Could Disease Chemistry Help Treat the Brain With Enabled Therapeutics

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[00:00:31] What if, instead of trying to force a drug into the brain, we could let the disease itself switch the medicine on exactly where it's needed? Sounds almost like science fiction. But an unexpected result in a laboratory led today's guest down that very same path. My guest today is the founder and CEO of a company called Enabled Therapeutics.

[00:00:56] And she joins me today to share her story and explain why neurological diseases remain so difficult to treat. But how one molecule behaving differently would open the door to an entirely new different approach to drug development. And why the answer to treating diseases such as Alzheimer's, ALS, epilepsy and brain cancer might not be finding new targets,

[00:01:21] but finally finding a safer way to reach the ones that we already know matter. And I know the diseases I've mentioned will impact a lot of families, a lot of people listening today. So I really want to explore the difference that technology could make in the future. But enough from me. Let me introduce you to my guest right now. Well, thank you for joining me on the podcast today. I'm really looking forward to speaking with you. But for everyone listening, can you tell them a little about who you are and what you do?

[00:01:51] Certainly. I'm a neuroscientist by training. I earned my degree from UC Irvine with an emphasis in neurochemistry. And I began my career as a bench scientist. That's where I learned to let the data lead the science, even when it challenged what we thought we knew. In 2004, I joined Biomarin, where I met Dr. Todd Zankal, who's a chemist. He has a PhD from Columbia University.

[00:02:18] In 2006, I spun off the neuroscience program from Biomarin with Todd. And we spun out and we formed a company called Raptor Pharmaceuticals. Well, what made our work unusual there was that I was looking at the neurological disease through the lens of a neuroscience, while Todd was looking at the same problem through the lens of chemist, like a chemistry look.

[00:02:42] That combination allowed us to recognize an unexpected result that eventually became the foundation of Enabled Therapeutics. So when Raptor was acquired around, no, 2016, 10 years later, the project was no longer going to continue. Todd and I believed the science was too important to leave behind. So we founded Enabled Therapeutics in 2016 to keep following the data. And since then, we've built the intellectual property, generated supporting evidence,

[00:03:12] and are now preparing to publish our first peer-reviewed paper describing this discovery. It's incredible, the work that you're doing here. And every day on the podcast, I try and get people listening, think differently about areas that technology and data and joining everything together, the kind of impact that can have on the world. And neurological diseases is something you don't associate with technology, and they have remained amongst the hardest conditions to treat,

[00:03:39] despite decades of research and enormous investment. So dig into that problem a little bit more. What makes delivering effective treatments to the brain so difficult? Well, for starters, the brain is probably the most complex and consequently least understood organ in the body. Our interactions with reality are entirely determined by its functions. While it might appear roughly uniform, you know, if you look at it on the bench,

[00:04:08] it's made up of a wide variety of interconnected substructures that govern almost every aspect of our life. Right? Thought, emotion, language, sensory experience, hunger, sleep, homeostatic control of our, you know, temperature, immune function. It all depends to various degrees on brain function. Now, restricting this discussion to the part of medicine that involves drugs,

[00:04:34] we have learned that it is very difficult to intervene pharmacologically when the organ suffers from damage and disease, when it controls so many things. First, the blood-brain barrier seals the organ off from most blood-borne agents. And when one does gain access, it tends to do so everywhere, acting on healthy and diseased area without distinction.

[00:05:00] So those are two of the central hurdles faced by researchers trying to treat the brain that they have yet to overcome, which is making it impossible to treat the brain. It's time. And before you join me on the podcast, I was doing a little research on you. One of the things I was reading, you described a fundamental catch-22 in neuroscience drugs, because they need to be potent enough to be worked,

[00:05:28] but that same potency can damage healthy tissue and cause serious side effects. So how has that problem limited the treatment that researchers have been able to develop? It feels like quite a balancing act. Yeah. Well, as I mentioned, right, the brain carries out extraordinary numbers of functions using tissue that is, from a drug's perspective, remarkably similar across all the regions, right?

[00:05:53] The hippocampus, cortex, hypothalamus, they all perform different jobs, but they share many of the same cell types, proteins, molecular targets. With other organs, say, we can often design a drug that preferentially reaches the, say, liver, kidney, or another tissue. Even then, treating the healthy parts of the kidney versus the disease along with the disease, it can cause side effects, including what we sometimes call on-target toxicity.

[00:06:24] You see a lot of adverse events with drugs. But that can be handled with most organs. The challenge is much greater with the brain, because a drug that enters one region of the brain usually does not recognize the difference between those different areas and will activate on the entire brain. So say you develop a potent drug for Parkinson's, which is to treat the substantia nigra, or Alzheimer's, which is in the hippocampus. It may correct an imbalance in the affected region,

[00:06:53] but now you've created a new imbalance in healthy regions that rely on the same molecular target for normal function. So this is one side of the catch-22. The potency needed for a therapeutic benefit can produce an intolerable effect elsewhere in the brain before the patient receives enough benefit. You see? But then the other major problem, which actually comes first, is getting the drug into the brain at all. The blood-brain barrier restricts most small molecules

[00:07:23] and is even more limiting for large agents, such as antibodies or peptides. So brain exposure may be only a tiny fraction of the administered drug. So therefore, to achieve the therapeutic concentrations in the CNS, developers may have to give much larger systemic doses, kilograms of the drug. So by the time the drug reaches the brain at the therapeutic levels needed,

[00:07:48] the liver, heart, kidneys, all those other organs may already be exposed to unsafe levels. So CNS drug development is trapped between these two barriers, getting enough drug into the brain without causing systemic toxicity throughout the rest of the body, and then achieving enough activity in the diseased tissue without disrupting the rest of the brain. And you've done a phenomenal job there of setting the scene

[00:08:16] and talking about the problem and doing so in a very complex problem in a language everyone can understand. And when we get to the solution side of things, I'm always fascinated by the story behind it. And again, when I was researching you, your discovery began with an unexpected result when one molecule behaved slightly different from other structurally similar compounds. So walk me through that moment and explain how investigating that anomaly

[00:08:42] would lead you to a completely different way of thinking about drug development. It feels like a real magical moment. Yes, it really was. And it's actually not that complicated. I mean, you know, the truth is actually pretty simple and elegant. So we were screening a group of similar compounds for their ability to prevent brain cells from dying under oxidative stress, which is a common feature in conditions such as ALS, Alzheimer's, stroke, even aging.

[00:09:12] Well, one compound stood out dramatically from the rest, which we weren't expecting. We thought they would all behave the same in this particular test. And it had this amazing ability to keep cells alive at a very low concentration. Well, this molecule also had some structural features that distinguished it different from the less active compounds, but we could not initially explain what made it so special. Well, we continued looking and reading,

[00:09:41] and then we found something interesting in the literature. The fully oxidized form of this molecule had been reported to protect culture brain slices from oxidative stress, the similar stress we were putting them under, such as from a stroke. Well, because we were working in this oxidative stress model, we asked, wait, maybe this original molecule might be undergoing oxidation inside the stress cells,

[00:10:08] and maybe that oxidized product was contributing to the rescue. Now, our first reaction was not excitement. It was skepticism, because we assumed this hypothesis was probably wrong, but it was the only one we could come up with. Because at this time, medicinal chemists didn't think a thiol would oxidize to completion without an enzyme. And one thing I should mention is these molecules were selected because they did not,

[00:10:37] the enzyme we were trying to avoid did not recognize these molecules. So we knew it wasn't an enzyme doing the work. So this transformation that we proposed, this hypothesis was substantial. What we were saying was we could convert a relatively neutral membrane permeable thiol into a permanently charged water-soluble sulfonate. And that product would be less able to move freely across the membranes

[00:11:05] and could remain near the site where it was generated. So, and this conversion is also irreversible. And I mean, I can't stress in the world of chemistry just how big this discovery, if it was true, would be. So we tested this hypothesis first in test tubes and then in rats. And in both cases, the data continued to support what we were seeing. This molecule did undergo robust oxidative transformation under conditions consistent

[00:11:34] with pathological oxidative stress in the brain while remaining stable under baseline conditions and in the rest of the body. So that was a moment where we realized we might not simply have a new compound, but we might have uncovered a whole entire new way to use disease-associated chemistry itself as part of the drug activating process, which gets you around those two major hurdles I was discussing.

[00:12:04] We can get into the brain as the file, then interact with the oxidative stress only, and then become trapped inside that area where you're needed to act upon the disease tissue only. Wow. What an incredible moment there. And the science behind enabled therapeutics is based on, as you said, using the chemistry created by the disease itself to activate a drug only when it's needed.

[00:12:31] But can you expand on how pathology-gated therapeutic activation works in a language that listeners, patients and their families can understand? Because I think it's phenomenal here. And it's something we don't hear enough stories like this, but it'd be great to bring it to people. This is very novel. It is true. And you wouldn't have read about this yet. So we're working with a class of molecules called aminothiols. And under normal conditions,

[00:12:58] these molecules can circulate in an inactive or less active form. But in areas of brain experiencing unusual high oxidative stress and elevated levels of reactive metals, such as these conditions I've described, including aging, the molecule can undergo an irreversible chemical transformation. Now that matters because many neurological diseases may already have known therapeutic targets.

[00:13:26] The problem is that the active drug either cannot reach the brain, or if it does, it spreads too broadly and affects healthy tissue. Our approach is to deliver a precursor that can cross the blood-brain barrier first. Then once it reaches a region where the pathological chemistry of disease, it converts into a more polar biologically active sulfony. Because the new molecule does not readily cross back through the membrane,

[00:13:56] it may then remain concentrated near the place where it was generated. So the simplest way to describe pathology-gated activation is this. The disease itself provides the chemical trigger that turns the medicine on. And that is novel. And we're the first to show it. Wow. And so you found that the oxidative stress can cause molecules to convert into sulfonates with biological activity in the brain.

[00:14:26] But again, why is that discovery so significant? And how could it help researchers reach neurological targets that have previously been considered too difficult or even unsafe to pursue that? So as I mentioned, the transformation of neutral thiols into bioactive sulfonates by conditions within the brain is a novel finding. So this opens a pathway to therapeutics that act only in locations within the CNS

[00:14:54] that might benefit from pharmacological intervention, excluding healthy tissues, both in the brain and the rest of the body, that don't require treatment and might actually be harmed by it. Most drugs act indiscriminately. This is one of the primary reasons for side effects, right? Drugs that only act where they are needed and nowhere else constitute all paradigm shift in neurology and in medicine as a whole.

[00:15:23] And the other thing I should mention is this chemistry does not happen if albumin is present. Albumin is a large protein. It's about maybe 20% of the blood plasma. It buffers. So that's why this reaction will only happen inside the brain and only inside diseased tissue. Again, getting around these two major hurdles that have prevented us from treating the brain.

[00:15:49] And before you join me today, I was trying to do a little research and before we would sit down and I was reading how you said, we're not inventing new targets. We're finally accessing the ones we already know that matter. So what opportunities could that approach create for diseases such as, I don't know, Alzheimer's, epilepsy, ALS, and so many others there that people listening will have family members that have these issues, especially where promising biological targets are already known.

[00:16:18] Anything like this? The opportunity is very great, vast. There are lots of bioactive molecules. Molecules have already been identified that bind to a lot of interesting therapeutic targets. Some of these active molecules are sulfonates. And some of these sulfonates, when converted to their thiol equivalents, have the structure amenable to this oxidation under neuropathological conditions.

[00:16:44] So we have already identified by searching public databases like PubChem. We've already found structurally promising sulfonates that engage many targets such as for ALS, there's a CD40, 40L surface blocker. There's an antibody in the clinic for it. We have a sulfonate that would engage that target. For glioblastoma, so brain cancer, we have two targets.

[00:17:10] We have a PI3 kinase beta inhibitor, which it would stop the cells from dividing. We also have an ACP1 antagonist, which would stop the cells from migrating. We've also found these sulfonates that will bind GABA receptors and the P2Y receptor, which is very important in inflammation. So these are very important targets that are currently being developed.

[00:17:40] Well, antibodies towards them are being developed in the clinic right now, but they're failing because you can't get antibodies into the brain. And again, once you do, it's acting everywhere. So this allows a way to now start drugging the undruggable, so to speak. And you've been on an incredible journey here and a massive discovery.

[00:18:02] But I would imagine that moving from that magical moment, that scientific discovery and making a difference to potential treatment requires much more than just promising lab results. So what have you learned from working with regulators, building biotechnology companies and advancing therapeutic programs about what it takes to turn that breakthrough science into something that could eventually help patients? Well, I've learned that a strong scientific idea is only the beginning.

[00:18:31] To turn a discovery into a treatment, you need the right team and a disciplined development plan and outside expertise early. No man is an island in science. For a small biotech company, that often means working with experienced CROs and academic partners who can generate data to regulatory standards and understand not only what was done, but why. So it's very important to engage the right partners.

[00:18:59] But engaging regulators like FDA or, you know, the European regulators early is also critical. You do not want to spend years running studies only to learn they do not answer the questions needed for clinical development. And the other thing is biotechnology advances in stages, right?

[00:19:19] You've got to think you identify the next experiment that removes the greatest uncertainty, generate that evidence carefully, and use it to earn the right to take the next step. So you've got to have a lot of patience. It can take a long, long time. And persistence, finally, I'd say persistence has to be paired with rigor. Okay? The goal is not to defend an idea or to show you're right. Okay?

[00:19:43] But it's to build enough reliable evidence to determine whether the hypothesis is supported. So when the data are rigorous, reproducible, and statistically sound, clinicians, regulators, and investors, and ultimately patients can have confidence in the science. And again, when researching you, I also learned that you've got an experience. You have experience in software development and applied AI.

[00:20:11] So from the tech point of view, where are you seeing AI and computational tools genuinely helping accelerate drug discovery and, indeed, early stage biotech today? And where do you think the industry needs to be realistic about their limitations? Because it must be hard to rein yourself in because there's so much excitement here and potential. But equally, you need to keep it real at the same time, I would imagine. You do.

[00:20:35] I mean, I think AI is already transforming early stage biotech, especially for small companies that don't have large internal teams. So we use it on many levels. One, to help prepare FDA meetings. The FDA materials organize regulatory documents, review scientific literature, draft presentations, identify inconsistencies, and build specialized agents that support operational work.

[00:21:01] Such as tracking communications and preparing pitch decks, you know, that level. But then there's tools. So one tool I love is Gamma. That's a tool. That's not, it is actually AI. You just type it and put in your data and it'll make a beautiful presentation. There's systems like Stanford Storm that help organize and compare publications across multi-disciplines.

[00:21:26] And that is especially valuable for work like ours because our discovery sits at the intersection of chemistry and neuroscience. And I think that's very important. I think the reason we've uncovered this and it hasn't been discovered yet is we were looking through two lenses. And in many ways, our own discovery demonstrates why cross-disciplinary thinking matters.

[00:21:51] And I looked at the problem C through pathways and Todd looked at it through electron flow. And that allowed us to ask different questions and see a connection that had been missed. So AI has the potential to do that on a much broader scale by connecting ideas across chemistry, biology, medicine, and computation far faster than any one person could.

[00:22:15] And in many ways, AI even encourages that kind of interdisciplinary thinking that led to our discovery. But we do also need to be realistic. AI can help generate hypothesis, find patterns, organize knowledge, and make scientists more productive. But it cannot replace experiments. And that's very important. Nature still decides what is true.

[00:22:39] And the laboratory, the data, and rigorous validation must always remain the final test. Wow. And I think that is a powerful moment to end on. But before I let you go, for anybody interested in learning more about enabled therapeutics, how instead of delivering an active drug to the brain, you let the disease chemistry create the drug exactly where it's needed. Anybody interested in digging a little bit deeper on this? We can only cover so much in a 30-minute podcast.

[00:23:09] So where would you like me to point everyone? The best place to follow us is LinkedIn through both my personal page and the Enabled Therapeutics Company page. That is where we'll share publication updates, upcoming talks, events, and company news. We have a website, www.enabledherapeutics.com. However, it's not up to date. LinkedIn is currently the most up to date source.

[00:23:35] We are preparing to submit our first peer-reviewed manuscript very soon. It describes the chemistry we have spent years developing and protecting, including evidence that a carefully structured file can undergo pathology-associated conversion to a sulfonate in the brain. Once our current IP filing is complete, because we're currently expanding the claims, we're growing the family, we'll then be able to share the manuscript more openly.

[00:24:04] So again, that's in a couple weeks. So if anyone would like to read it, please reach out to me on LinkedIn, and I'd be more than happy to share a copy. We are also actively looking for investors and partners to help fund the next studies. So if the science resonates with any of your listeners, or someone knows someone in chemistry, neuroscience, drug development, or early-stage biotech investment, please just contact me directly.

[00:24:29] Even sharing our company page or making the right introduction to a scientist could make all the meaningful difference. And there it is. It's out there in the universe now. So let's hope somebody listening somewhere in the world can join you on this. I'd love to invite you back on in six months' time, see how things are progressing and evolving for you. Incredible work, what you're doing, and incredibly complex. So thank you for taking the time to come on here and share your story. I'll add links to everything.

[00:24:59] Please, everyone listening, check the show notes out. You'll find the details there. But thank you for sitting down with me today. Really appreciate your time. Thank you, Neil. I think my guest today gave us one of those wonderful reminders that scientific breakthroughs don't always begin with somebody finding the answer. Sometimes they begin with somebody noticing that the data doesn't behave as expected and being curious enough, honing that curiosity to ask why.

[00:25:27] And my guest explained today how disease-associated chemistry could potentially become the trigger that activates medicine exactly where it is needed, all while leaving healthy tissue alone. And we also heard how AI is helping small biotech teams connect ideas across chemistry, neuroscience, medicine, and computation. But there was also a reality check in there too.

[00:25:55] Yes, AI can generate hypotheses and find patterns, but it's still nature that decides what is true. And the laboratory and the data, they remain at the final test. And I'd love to hear your thoughts, especially if you work in the medical industry here. Could using the chemistry of the disease itself to activate treatments, do you see this changing how we approach some of the hardest neurological conditions to treat?

[00:26:23] And I would also encourage you to check out the blog post associated with this episode at techtalksnetwork.com. I'll include links to everything that my guests mentioned. I urge you to check that out, have a conversation with my guests, and let me know your thoughts. But that is it for today. So thank you for listening as always, and I will speak with you all again very soon. Bye for now.