Delivering Large Genetic Payloads With SonoThera's Ken Greenberg

Videocast host Tom von Gunden talks with CEO Ken Greenberg of SonoThera about delivering large payload gene therapies to targeted indications, particularly those requiring redosing. Using Duchenne Muscular Dystrophy {DMD] as primary example, Greenberg describes how ultrasound-mediated, in vivo infusion of naked, or non-encapsulated, DNA to organ targets allows for larger cargo sizes than do vector-based approaches. 

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Episode Transcript

Tom von Gunden, Chief Editor, Drug Delivery Leader

Welcome to another episode of Sit and Deliver. My name is Tom von Gunden, Chief Editor at Drug Delivery Leader and your host for the series. Today, I'm pleased to be joined by Ken Greenberg, who is the co-founder and CEO of SonoThera, a company working on advanced delivery of cell and gene therapies.

Welcome, Ken.

Ken Greenberg, Co-Founder and CEO, SonoThera

Thank you, Tom. Great to be here.

Well, Ken, I like to start these episodes by talking about the patient populations and therapeutic targets and conditions that are front of mind for the folks I speak with. So, as you and the folks at SonoThera look out over that landscape, who's out there? What are they dealing with that your initial focus is on?

So, as we looked at different indications and looked at prioritizing those to focus on initially, we selected indications with a very high unmet medical need and clear genetic connection to the disease, as well as indications where the current gene delivery modalities really struggled to get effective delivery to the target organ of interest.

We also prioritized indications where the genetic payload is extremely large, far too large to fit within the existing viral vectors that are available today.

And then, finally, we looked at those indications that required redosing in order to be able to provide a therapy for the patient over time.

As we evaluated various indications, we selected Duchenne's Muscular Dystrophy [DMD] as our initial lead program because it really fits all of those criteria: clearly high unmet medical need, clear genetic link to the disease, challenging to deliver. In the case of DMD, one needs to deliver to the skeletal muscle as well as the heart and the diaphragm because these patients unfortunately ultimately die from cardiopulmonary collapse.

And then DMD is also a case where the protein, the dystrophin protein, is extremely large. So, the nucleic acid encoding that protein, the full-length dystrophin, is far too large to fit within existing viral vectors, like AAV [Adeno-Associated Virus].

Finally, it is also a disease that really warrants redosing over time because, ideally, one treats these patients at a very young age, around the time of diagnosis, which is typically 4 to 5 years old. And as their body grows and their skeletal muscle system expands, one would ideally want to redose over time to provide a stable therapy for these patients.

So, that was largely what drove us to select DMD as an initial program.

Gotcha, thanks for that. So, as I understand it, the approach that you're taking can be, at a very high level, described as ultrasound-mediated delivery [of] in vivo therapies.

So, let's dive into the science and technology a bit. How does that actually work to deliver these payloads to these folks?

Certainly. So, the way this works is we do an IV injection of two components. The first is naked DNA. So, our therapeutic nucleic acid is not encapsulated within a viral vector or a lipid nanoparticle or any carrier, for that matter. It is co-infused along with an ultrasound contrast agent. These are called microbubbles, and they're used for diagnostic contrast-enhanced imaging. They have been approved for several decades, and they have a very safe record in use in human diagnostic imaging.

So, the way we do this administration is the co-infusion of the nucleic acid along with the microbubbles, and we apply the ultrasound energy targeting the organ of interest.

So, the sonographer is visualizing the organ. They can see the microbubbles perfusing into the organ because the microbubbles serve as a contrast agent, after all. And then the sonographer applies our therapeutic acoustic energy profile, which we refer to as Ripple™. And that actually mediates the delivery of the naked DNA into the target organ of interest.

So, in the case of muscle, the ultrasound probe is rastered over the skeletal muscle system as well as the heart and the diaphragm in order to mediate delivery there.

It will be performed in an outpatient setting. There's no anesthesia required. A typical registered nurse and a sonographer will be able to perform it in a typical ultrasound imaging type setting.

You mentioned redosing, so I'm assuming that this regimen for patients includes a return. So, how frequent would you envision that to be, ultimately?

We're envisioning redosing to occur anywhere between every 6 to 12 months. Ultimately, that will be guided by our clinical studies so that we can understand using certain endpoints in the clinic to determine what is the optimal redosing frequency.

We have been successful in demonstrating in preclinical models [that] redosing is very effective, both in terms of maintaining and achieving the therapeutic level over time.

You mentioned preclinical and then moving into the clinic. So, tell us about where you are in terms of the innovations and advancements and what's next in terms of additional questions to answer or problems to solve or challenges to overcome. And what's front of mind and next up for you and the folks there at SonoThera?

So, as we sit here today, we're in the midst of our IND-enabling studies so that we can initiate our Phase 1b clinical studies next year in human DMD patients. The key is to demonstrate the type of safety and efficacy that we've seen in animal models to demonstrate that in human patients. Ultimately, that's the next major milestone that we're very focused on achieving.

Gotcha. So, as you look out over the horizon, whether that's near or far, but certainly toward a future state for these patients, do you have a vision for what their health and lives might be like that's different from today? I mean, obviously, some kind of cure or disease management would certainly be an obvious goal, but how do you envision what the picture might look like differently down the road?

It’s important to recognize that this disease is, it's really a horrible disease, you know. Shortly after diagnosis, there's a gradual decline in neuromuscular function. Eventually, these patients typically die in their 20s to 30s.

Our aspirational goal is, really, to return these patients to a high quality of life, both restoring function as well as increasing their longevity and mortality. So, we really envision that this therapy will be able to do that and take a disease that unfortunately really shortcuts these patients' lives and turn it into something that can be managed over time and restore healthy function.

Gotcha. I think just one more question for you, Ken, and that is: Are there thoughts beyond the population of folks who suffer from muscular dystrophy? Any other therapeutic targets or indications that you believe that this or hope that this technology can target and treat?

Yes, absolutely. In addition to DMD, we are also working in the kidney. The kidney has been a very challenging organ for genetic payloads to achieve adequate delivery.

So, using the same criteria that I mentioned earlier, we selected Autosomal Dominant Polycystic Kidney Disease [ADPKD] as our lead kidney program  because it is also a disease that requires a very large payload to be delivered. It's actually about twice the size of our DMD nucleic acid.

The standard of care is  really inadequate to provide these patients with a healthy life. So, we see that as yet another opportunity to really positively impact these patients and provide them with a potentially curative therapy that will improve kidney function and reduce the development of these cystic kidneys in ADPKD patients.

Well, it all sounds very promising, Ken. I want to thank you for joining to share the work that's underway there at SonoThera in terms of delivering therapies to patients in need. And I want to thank our audience for joining for another episode of Sit and Deliver. And we'll see you next time.