TechTalk: Gene Therapy Redefined: A Startup’s Non-Viral Approach to Treating Inherited Diseases

Jake Lesnik: 

Thanks, Janina. It's a pleasure to be here. 

Janina Teoxon: 

All right. Tell our listeners a little bit about yourself. 

Jake Lesnik: 

Sure. I'm originally from New Jersey, but I moved out to the Bay Area over 20 years ago. Lived out here now for more than half my life. I studied biomedical informatics at Stanford and decided that, yeah, this was a beautiful place to live with access to the ocean and beautiful California area. After Stanford, I went right into industry. I spent the last 20-plus years working on a variety of gene delivery and gene editing technologies. I was recently at a company called Mekonos, which was working on cell engineering for cell therapies. After that, I actually started my own consulting company called Natural Bridges Bio, where I worked with biotech companies forging strategic partnerships and working on their commercial strategy. Now, I have the pleasure to have recently co-founded DM Therapeutics, which is a gene therapy company developing a next generation platform for gene therapies. 

Janina Teoxon: 

Amazing. It's always inspiring to hear how personal experiences drive innovation. Let's start with your journey, Jake. What inspired you to start DM Therapeutics, and what impact do you hope to make in gene therapy? 

Jake Lesnik:  

Yeah. Well, I think right now, gene therapy is really at an inflection point. We've seen some incredible breakthroughs, but also many diseases remain untreatable due to delivery and safety challenges. Now for your audience who may not be familiar with what exactly is a gene therapy, because I do get that question sometimes. A gene therapy is delivering genetic material to a patient's cells to treat or cure a disease. This is an area that has a lot of potential and we've really seen some great new therapeutics come out in the field, but there are still areas where there are challenges and where is in need of further improvement. As far as starting DM Therapeutics, my co-founder Chris developed a novel non-viral DNA platform. That is what we call Dark Matter DNA. We realized that it could have an enormous impact on gene therapies to create those safer and more efficacious medicines, and really expand the range of treatable diseases. We formed DM Therapeutics to turn this breakthrough into new medicines. We're looking to expand the impact of gene therapies into additional inherited diseases than can be treated today. 

Janina Teoxon: 

Right. That's powerful and very bold. As you said, in the field of gene therapies, we've seen some remarkable progress. Also, as you said, there's still some hurdles to overcome. What are some of the biggest challenges holding the field back today? Where do you see it evolving in the next few years? 

Jake Lesnik: 

Yeah. I think that there are three major challenges limiting gene therapy today. The first has to do with efficacy and delivery. Many gene therapies today use what are called viral vectors. For example, there's one called AAV, which is an adeno-associated virus. These are engineered viruses that can be used to deliver genes. This technology has enabled some amazing breakthroughs. We have drugs like Zolgensma, which treats spinal muscular atrophy, which is really a devastating disorder that can now be cured with this type of gene therapy. However, AAV has very strict size limitations. Some disease causing genes are simply too large to fit into the virus. When you look at things like gene editing, you also have challenges where certain cell types can be accessed, but others, it is not as effective. We're really looking I think, in the field, for how we can improve the reach of gene therapies in terms of efficacy. Safety is another area where there are some concerns. You have the potential with viral vectors to trigger immune system responses. You could have certain toxicity issues, especially if repeated dosing is needed. Then also, with gene editing, there's a concern around off-target effects. Do we make the edit exactly where intended, or is there a risk of having unintended genetic changes that could lead to side effects? Then lastly, I think we do have an issue in the field around manufacturing and patient access. Viral vectors, you can imagine, require very complex cell-based manufacturing. You have these producer cells that make the virus, and you need to strictly control their growth. The quality control is quite important. The overall manufacturing process can be quite expensive. It can actually cost over $5 million to produce a single batch of recombinant AAV. This has impacts, both in terms of the ability to reach patients, as well as the potential for manufacturing bottlenecks. I think the future of the field, it's really important that we have new approaches that can improve in these areas, in terms of efficacy, safety, and scalability. This is where non-viral platforms like Dark Matter DNA, we think can make a very big difference. 

Janina Teoxon: 

Well, you said a lot of science there, but it's so fascinating to hear how you are tackling these very specific challenges that you just said. You mentioned it. One of the things that really stands out about DM Therapeutics is your Dark Matter DNA platform, so let's talk about that. How does your Dark Matter DNA platform help overcome these three challenges you just said, and what makes it different from existing gene therapies approaches? 

Jake Lesnik: 

Yeah, absolutely. Dark Matter DNA is the core of our platform and it refers to this non-viral technology that we have developed. We've developed it to overcome these limitations that we saw in the field. For example, there's a lot of interest in getting away from viral vectors to non-viral vectors, but often times DNA tends to be degraded in cells, so a therapeutic effect doesn't last. Dark Matter DNA has been engineered to persist in cells so that we could have a long-lasting therapeutic effect that is as comparable to viral vectors without the complexity of having a biologic manufacturing like that. Another key difference has to do with the size limitations of viral vectors. We are able to deliver larger, more complex genes. As an example, there's a disease called Stargardt disease, and this is a form of juvenile macular degeneration. It's caused by mutations in a gene called ABCA4. This gene encodes a 7000 nucleotide coding sequence that is too large for AAV. Dark Matter DNA is able to deliver the full length gene, which we believe will be possible to offer a potential cure for this form of progressive blindness. We also have the ability to expand gene editing into sentiative and hard-to-reach cells. Then, just as importantly, we have the ability with Dark Matter DNA to have a cell-free manufacturing process. We avoid the use of cells in producing our material, making it fully synthetic, which actually allows us to reduce costs by over five-times compared to viral vector manufacturing. Which we think will make these therapies both more scalable and accessible to patients. 

Janina Teoxon: 

Wow, that's incredible. Your platform sounds revolutionary. Let me just say that this, Jake, as an accounting and business advisory firm, we're proud to support companies like yours, where you're pushing boundaries to what's possible. 

Jake Lesnik: 

I think that, to that point, obviously we need our scientists pushing the limits of what's possible on a technical level. But of course, it's just as important for the company to be a viable business. It's a team sport. If you think about it, it's not just scientists at the bench. Obviously, there's clinicians, but there's accountants, lawyers, and so many other disciplines I think that all need to come together to make this work and to turn it into a business that can actually create medicines and get them to patients. 

Janina Teoxon: 

Yeah, absolutely. Innovations like this don't just push science forward. You said this, they directly impact people's lives. What kind of impact could your therapy have on patients, and what would success look like for them? 

Jake Lesnik: 

Well, at DM Therapeutics, our goal is to develop curative therapies. These are therapies that don't just manage symptoms, but they actually correct the underlying genetic cause of disease. For a disease like inherited blindness, success would mean preventing or restoring vision loss in patients who currently may not have any treatment options. We'd really like to enable early intervention and treat patients before irreversible damage occurs. More broadly, for us success means having patients having access to the right therapy at the right time, and to expand gene therapies' reach beyond today's limitations so more people can benefit from these life-changing treatments. 

Janina Teoxon: 

It must be incredibly rewarding to work on something that has the potential to change lives in such a profound way. Of course, getting breakthrough therapies to patients isn't just a scientific challenge. It's also a business one, especially when it comes to fundraising. Biotech startups, especially in gene therapy, face unique hurdles when it comes to funding. What have been the biggest challenges for you in raising capital? What advice would you give to founders navigating the space? 

Jake Lesnik: 

Yeah. Right now, there's no doubt that it is a tough market for gene therapy investment. We've seen some early gene therapy companies have struggled recently. Commercialization challenges have made investors more cautious. But we're really building for the future. We're confident that gene therapy will be a major pillar of medicine. Next gen technologies like Dark Matter DNA are essential to its longterm success. Even in the face of current headwinds, it's important to be thinking for the future. If a pendulum is swinging one way right now, we can expect it will swing another way in the future, especially if innovation can address some of the challenges today. That's my big picture perspective. Then on a more practical level, I think for founders raising capital, I have probably three key suggestions for them. The first is to really understand each investor, venture capitalists, versus angel investors, versus strategic investors. They will each have different risk tolerances and expectations. In my field, the expectation for what type of data and what type of progress you've made will differ between these different investor classes. It's important to think several steps ahead. Most importantly, in a given round, your milestones really need to derisk your technology, and also set up the next funding round. Really thinking through what investors will want to see you achieve in your previous round to say, "Yeah, this is working, this is going somewhere that I believe in," and to want to make them feel comfortable to write that next check, you've really go to make sure you have the right milestones. Then, start relationships early. Investors that may be relevant for you in a future round, you don't want to just start the relationship and reach out to them when you need the money at that point. You want to build those relationships early, want to give them updates, "Here's what I'm going out to do." You can check back in and say, "Here's what I did." Really understand from them what they're looking to see you accomplish before they're ready to get on board with your journey. Building those relationships early I think is also crucial. 

Janina Teoxon: 

Right. Many of our clients, Jake, in the life sciences sector have echoed similar concerns about funding challenges, so those are great insights you said there. I heard understand each investor, think through what investors would like to see, and start relationships early. Thanks for sharing those great insights. With all that in mind, let's talk about what's next. What are the next big milestones for DM Therapeutics in advancing gene therapy? 

Jake Lesnik: 

Yeah. Well hopefully, I'm putting my advice into practice here and really thinking through what are the milestones that are going to unlock the next inflection point for us. It's both about what do investors want to see, and in our case it's also thinking through what might future partners want to see on a strategic basis. Understanding what the strategic partners in the future may want to see is also important. For us, we have three key objectives that we're focused on over the next year. The first one is generating in vivo proof-of-concept data for our lead gene therapy program. We have a lot of really exciting data showing the power of Dark Matter DNA. The next step is to generate in vivo proof-of-concept data which will allow us to ... In our case, we're targeting a genetic retinal disease and we want to demonstrate a durable, curative effect in a relevant model. This is really important for us because we are looking to derisk an area of unmet need in ophthalmology. But we also, as a proof-of-concept indication, want to pick something that will have high translatability to other genetic retinal diseases to show what our platform can do. Then we're also looking to validate the platform in additional applications. We can use Dark Matter DNA not just for gene augmentation, where we're trying to express a gene that may be missing or damaged in a patient. But we can actually use it as well for gene editing, where we're trying to edit a patient's genome and maybe trying to knock in a corrected gene. We can deploy our technology and are looking to validate it into novel cell types, such as non-dividing cells. Overall, with this additional validation work, we're looking to unlock new programs for our clinical pipeline, as well as new partnership opportunities. Then lastly, our third milestone for the next year is focused on intellectual property and strengthening our IP portfolio. We're looking to secure additional foundational patents around Dark Matter DNA and our cell-free manufacturing process, as IP is critical for longterm success and our strategic partnerships ahead. 

Janina Teoxon: 

Wow. Great milestones you have there. It sounds like the next few years will be pivotal for DM Therapeutics. Jake, let's look even further ahead into the future. How do you see DM Therapeutics helping to redefine what's possible in gene therapy and beyond? 

Jake Lesnik: 

Yeah. At DM Therapeutics, the way my co-founder Chris and I are thinking about things is we are not just trying to develop a single therapy. We're trying to really pioneer a new way that genetic medicine can be delivered to patients. We see non-viral gene therapy as an important next frontier in gene therapy. Viral vectors have driven this first wave of gene therapy successes, but we think that the longterm growth will require more scalable, flexible, and safer technologies. We see Dark Matter DNA as a new paradigm that can enable bigger, more complex gene therapies, safe gene editing, and really, again, unlocking new therapies that are not possible today. The way we see it, we're really aiming big to redefine what's possible, expand gene therapy's reach to diseases previously considered undruggable. And doing that with a platform that can cost-effectively scale the manufacturing so that gene therapy isn't just for rare diseases, but can actually become a mainstream medical treatment. And I should say, one that is not just accessible to wealthy Western nations, but is able to really impact patients globally in a way that is accessible and cost-effective. If we're successful, we really hope to unlock the full potential of genetic medicine with our platform. 

Janina Teoxon: 

Wow, that's inspiring to hear such a bold vision for the future. Jake, this has been such an insightful conversation. Thank you for sharing your insights, your expertise, and your perspective on gene therapy. 

Jake Lesnik: 

Janina, it's been a pleasure. Thanks for your great questions. I appreciate the opportunity to talk about DM Therapeutics today. 

Janina Teoxon: 

Right. For those who want to follow DM Therapeutics, where is the best place to connect with you? 

Jake Lesnik: 

Yeah, you can contact us through our website, dmtherapeutics.com, or look for us on LinkedIn. 

Janina Teoxon: 

Perfect. Thanks again, Jake. Thanks to our listeners for tuning in to TechTalk, the entrepreneurs and innovators who turn to EisnerAmper for accounting, tax, and advisory solutions to help propel their success. Again, subscribe to the EisnerAmper podcasts to listen to more TechTalk episodes, or visit eisneramper.com for more tech news you can use. 

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