Exosome-Based Gene Therapy Delivery With OmniSpirant's Gerry McCauley

In this episode of Sit and Deliver, host Tom von Gunden talks with OmniSpirant Therapeutics CEO Gerry McCauley about leveraging stem cell-derived exosomes for platform delivery of gene therapies targeting cancers, respiratory diseases, and other indications. They consider patient safety along the way of transforming life-threatening diseases into manageable, treatable conditions. 

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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 episode.

Today, I am joined by CEO Gerry McCauley from OmniSpirant Therapeutics, which is a company working on gene therapy delivery with a platform that is based on stem cell-derived exosomes.

Welcome, Gerry.

Gerry McCauley, CEO, OmniSpirant Therapeutics:

Hi Tom, great to see you, and thanks for the opportunity to be here

Well, good. Well, it's my pleasure to have you here.

Let's start with the patient population and the needs out there. So, I know that some of the indications you're working on targeting are cancers and respiratory conditions. So, let's start there before we get into the science and technology of the platform. Why those targets, and what do you hope to do for those patients?

So, Tom, we really do have a true platform technology, the OmniSome platform, and this can be applied to pretty much any disease. And how we're doing this: we're addressing a problem, and the fundamental problem is delivery of gene therapy.

So, we're tapping into nature's way of sending RNA and proteins from cell to cell. And we are initially focused on getting these platform-based treatments translated in cancerous and serious respiratory diseases. And we feel these are areas that affect huge numbers of patients, more effective treatments are desperately needed, and traditional gene delivery has faced limitations in safety, tolerability, or tissue accessibility.

So, looking at the size of the problem: Acute and chronic respiratory conditions affect over half a billion people worldwide. Our proprietary technology allows us to access the lungs with non-invasive aerosol delivery. And the inherent regenerative medicine properties of stem cell exosomes have obvious benefits for these patients. And we believe that, by adding disease-targeted cargo, we can develop transformational treatments, which can have huge impact.

These diseases are often progressive and chronic, such as pulmonary fibrosis, COPD, and cystic fibrosis. And they're characterized by persistent inflammation, often senescence-driven tissue remodeling or fibrosis, impaired lung function and quality of life, and quite often these diseases are fatal. So, just COPD is the third leading cause of death globally, and it's rising in incidence.

So, when we look at what we're targeting for clinical translation, it's essentially acute lung injury, or what's known as Acute Respiratory Distress Syndrome [ARDS], which is a major killer. It doesn't have any approved treatments.

And it's characterized by immune overactivation and cytokine storm, which leads to epithelial barrier dysfunction. And in severe disease, it has a mortality rate of around 40%, so unacceptably high. And as we all know, cancers… many cancers are intractable to treatments or develop resistance.

And furthermore, solid tumors can initiate and spread anywhere in the body, so the ability to cross biological barriers is mission-critical for treating cancer. This is one of the key characteristics of exosomes, and stem cell exosomes, in particular, have these tumor-homing properties.

Let’s talk more about that for those members of our Drug Delivery Leader audience who may not be completely familiar with stem cell exosomes. From a science and technology level, give us a little 101. What are they?

Yes, so exosomes are essentially extracellular vesicles. They're also known as nanoscale carrier messengers from cell to cell. So, to give an idea of the scale, 70 exosomes across would just be the width of a human hair. And exosomes are naturally released by all cells and are a really important part of the body's natural intercellular communication system.

So, by tapping into that, we do it with a very specific type of exosome. It's not a catch-all. I'll go into more about the regenerative part in a second. But exosomes are lipid bilayer vesicles, and they encapsulate and protect nucleic acids from degradation. And then, once they get into their target cell, they release that cargo functionally.

Now, the source of the exosome is critical, so we use stem cells and immortalized stem cells, which give us the ability to scale and produce reliable, reproducible lots. It's one of the key cornerstones of how we see this addressing large patient populations.

But these stem cell exosomes have inherent regenerative medicine and immunomodulatory signaling properties, so they're anti-inflammatory, anti-fibrotic, pro-survival. And these properties vary from donor to donor and tissue source, and they can be influenced by manufacturing, isolation techniques, to name but a few variables.

But OmniSomes are exosomes that we have loaded with therapeutic payloads, so either through engineering — bioengineering of the parent stem cell — or exogenous loading of RNA cargoes. So, these therapeutic cargoes are tailored to target the disease.

So, in cystic fibrosis, you've got the CFTR [cystic fibrosis transmembrane conductance regulator] protein, which is mutated, and reintroducing a wild-type protein is a simple and very obvious monogenetic target. But we do have epigenetic targets, like microRNA modulation, that you can use to address many other diseases, loading with siRNA for targeting certain oncogene knockdown or a pathogenic protein. So, it's an incredibly versatile platform.

But the key attributes are that stem cell exosomes are immune privileged, so they don't have the immunogenicity issues. They can be repeatedly dosed. And often, carriers for gene therapy are actually immunogenic, but stem cell exosomes will be the opposite. They can modulate the immune system, and that's a really key advantage, we think is a critical problem that needs to be solved.

And speaking of the dosing and the delivery, what would be a typical scenario, a typical regimen? What would this look like to get these therapies into patients in these ways?

Well, it's a little bit early to tell for certain, but certainly for lung diseases, route one to deliver to the lung by non-invasive aerosol delivery is generally the route we would take. And depending on the gene expression, or the kind of preclinical studies, we'd estimate that weekly dosing would be possible in the context of cystic fibrosis or other chronic respiratory diseases.

And we'd envisage this will be done in outpatient clinics, and potentially self-administered at home into the future, if you're really addressing a mainstream disease population. So, for Acute Respiratory Distress Syndrome and severe ARDS, this will be in an intensive care unit setting for clinical translation. And we'd envisage that your aerosol device is integrated into the ventilator circuit in ICU, but this could be used in a smart nebulizer device for prophylaxis or deterioration to severe ARDS as well.

And in a cancer setting, we'd see that these are going to be in outpatient infusion settings. But, if we have a carrier that's got the ability to be repeatedly dosed, and it's got that tolerability, that gives you the ability to titrate the dose, so you don't have to go for the sledgehammer first thing. So, for safety, this could be a real, key advantage.

So, intravenous or subcutaneous infusions, depending on if you're targeting immune cells, or if you want to go straight in for delivering a cancer gene therapy. So, difficult to say for sure, but in preclinical models, we think dosing every 3 days, every 72 hours, is what we would see as the duration of action to give that cytotoxic effect for cancer gene therapy.

Gotcha, gotcha. So, as the work continues there at OmniSpirant, what are some of the key questions that still need to be answered, problems to be solved, challenges to overcome that you and the folks there are addressing and looking at?

Yes, well, drug delivery, as you know, is difficult, and challenges are everywhere, let's say. But what we're working on now is scaling GMP manufacturing of these engineered exosomes. So, immortalized stem cell banks make this mission possible, but manufacturing is complex. As you know, the process is the product. There's a very large number of parameters, and each of those need to be set to ensure that we get a consistent cargo loading, which equates to your dosing and batch reproducibility.

So, when we started this out, we've seen huge advances in bioreactor technologies, downstream isolation technologies, over just the last number of years. And they've completely changed from when we started out 10 years ago. So, people were isolating these exosomes with ultracentrifugation. They were doing very small amounts. Now, we've seen that the ability is there to produce on upstream and downstream. We've got a much better handle on product characterization. And I think where we're going to clinically translate; it's obvious that the regulators will understand the risk-benefit of our clinical beachhead indications that we've selected to mature the platform.

So, when we have TP53 mutated cancers, they're often very refractory to treating patients, even with the advances in standard of care. It's a very dire situation. And acute respiratory distresses: as we said earlier on, it's life or death. So. these are very different, clinical indications than looking at long-term administration in a pediatric population or Alzheimer's studies that will require years of Phase 3.

So, these we feel are clinical; they've got real potential for accelerated approval. And, if they get that, that means they're saving lives, which is, I think, the most streamlined way to mature this platform.

But the challenges: they're definitely worth taking on, as the vision here is for OmniSome-based treatments to make an impact on mainstream diseases. So, establishing safety and efficacy in these clinical beachheads would lead to that. And I think that all of the work we're putting into CMC and manufacturing, that's going to stand to us.

We're laying the foundations for partnering with larger companies, and our data milestones over the next couple of years should allow these companies to share that vision we have, that is, to make affordable disease-modifying treatments for mainstream diseases. Say, for example, COPD and Alzheimer's, which affect hundreds of millions of patients.

So that's the strategy. I think it's the right one, but it takes a lot of doing. The team here are capable of delivering.

Well, that all sounds very reassuring and promising. So, you've already started down the path of the way I usually conclude these conversations, but I'm going to extend it just a little bit. You talked about the vision for the future, and saving lives, and the goal of that, obviously.

And so, as you look forward to the potential future state, should these advances move forward and take hold as we anticipate and hope that they will, beyond just the goal of saving lives, but the lives that those folks will be living: How might that differ from the way folks who get diagnosed with these conditions today might go through a therapy and move toward an outcome? How do you envision what that future state of the life and health of patients will actually feel like from a patient experience standpoint?

Well, the hope is that, in the context of cancer, we get less toxic and more effective cancer treatments. If we can beat cancer into a chronic disease that you can live with, rather than a fatal one, it'll make a huge impact on patients, their families.

And that may not be as simple as just a cancer-targeted gene therapy. We've got the whole area of immunotherapy where we feel this platform can be leveraged as a real, key delivery vehicle for in vivo CAR-immune cell therapies.

And then the ability to re-dose there is going to be critical. So, we're working on lots of different targeting technologies for CNS delivery, but also for immune cell transformation with CAR constructs.

So, the war on cancer is going to be ongoing; it's going to be multifaceted. But we think this can make a real significant impact, and the potential is there for accelerated approvals if you can show a significant improvement in overall survival. And as we said earlier on, doing that in these disease means saving lives.

So, the ambition is, if we can do what we're planning to do, we can make gene therapy more accessible and safer. And to leverage the platform scalability to address these mainstream diseases through partnering, which, in turn, accelerates the impact that we can have.

So, a lifetime of work ahead of me. I've got, probably I'm more than halfway there already, but I'll finish off what I have left, and I think that this is the one where we can see a couple years to the clinic now, and when we get there, with enough trial sites, the outcomes we'll see can really accelerate and take hold. From a pharmacist, from a drug delivery perspective, the challenges I looked at in the field of how gene delivery was being done, and looking at the attempts and the failures and the reasons why, I really do believe that this is piggybacking on how this RNA delivery is happening in both of our bodies right now. So, if we  can leverage that, I think there's huge benefit to come out of this.

Well, I obviously appreciate your life commitment to the work. Also, of course, I want to thank you for joining today, Gerry, to share the work being done there at OmniSpirant Therapeutics with our Drug Delivery Leader audience. And to that Drug Delivery Leader audience, I want to say thanks for joining for another episode of Sit and Deliver. And we'll see you next time.