Veterinary Vertex
Veterinary Vertex is a weekly podcast that takes you behind the scenes of the clinical and research discoveries published in the Journal of the American Veterinary Medical Association (JAVMA) and the American Journal of Veterinary Research (AJVR). Tune in to learn about cutting-edge veterinary research and gain in-depth insights you won’t find anywhere else. Come away with knowledge you can put to use in your own practice – along with a healthy dose of inspiration to remind you what you love about veterinary medicine.
Veterinary Vertex
Bumped-Kinase Inhibitors: A New Path Toward Treating EPM in Horses
A small structural “bump” on a molecule might be the big breakthrough EPM care has been waiting for. We sit down with researcher and clinician Izabela de Assis Rocha to unpack how bumped kinase inhibitors exploit a tiny difference between parasite and mammalian kinases to hit Sarcocystis neurona where it hurts—motility, invasion, and replication—while sparing the horse. It’s a molecular strategy with practical promise, and the conversation bridges the stall, the lab, and the future of equine neurology.
We break down the science behind CDPK1, the gatekeeper residue that drives selectivity, and why unique parasite structures like the apical complex and apicoplast open new therapeutic lanes. Then we move into what really matters for care: pharmacokinetics and clinical fit. BKI-1708 shows strong systemic distribution that positions it as a prophylactic candidate, while early data on BKI-1553 suggests better CNS penetration and a path toward active EPM treatment. Isabella explains how EPM’s dead-end host biology may lower the risk of widespread resistance, a rare bright spot in the antiparasitic landscape.
Clinical trials are the hard part. With no robust experimental infection model and fewer than 1% of exposed horses developing disease, enrolling enough cases takes patience and teamwork. We talk about building pragmatic, clinician-led studies, harmonizing diagnostics and neurologic scoring, and tracking relapse to find outcomes that matter to horses and owners. The One Health angle also shines through: BKIs show activity against equine piroplasmosis and have potential roles in toxoplasmosis and cryptosporidiosis, linking equine research to human and livestock health.
If you care about evidence-based equine neurology, new antiparasitic strategies, and turning elegant biochemistry into barn-side change, this is your roadmap. Subscribe, share with a colleague who manages EPM cases, and leave a review to help more veterinarians find the show. What question would you ask about bringing BKIs into practice?
AJVR article: https://doi.org/10.2460/ajvr.25.07.0270
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SPEAKER_03:Welcome to Veterinary Vertex, the AVMA Journal's podcast, where we delve into the behind-the-scenes look with manuscript authors. I'm editor-in-chief Lisa Fortier, joined by the fabulous associate editor Sarah Wright. Today we're discussing bumped kinase inhibitors in horses for the prevention and treatment of EPM, which is equine protozoan myelitis, with author Isabella Rocha. Hey Isabella, thanks for being here with us today to talk about my favorite species, the horse. Thank you for the opportunity to discuss this research.
SPEAKER_01:We're so happy to have you here today. Thanks for joining us. So let's get started. So before we dive in, could you share a little bit about your background and what brought you to EPM research?
SPEAKER_02:So, since early when I started vet school, I became very interested in horses and urology in general. I had an opportunity to attend one of Steve's lectures on EPM when he visited Brazil. And that's when I knew that's what I wanted to work on, being able to put together horses and urology.
SPEAKER_03:Isabella, your AJVR article discusses the potential utility of bump kinase inhibitors for the prevention and treatment of EPM. What's the background on this research?
SPEAKER_02:So historically, protein kinase inhibitors were considered for therapy of parasitic diseases, but the challenge of specific inhibition of parasite kinases versus the mammalian kinases had limited the practical application. So in the case of the bumped kinase inhibitors, uh, they were originally generated to build specificity into this drug class to compete with the ATP for the kinase active site. The bump on the BKIs uh precludes there to bind to almost all mammalian kinases, because those have a bulky uh gatekeeper residue in the ATP binding pocket. So West Lab uh at the University of Washington were able to determine that the Picomplexin parasites have a naturally occurring small gatekeeper residue in their ATP binding site, and that is on a protein called calcium-dependent protein kinase 1 that we called CDPK1. This is a protein important for parasite motility, host cell invasion, and decres. Considering that, they embarked on a medical chemistry project to optimize BKIs for use against several apicomplex species, including sarcocystisous neurona.
SPEAKER_03:Yeah, really thorough answer. So you've answered a lot of my follow-up questions, but does the biology of sarcocystis neurona create challenges or provide opportunities for BKIs?
SPEAKER_02:Yes, sarcocystis neurona is a single-celled uh eukaryotic parasite. Uh, this means that it relies on many metabolic pathways shared with mammals. And that is a challenge to identify selective drug targets. Thankfully, this parasite also has many unique features that are not shared with mammals, such as what we call the apical complex, which is involved in the process of motility and invasion of the host cells, and it also has a unique organelle called the apicoplast, that is a vestigial non-photosynthetic plastid, and that's involved in fatty acid biosynthesis. So the presence of these unique structures, they are promising for targeting these parasites.
SPEAKER_01:So, Isabella, what are the key take-home messages you hope veterinarians will remember?
SPEAKER_02:I believe this research is a great example of how foundational studies in parasite biology inform translational research. Uh, without sequencing the Zaccousitis Neurona genome and a lot of the in vitro studies, the BKIs wouldn't have advanced to pharmacokinetic studies in horses. So, foundational study may take a long time to lead to the clinical applications, but it often leads to the great advantage advancements in our field.
SPEAKER_03:Isabel, are there concerns around drug resistance with BKIs like there are with other antiparasitic treatments?
SPEAKER_02:Uh so it's interesting uh because in the psychostatisms aurona life cycle, horses they're at dead-end holstices in which only a sexual reproduction occurs. That this means that the use of the drugs in the parasites are unlikely to lead uh into the resistance. That means that infection is not transmitted from one horse to another. So even if the resistance occurs at the individual horse, it's not going to become widespread. And we need to consider that the parasites they replicate very slowly over a course of many days. Uh so they are very careful when they are uh multiplying and dealing with their genome. So mutations are unlikely to occur in these uh parasites. Uh so even if it were at the horse level, we think it's unlikely that resistance would occur, which is very interesting considering the biology.
SPEAKER_03:Yeah, very cool. You talked about this or touched on a little bit earlier, but maybe a little bit more. Do BKI show promise against other equine pathogens or even human diseases caused by related parasites?
SPEAKER_02:Yes, absolutely. So in horses, the BKIs are also effective against Babise Cavalli and Telluria equi, which are the causes of equine throughplasmosis. Uh, and this drug class has also been investigated for the treatment of toxoplasma-associated abortion in sheep, toxoplasmosis, and cryptosperidiosis in humans. So it's an example of uh one health research for sure.
SPEAKER_01:Yeah, I love that one health tie-in. Thanks for providing that. And looking ahead, what are the next steps for research in this area?
SPEAKER_02:So the current lead compound, BKI1708, has a great systemic uh distribution in horses, but it has low CNS penetration. So it's a very promising compound for prophylaxis as it can control systemic infection, but it may not be suitable for EPM treatment at this point. So after we published this paper, we started some preliminary uh work with a different lead called uh BKI-1553. And so far, we were able to show um very good drug levels on CSF, which means that this compound might be more suitable for um treatment than what we have studied so far. Um, so hopefully, with uh more PK experiments, uh, this other lead compound could potentially advance to a clinical trial in horses with EPM.
SPEAKER_01:Very cool. And how do you envision collaborating with clinicians or other researchers to advance this one health work?
SPEAKER_02:So, the main challenge with EPM clinical research is that we do not have a robust experimental infection model. That means that we need to work with naturally occurring EPM cases, and for that, we need to um work with the clinicians. Uh, the main challenge is that less than 1% of the horses exposed to sarcosys develop EPM. So it takes a long time to achieve a good sample size in a clinical trial. And we also struggle uh with testing the efficacy of prophylactic um uh approaches. So working with the clinicians, not only in recruiting horses for this type of study, but also brainstorming ways that we could assess uh how prophylactic approaches help horses. That is certainly very important.
SPEAKER_01:And how might future findings translate into practical changes in day-to-day veterinary practice?
SPEAKER_02:So we hope that the BKIs would eventually lead to a commercial product, which would provide a third treatment option for uh EPM? This would be especially important for treating horses that either do not respond well to the current Antaprotozoas or animals that tend to relapse after treatment completion.
SPEAKER_03:Isabella, let's talk a little bit about your journey. How did your training, all the way from uh interest in becoming a veterinarian and your previous work prepare you to uh come up with this idea, implement the study, get across the finish line all the way through publication and write this article?
SPEAKER_02:Uh so it's been uh, as I mentioned, since vet school, I became interested uh in neurologic diseases of horses. And it was especially for me during residency that I started treating uh the neurologic cases, and it that became clear that compared to all other diseases that we see in horses, the neurologic diseases are the most challenging ones. And even in the case of EPM, which is a disease we know a lot about how to diagnose and treat, there is still uh shortcomings with that. So it was not only my interest in the quine neurology, but also the day-to-day struggle as a clinician that led me to pursue uh training and research in this area. And it was very interesting for me as I was studying uh the success rate and the relapse rate for the current treatments for EPM, and they are about the same for uh the different drug classes that we had. So trying to develop a new product that had the potential to have a superior um successful rate in voices that would was very appealing uh to me.
SPEAKER_03:Yeah, it's surely a frustrating disease, those shortage of experiments that need to be done. And it it is interesting that we can't really replicate it uh in a clinical model. Yes. Yeah, certainly hampers progress. Yes. Were there any mentors or colleagues that play the pivotal role in guiding your thinking or these research methods in this article?
SPEAKER_02:Absolutely. So both uh Steve and then uh were great. Uh so Steve's just the amazing neurologist, and he's been my uh great mentor on the clinical side of this research, and he's the person I look up to as a clinician. But also my uh PhD mentor, uh, then he's also for me the role model as a scientist. So it's very interesting because, as a clinician, as we're trying to diagnose an animal, we try to gather evidence to support a diagnosis as we go through uh our different uh differential diagnosis. But as a scientist, it's a little bit of the opposite as we try to prove ourselves wrong before we move forward. So we want to do a great number of experiments and test all the possibilities before we can say, yes, this is the direction we need to forward. So it's learning to think in different ways and blending being a clinician and a scientist is certainly being very interesting. And I'm grateful to my mentors for that.
SPEAKER_01:Now, before we wrap up, let's have a little bit of fun. So we have two fun questions for you today, Isabella. First one is about communicating with animals. So if you could instantly communicate with any one species, which would you pick? And what's the first thing you would ask them?
SPEAKER_02:I would pick dogs, and the first thing I would ask is what do they dream about? Sometimes it just looks like they're having fun, and I wonder if they're just reliving their day or prepping for the next day, and but also knowing what in nightmares look like, what they have to worry about so much that they have nightmares.
SPEAKER_03:I like the dreaming one. I'm not so sure I want to know about the nightmares. Maybe I pet them too fast, came at them too fast, didn't let them out enough. On the human side, if you can instantly master any skill related to patient care behavior, uh, what would you choose?
SPEAKER_02:Certainly they spinal taps. Uh as Steve likes to say, whoever says they never struggled with a spinal tap, haven't done enough spinal taps. Every once in a while we grab, we got a horse that is a little bit crooked in their back, or we're just not having a good day. So I like to think that spinal taps are half technique and half luck. You never know.
SPEAKER_03:That's awesome and true.
SPEAKER_01:It's a very good answer. Well, Isabella, thank you so much for joining us. We appreciate you being with us today and for sharing your work too with AJBR.
SPEAKER_02:Thank you very much for the opportunity to share this research. It's very exciting to me, and I'm grateful for being able to talk more about TPM, which I'm fascinated about.
SPEAKER_01:And for our listeners and viewers, you can read Isabella's article on AJVR. I'm Sarah Wright here with Lisa Fortier. Be sure to tune in next week for another episode of Veterinary Vertex. And don't forget to leave us a rating and review on EPA Podcasts or wherever you listen.
