Extracellular Vesicle Breakthroughs with Aegle Therapeutics' Dr. Gloria Matthews

Thank you. It's my pleasure. Thanks for having me.

Well, Egle is a clinical-stage regenerative medicine company. We work to develop therapies for rare and severe dermatologic and immunologic disorders. We work to extend the lives and improve the quality of life for patients suffering from these devastating diseases by restoring affected tissues to a more normal state. So we focus on not just healing but regeneration, and then restoring back to the way tissues were meant to be. We provide treatments that are effective with added safety, without sometimes intolerable side effects such as severe itch or exacerbation of that disease.

Sure. Well, we know that MSCs are known to be crucial for tissue repair and regeneration. We know they provide bioactive signals that modulate immune response and inflammation and drive regeneration, which are our goals. This can lead to effective healing. The bioactive cargo that they deliver is sequestered in these little tiny carriers, or extracellular vesicles, that are waiting to be secreted from the cell. And literally billions of these extracellular vesicles can be secreted from these cells. Then they are capable of delivering cargo such as genetic material, DNA, RNA, protein, signaling factors that can reduce inflammation, modulate the immune system, and even provide regenerative healing cues. In fact, we now know that this is the way that MSCs exert their effect on local cells in the body. Unfortunately, the MSCs themselves are rapidly cleared from the area in which they are injected. This often results in lower efficacy than we might expect from laboratory studies and even from some clinical studies that have been conducted.

Some of the main advantages of EVs over cells are that the EVs that are injected, applied locally, fuse with the cells in the tissues and deposit the bioactive cargo into the cell. So they provide the benefits of the MSCs without the concerns around residence time of the cells or survivability of the cells in the body, which tend to be rapidly cleared once they're administered — the cells, that is, not the EVs. EVs are not living cells. They're easier to create into a product format and to maintain long-term. EVs — you can make billions of these. And there is a limit to how many MSCs one can culture from an individual donor, but their MSCs make EVs that then can amplify that ability to respond exponentially. We can do precise dosing. This can be delivered in terms of numbers of EVs in a given dose volume without concerns about cell death or proliferation or any kind of differentiation of the cells. They're very robust in harsh environments. They don't engraft in the tissues. They are easily destroyed. So they really provide an off-the-shelf option for people.

And I guess the last thing I'd say is that, you know, there are only so many MSCs that can be harvested from an individual donor. And as I mentioned before, each cell makes, you know, volumes of EVs. So these can be purified and result in an efficient scale-up with less concern regarding the eventual availability of the product and donors.

Sure. Well, DEB, or epidermolysis bullosa — EB — has been referred to as the worst disease you've never heard of. So lots of people, even in the dermatologic medical community, have either never seen or never heard of EB. It's really a rare disease. There are multiple forms. We are looking at recessive dystrophic epidermolysis bullosa. There are another few forms that I won't go into in the interest of time. But these are severe skin blistering diseases, and especially dystrophic and recessive dystrophic — these are very severe diseases, and they're caused by a genetically driven inability to make collagen protein, or make effective collagen 7 protein. And they also exhibit chronic inflammation and immune imbalance. So it's not just about collagen 7 deficit, which would be easier to just replace, as in, you know, a protein replacement therapy. But we also have this chronic inflammation and immune imbalance. So the collagen 7 is critical for anchoring the epidermis to the dermis. And when you can't anchor those two, in its absence — which is particularly severe in the recessive form, which we call RDEB, recessive dystrophic epidermolysis bullosa — this results in lifelong formation of recurring blistering wounds all over the body, significant healing delays, significant scarring. These wounds often lead to early and recurrent development of squamous cell carcinoma, which in many cases can be fatal even at a pretty early age.

Clinically, some of the things that we've seen in our current ongoing Phase 1/2a clinical trial is that, first of all, they're remarkably safe even in severely compromised patients. We've also done clinical studies in deep second-degree burn wounds, where people — presumably healthy people — are suddenly compromised by significant burns from gasoline fires or other pretty damaging explosions. And these have been incredibly safe. They rapidly stimulate bioactivity in chronic non-healing wounds that is not seen in matched control wounds. In our RDEB trial, we currently provide up to six doses two weeks apart in those patients. And we see detectable changes start as early as after the first dose. So we check them two weeks later and we start to see differences in the bioactivity of the wound. And sometimes it takes a few doses to close. Sometimes they close very quickly, and sometimes they don't. But even before full wound closure, we see the patients' symptoms and quality of life improve, based on both patient and physician-reported validated outcome surveys. So it's been quite encouraging.

The wound closure we see is also notably regenerative, with restoration of the dermal layers. And that's something that, if you're just supplying collagen 7, you're helping with the anchoring of the epidermis to the dermis, but there's really no opportunity to provide dermal healing with just supplying collagen 7. And that's really just kind of a restoration of the bungee cords, if you will, connecting the dermis and the epidermis. Our preclinical work in the immunologic disease graft-versus-host, in which a recipient of, say, a blood cell transplant is immunologically attacked by those cells — by the donor-derived cells which see the recipient as a threat — has also shown remarkable reversal or prevention of these effects using systemic administration of EVs, which is a departure from our local administration of the wounds, but it does suggest significant potential beyond the topical application.