors see this as a natural progression and that our approach enables us to do something that other approaches can’t do and to do it in a way in which we think is going to be safe and highly effective. It has a great breadth of possibilities because of all the different mechanisms we can engineer into our RNA binding proteins to manipulate RNA.
GEN Edge: What milestones are you trying to hit on the horizon?
Burns: Raising $100 million was really important for us to bring multiple programs forward into the clinic. Beginning this year, we hope that we will have multiple candidates we can bring into what we call IND-enabling studies. We further hope that would get us into multiple clinical trials with this funding. It all comes down to the science. Not only are we plowing new ground, we’re cutting the trees down as we go and then blowing the ground. What makes it so exciting is it’s that new.
We expect this funding to get us into the clinic with multiple candidates and on multiple platforms. It’s a single platform, but multiple ways of manipulating RNA. We’re primarily working on destruction for repeat expansion diseases (myotonic dystrophy, amyotrophic lateral sclerosis, and Huntington disease), but we’re also looking at other ways of using this tool, such as splicing modifications.
GEN Edge: Is Locanabio trying to grow autonomously, without involving a strategic partner?
Burns: The bulk of what we’re doing is for local delivery. Most of it is, for example, for the CNS or the back of the eye. The amount of materials one needs to make for those applications is going to be less than for a systemic application. We have one application at this point for that, which is for muscular dystrophy type 1 (DM1). We have already worked on the process of lining up CDMOs for making the plasma and for making the actual product that would go into pivotal toxicology studies and into the clinic and patients.
We’re securing what we need to secure to be able to have enough material to get that done. We will always look at what’s the best for a program to make sure that it gets into the patients and beyond. It’s possible that a strategic partnership might make sense having a partner that can ensure that we’re able to get it to the patient and then also bring other potential skills and technology to the table could be interesting.
GEN Edge: Is there a reason you are primarily focused on the CNS? Are there more tissues or organs that you’d like to target?
Burns: I think our approach is very pragmatic—it’s local delivery, which just makes things a bit simpler. For the indications we’ve initially targeted, we feel that once we get into the clinic, we should be able to ascertain a biological proof-of-principle relatively quickly. There’s been enough work done in this space that we would know how to approach this from a safety and a delivery standpoint.
These diseases have terribly unmet needs—they’re devastating diseases. There needs to be a treatment. You put all that together, and it makes sense to start there, but that’s not our role. Then the potential is much broader than those initial CNS diseases that we’re going to go after.
GEN Edge: What would you say are the one-year, five-year, and ten-year goals for the company?
Burns: A one-year goal is that we’re going to get in multiple programs, in the next 12–18 months hopefully, into IND-enabling studies. That’s a tremendous validation of our approach. Once we get on the other side of that and are preparing them for an IND and getting INDs submitted. That’s huge for us.
Also during this year, we have this successful funding a series B financing. With it, We’ll be building out the development of the organization, both from the perspective of chemistry, manufacturing, and control (CMC) and clinical medical and regulatory and quality. We’re still driving on those programs you see in our pipeline, we’re building the organization to deliver. We’ll also be expanding our platform beyond just destruction of microsatellite repeat expansion diseases, and that’ll become more apparent in the next year. It could be as exciting if not more so than other things that we’re already working on.
In the five-year period, I’m feeling pretty good that we will get some readouts from clinical trials on a proof-of-principle for this approach, both from a safety standpoint, and efficacy standpoint in the programs we have now. I’m hopeful for maybe one novel approach, whether it’s cancellation or enhancement or splicing.
Ten years from now, I’d like to see that we’ve really achieved that vision that this is seen as a new advance in genetic medicine. That we can leverage it to go beyond genetic medicine and use it for other types of diseases, even non-genetic diseases. You start with genetic diseases because they’re so devastating. Then potentially, once you’ve been able to show that it can have utility there, it opens up the possibilities to go into other disease areas.
GEN Edge: What are the major challenges to the trajectory that you just laid out?
Burns: The biology isn’t completely known yet. It’s like anything that was at this stage in the early days, whether it was mRNA therapeutic or antisense oligonucleotides gene therapy, you can go down the list. We know a lot about genetic medicines now that we didn’t know before. We had the benefit of being able to learn from that, but from a gene therapy standpoint or the issues with our targeting RNA and all, this approach is still novel enough that I’m sure there’s going to be some surprises.
What’s great is that we’ve built a very experienced team in product development and translating research into products into the clinic. I feel pretty good that if we run into those obstacles, we’ll have the breadth of experience to navigate through those experiences.
GEN Edge: Have you formed any strategic partnerships?
Burns: We have formed no strategic partnerships, not because we haven’t had those conversations, but it’s also because we wanted to understand more about the technology platform and what its real capabilities are. In my experience, you don’t want to wholly depend on a partner for skills and capabilities. You want to be the expert as much as you can because you’re going to run into problems and you want to depend on yourself and have those learnings that you circulate back into the organization, as opposed to it being someone else’s learnings. That’s why it’s very important that we’re building out the organization as we are.
Having said that, do I anticipate in the future that we might have a strategic partner? It’s possible. It depends on whether they would bring something to the table that would be better for a given program, then what we could do now. We’re still a small company, we can’t do everything.
GEN Edge: How big is the company right now?
Burns: By the end of 2021, we anticipate being around 60 to 65 [employees]. In some ways, that’s smaller than you might anticipate. It’s because there’s a great efficiency that we have on our platform. We can adapt. We don’t have to have one platform for destruction, another platform for translational enhancement, and others for splicing. We engineer what we have, which is still difficult, but you don’t have to start completely from scratch. There’s great efficiency there. In these repeat expansion diseases, there is also an efficiency in that if you have something that works for one, you can adapt that to work for similar repeat expansion diseases.
The organization is very passionate about transforming this research into something that can help patients. I know everyone says that, but when we were hit with the COVID-19 outbreak, we talked about the fact that we can’t stop. The patients that have these genetic diseases are still getting sick. They’re still dying. We must find a way of continuing as an organization to deliver for them.
I’m very proud that this organization stayed as productive as they did. I would say as productive before the outbreak, as they did afterwards. They’re very passionate about what they do and it shows. We’ve been able to practice some really tough biology and to show that it can work in vivo.