Solving the Delivery Challenge in Genetic Medicine featuring Niren Shah

Today's episode is brought to you by the letter C, Connect, Cool Companies, and Cove Therapeutics.

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Welcome to the Connect Current, the flow of innovation in San Diego. I'm your host, James Zanewicz, and this episode is being recorded at the UC San Diego Park and Market building. Located in the heart of downtown San Diego, UC San Diego Park and Market offers an event venue with cityscape views and state-of-the-art technology available for meetings, conferences, and special events. It's conveniently located near hotels and the convention center. You can find more details at parkandmarket.ucsd.edu. Now on today's show, where I'm joined by Nirin Shah, PharmD, MBA, co-founder and CEO of COVID Therapeutics, also one of Connect's 2026 Cool Companies. Cove Therapeutics is a biotechnology company working to advance the next evolution in genetic medicine through non-lipid, non-viral delivery technology. The company has bioengineered a new class of biodegradable polymeric nanoparticles that designed to address some of the major limitations that have held back genetic medicine, including delivery efficiency, safety, manufacturing, redosing, and the ability to package larger genetic payloads. Niren brings a unique background to this work spanning pharmacy, academic research, biotech leadership, business strategy, and company building. His path into biotech leadership reflects something we talk about often on The Connect Current. The best founders do not always arrive through a straight line. They bring together technical understanding, market awareness, operational discipline, and the ability to build the right team at the right time around the right hard problem. All right, so we're talking about platform science, patient need, founder execution, and the realities of building a venture-ready biotech in San Diego. And I want to begin talking about how you're building Cove and why delivery is one of the biggest challenges in genetic medicine, how you think, Nirin, about turning platform science into a company, and what investors, partners, and collaborators should understand as Cove moves into its next So I guess to start with that long list I just gave you as the roadmap for today, if people are listening for the first time and learning about you and Cove Therapeutics, what is the company building? What problem are you solving? And why did this feel like the right company to create right now?

Thanks, James. Well, first of all, I just wanted to say thank you for selecting Cove as one of the Connect Cool Companies this year. We're really honored, especially with the caliber of companies that we're surrounded by. And so with that, you know, I'll tell a little bit about what Cove is up to now. So we're working on non-viral polymeric-based nanoparticle technologies, as you mentioned, and we're really excited about our applications with this technology as well. So our history as a management team in this space has spanned across multiple decades now, and we've been involved in gene therapy across the board for CNS disorders, for systemic applications, and then also for ocular disorders as well. Our team and I have seen it all. We've seen good successes in gene therapy all the way out to commercial products. We've worked on discovery products that have never made it to the clinic, and we worked on others that have made it to the clinic. And so we're really well-equipped now to understand what works and what doesn't work. And I think there's a broad consensus amongst, you know, gene therapy communities here that there is a need for novel technologies that do overcome limitations.

Mm-hmm.

And those limitations have unfortunately left us in a place Where even though there's tantalizing opportunities with novel therapies or with viral vectors, there's limitations that unfortunately prevent them from being commercialized. And so what we're doing now is we're using these polymers that really enable us to have safety in manufacturing as a checkbox item. But as we've developed these nanoparticles, we're also realizing that we can enable broad distribution throughout the eye. We can enable cell-specific tropism. And then because they're biodegradable, it really unlocks a brand new safety paradigm That's not been seen before. So unlike previous modalities that typically lead to thinning of the outer nuclear layer in the eye, for example, our nanoparticles don't have that feature associated with them. And we're really excited. This year, we actually got some new data that shows the applicability of our platform in actual therapeutic uses. And so Stargardt is our lead application. Here, we just showed 9 months of data with treatment showing the largest reductions of A2E in the space that have been shown in the public domain. And why this is exciting is that the A2E biomarker is really the precursor that leads to lesion formation. Now, if we can prevent the accumulation or reduce the accumulation of A2E, this then can lead to prevention of lesion growth, which is what we'll study in the human setting.

Mm-hmm.

So we now have proof or proof of concept that this therapeutic application with a brand new polymeric nanoparticle-based platform has some therapeutic use, and it's something that we want to continue to take forward.

Well, as we did your intro, we talked a bit about your path to CEO as well, which has included pharmacy, academic research, other roles in business, which you sort of referenced, business training and company building. How does that mix of experiences shape the way you think about genetic medicine in particular and the kind of company you needed to build now, having had multiple experiences in this space, to have the best chance to bring something to market successfully?

One thing that I'm very fortunate for and very grateful for is always having been a part of amazing science. And that's what really has been my North Star, is to follow amazing science. It's usually to identify where patients are struggling the most or don't have opportunities. And I've just been really fortunate to be a part of a lot of great products. So in my early years during my fellowship, I was in mostly cardiovascular outcomes trials, phase 2 and phase 3, and I was working with large pharma on drugs like Repatha, ticagrelor, rivaroxaban, prasugrel, and a few others with diabetic applications for looking at MACE outcomes. And those products, sometimes we got our chance, we got a chance to put our patients on drug maybe 5 or 10 years before those drugs are approved. I'm very proud of that work because it's led to a lot of patient outcomes that ultimately are better as a result of it. Through the years in biotech and pharma, I've also been very grateful for the opportunities to have commercialized over 6 therapies now. And this spans across cystic fibrosis, chronic idiopathic—

Did you start when you were like 3?

Yes. No, it's just been all luck. Right time, right place. But because of that, I'm grateful. So I've gotten a chance to commercialize products in chronic idiopathic urticaria, short bowel syndromes, hypoparathyroidism, DMD, SMA. And so having the privilege of working on so many great therapeutics over the course of the last, call it, 2 decades, it's been really remarkable to see how much it takes to enable a therapeutic program. And so what we're doing at Cove is we're taking our time. We've spent the first couple of years really working on the platform and making sure that the components that we're using as part of the platform are not only commercially scalable, but something that works and is safe. And so we've spent a significant amount of time and resources looking at different plasmids, different polymers, different enhancer elements, and then different ways to enhance nuclear uptake as well. And so we have a construct that works for us in the eye. We're now working on new areas as well beyond what Cove is trying to drive value in. As mentioned earlier, our pipeline's really a pipeline that's focused on ocular disorders, but through partnerships with big pharma, we're also looking at CNS, ear, muscle, and other new ways to deliver these polymer nanoparticles, which we're encouraged and excited about.

Well, I want to zoom out a little bit because we've just talked about kind of the distinct problem that Covey's solved on your journey there, but genetic medicine as a whole has enormous promise as a field, but delivery has remained one of the biggest difficulties or hurdles to overcome. So kind of telling the general audience out here, what makes delivery of genetic medicine so challenging, and why does solving that problem matter so much for patients and the future of the industry?

I mean, there's no question on how tantalizing gene therapy can be.

Mm-hmm.

I mean, you got potential monogenic disorder driven by a single gene mutation, and now we're telling you that you have technology to be able to deliver DNA back into cells to make them healthy again. This is incredibly tantalizing, but how we get there has been a challenge, and this is what Cove has really focused on. Some of those challenges has been around delivery into the right cells, Once you get into the right cells, then is safety compromised by your delivery technology? And then ultimately, as we think more broadly, can we scale this commercially to applications in larger disease areas? And so, as we try to tackle some of those challenges, what we've realized with COVID is that we now have many attributes that overcome those limitations. And so I'll start with a couple and work through a list here. So in terms of safety, These polymers that we're using are biodegradable. That means they get into the cells and then they're broken down into monomer components that are bioluminescent byproducts that can be excreted through the urine. And so now we can track this. And it's interesting to see when you look at a safety profile of these polymers, how quickly you may see some inflammation and then how quickly that's resolved. So this transient effect is something that's very novel in this space. Typically, with previous modalities, you may have lingering components that continue to drive inflammation and cytotoxicity, such in a way where you may have thinning of the outer nuclear layer in the eye, for example. We don't see this with our nanoparticles.

Sure.

The second thing is manufacturing. So we always knew that we could scale these polymers because they are synthetic. And so the idea of taking a synthetic monomer component and then ultimately making a polymer was something that we knew was going to be cheap and scalable. And so we've now done that. We now have scales up to 50-gram batches, and that's something that could ultimately treat an entire population in our Stargardt disease area, for example. The other thing is tropism. So as we've continued to work with different polymer subtypes and classes, we know that we can now drive tropism to certain cell types. And this is really enabled by small molecules that we put on the back of these polymers that really enable this new tropism. So we've now seen tropism in local compartments like the eye or CNS, but also systemically. We can now avoid the liver and drive these polymers to the heart or to the lungs. And this is all published work now. So we're quite excited about these 3 leading paradigm shifts with our technologies. And there continues to be new application— there continue to be new applications that we're looking through as well.

As you've been approaching overcoming these hurdles, I've heard that you've developed a lot of partnerships, and that really can help advance science in a much faster way, but they're often hard to establish and come by. So what has enabled Cove to establish so many partnerships? Or I guess, what makes you guys special that has brought so many suitors to the table for you?

So there's really been an explosion for us in the last 2 years in terms of interest in our delivery modality, and that's driven by the need for novelty. I think we talked a little bit about the challenges in gene therapy already. But with our technologies, we now have the chance to overcome a lot of previous issues. And with our latest data in Stargardt, we're showing now that it is translatable to take a concept of a polymer-based nanoparticle to new areas. And so where our partnerships are currently is that we're working with large pharma and mid-sized pharma across CNS for DNA delivery, muscle for DNA delivery or mRNA delivery. into the ear with DNA or mRNA delivery. And then through midsize pharma, we're also looking at novel applications with new cargoes that really haven't previously been explored. And so not only are we driving value in our ocular pipeline, but there's so much potential beyond that. And we're just, again, grateful to use that word, to have partners that see the value of this technology that are willing to step up and help us build new areas to treat new applications like in the brain or like in the muscle, for instance.

Well, and as you just alluded to, you're not just developing a single product. You're building a platform that could have broader applications across genetic medicine as a whole. So what has been most important in your view as you move promising science to a company that can scale, attract partners, and advance to the clinic?

I think the value proposition for Cove is pretty straightforward. So if the idea is that there's safety challenges, manufacturing challenges or challenges with tropism and the idea for redosing, then this is something that Cove has really spent a lot of time developing either on our own or through partnerships. And what we know now is that as a company, we really had the goal of delivering DNA, but what we know now is that we can deliver different types of cargoes. And so we can reach into our polymer library, identify new polymers that enable new ways of delivering cargo.

Mm-hmm.

And creatropism to basically prevent any off-target toxicities that could have previously been seen with different modalities. The other thing that is unlocked with Cove's platform is the delivery of large genes. So in our first application in Stargardt, there's a mutation in the ABCA4 gene, which when compromised leads to an accumulation of A2E, and then ultimately downstream there's lipofuscin that accumulates that causes cell death in the nuclear layers. That's a large gene, so it's too large to fit into a traditional viral vector. Other approaches then take on dual vectors or split intenes. Our approach is a little bit different in that we can deliver the entire gene in a single construct. These are the novel ways that we have thought about taking a new platform into therapeutic uses. We're starting now with local delivery. But through partnerships, we're excited to branch out into systemic applications as well.

Well, and as we mentioned before, COVID is one of Connect's 2026 Cool Companies, and that means that you're at a stage where, I'll be honest, the investors that help us select you all have said you're ready to spotlight as a venture-ready company to the region. Our standard question here is, are you raising right now? If so, what kind of round are you raising and what will that capital help you accomplish? And is there anything you want the investors out Or to understand about the opportunity ahead of you?

Yeah, that's a great question. So we are raising right now. The next round is going to be focused on us getting clinical data. So we're now moving away from platform a few years ago into now therapeutics where we are currently. And then the next round is really going to be focused on putting this in humans and evaluating efficacy and safety in a Phase 1/2 study for Stargardt patients with the transformational data that I just talked about where we saw a 45% reduction in A2E after 9 months of our gene delivery with ABCA4, we now think that data sets the stage for us to move into humans. And so we've been fortunate to raise 2 rounds of fundraising. This will be our 3rd that we're closing to then enable clinical data. But that clinical data will have an efficacy readout. And what we're going to look at is the growth of the lesion. So in these Stargardt patients, who have accumulation of lipofuscin and then lesion growth, we want to see if use with ABCA4 therapy could then prevent the growth of that lesion. And that's something that's measurable within 12 months and something that we're tracking very closely for the clinic.

So we always like to close on the same last question. It's a very Connect Current question and a very San Diego question. What drives your innovative flow?

Well, I do a lot of things. Because I'm interested in novel technologies. I'm interested in therapeutic applications for patients. I'm interested in patients' outcomes. I've spent the first part of my career really focused on late-stage development and now on early-stage development. So the concept of bringing a new therapy into mid- to late-stage development is really exciting for me. But in the backdrop of all of that, there's 2 beautiful children, 6 and 3 at the time of this recording. And they're wonderful. And I spend all of my free time with them. There's a beautiful wife who is also in biotech, so we get to nerd out on biotech-related things. But then also in our family life, we get to travel, we get to do these wonderful things. We have a large extended family, so that takes us around the world. And we love seeing new cultures. We love learning about new things through the lens of different people. and different upbringings. So these are the things that drive us in general, but it's usually work and kids is the focus currently.

I love that. Building their future. And it sounds like seeing the world through their eyes as you go to new places and seeing how they experience them for the first time.

Amazing. Yeah. You learn so much just looking at things through their eyes, and I wouldn't pass that opportunity up for anything.

That is a perfect closing moment, Nir. And I want to thank you for such a great conversation. Again, thank I think it's a strong reminder that some of the biggest breakthroughs in medicine depend on solving both hard infrastructure problems in science, but taking those moments to recharge with friends and family and really recenter yourself so you can come back and do the good work. And with that, Cov Therapeutics sits at that intersection of good work because you're doing genetic medicine, you're working on delivery platforms, and honestly, you know, executing to the utmost ability as a founder. And so for investors and partners out there, I think it's also a reminder that meaningful biotech opportunities are right here in San Diego. They are with companies like Cove, and they're built on that combination of deep science, market need, and the ability to turn those technical problems that you're solving into a scalable company. And that's one of the many reasons we were super excited to recognize Cove as one of our 2026 Cool Companies and why we were excited to have you on this podcast. I really appreciate you coming and sharing your story.

Thanks, James. Yeah, it's been an honor to be on this podcast and And again, we're really grateful for the opportunity to be selected as a CONNECT Cool Company.

Thanks for listening to The CONNECT Current. If you want to learn more about CONNECT and explore resources across San Diego's innovation ecosystem, follow us on LinkedIn or visit connect.org. We'll see you next time on The CONNECT Current, where San Diego's innovation story keeps moving forward.

This podcast was edited by Resonate Recordings.