Kallyope Is Digesting Gut–Brain Biology into Medicines

GEN BiotechnologyVol. 2, No. 5 News FeaturesFree AccessKallyope Is Digesting Gut–Brain Biology into MedicinesJonathan D. GrinsteinJonathan D. GrinsteinE-mail Address: [email protected]Senior Editor, GEN Media Group.Search for more papers by this authorPublished Online:16 Oct 2023https://doi.org/10.1089/genbio.2023.29116.jgrAboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail Founded by Columbia University stalwarts Charles Zuker, Richard Axel, and Tom Maniatis, the New York City company is advancing a portfolio of oral small-molecule therapies across metabolism, gastrointestinal disease, and neurological disorders.Charles Zuker, Professor of Biochemistry & Molecular Biophysics and a Professor of Neuroscience at Columbia UniversityCharles Zuker had been studying taste for decades when his lab performed an experiment knocking out the receptor for sweetness in mice to test whether it would be able to distinguish sugar water from plain old water.At first, the mice lacking sweet receptors drink equal amounts of each type of water, whereas a wild-type mouse soon figures out that one of the two is sugar-laden and consequently favor the sweet one. But return 2 days later, the mice are drinking exclusively from the sugar-rich water, even if they lack the receptor for sweetness.1“We figured that there has to be some post-ingestive effect that's triggering this preference. We discovered that this maniacal desire to consume sugar—not sweet, but sugar in particular—was driven by the activation of the gut-brain circuit,” said Zuker when describing the discovery that was the basis for his a-ha moment.“That led to the idea that, my goodness, if activating the circuit can so dramatically transform an animal's behavior, then maybe accessing the gut-brain circuit could also be used to change physiology, metabolism, and so forth,” said Zuker, who is a Professor of Biochemistry and Molecular Biophysics and a Professor of Neuroscience at Columbia University and a Howard Hughes Medical Institute Investigator (Box 1).Box 1. The gut–brain axis: a critical conduit for neural signals informing the brain of the body's metabolic and physiologic stateSurvival requires the integration of external information from senses such as sight, smell, sound, touch, and taste as well as internal sensory cues from the digestive tract.2 To guarantee proper regulation of body physiological processes and behaviors and to promote overall health, informational elements, such as ingested food, energy homeostasis, inflammatory signals, and digestive progress, need to be monitored from the gut.3 The intricate network of neural, sympathetic, endocrine, immune, humoral, and gut microbiota connections—also known as the “brain–gut axis”—controls gastrointestinal homeostasis and connects the brain's emotional and cognitive centers to the gut's functions. This network enables two-way communication between the brain and the gastrointestinal tract, which is home to half a billion neurons, over 100 trillion microbes, and most the body's immune cells.4 The brain–gut axis is becoming increasingly important as a therapeutic target for gastrointestinal and psychiatric disorders, such as inflammatory bowel disease (IBD),5 depression,6 and posttraumatic stress disorder.7Specialized epithelial cells called enteroendocrine cells that line the gastrointestinal tract are always monitoring the contents of food, and sensory nerve endings, enteric neurons, and enteroendocrine cells within the walls of the gastrointestinal tract detect mechanical changes related to ingestion and digestion.8 Sometimes referred to as the “second brain,” the semiautonomous enteric nervous system has multiple roles, including movement of the gastrointestinal tract, changing local blood flow, modifying nutrient handling, and interacting with the immune and endocrine systems of the gut.9,10 Intriguingly, a clear association between many neurological disorders and digestive problems in human patients was noticed and extensively demonstrated in early studies,11 suggesting that the gut–brain axis is not only important for appetite control and intestinal immunity but also essential for brain cognitive functions. The critical neural relay between the gastrointestinal system and the central nervous system is the vagus nerve, which is an essential part of the brain–gut axis and plays an important role in various functions, such as energy homeostasis, food intake, fluid homeostasis, digestion, immune responses, reward, memory, and cognition.12 The vagus nerve also serves an important link between nutrition and psychiatric diseases, including mood and anxiety disorders, as well as inflammatory diseases like IBD.13Accessing the brain through the gut is transformative because it can bypass some of the biggest challenges such as off-target effects, brain accessibility, and the blood–brain barrier. What's more, this pharmacological manipulation can impact human biology systemically to change physiology and metabolism. But understanding the gut–brain axis—the bidirectional communication between the gut and the brain—provides more than a direct link to the brain. It also provides access points to the communication between the brain, gut, and body, which can influence all sorts of hard-wired systemic circuits.These concepts led Zuker to found Kallyope, whereby the Chilean neurogeneticist is changing the drug paradigm by targeting the natural circuits of the gut–brain axis.“When we think about drug discovery, more often than not, we think about a molecule and a protein or receptor,” said Zuker. “Those are critical players, but what we're trying to modify is the way the natural circuit is signaling, and that significantly broadens the way we can find the appropriate targets because now it's not about this one protein that's defective or this one molecule that we have to tweak. The goal is: can we change the way communication happens so that the brain now responds with the proper tweaking? There's an extraordinary opportunity to change body physiology, metabolism, immunity, and organ function by simply taking advantage of natural biology without ever having to literally send a molecule into the brain.”In 2015, with support from Lux Capital, Zuker brought on his “two closest friends and colleagues” at Columbia University, Nobel laureate Richard Axel, and renowned molecular biologist Tom Maniatis, to take this premise of using the gut–brain axis as a platform to form Kallyope.To date, Kallyope—which in Greek means beautiful voice and is also the name of a Greek goddess of epic poetry and eloquence—has raised nearly $480 million, including a $112 million Series C financing in March 2020 and a $236 million Series D financing in February 2022, and has two lead programs in the clinic.The Complete Atlas of the Gut–Brain AxisAround the time that Zuker was launching Kallyope, Nancy Thornberry was leaving her longtime position at Merck, where she was head of diabetes and endocrinology research. She wasn't necessarily looking for a position in operations, but Zuker's concept of using the gut–brain axis to treat disease areas with a high unmet need—including a variety of neurological disorders—captivated her. Thornberry was brought in as the founding CEO and Chair of R&D at Kallyope. In turn, Thornberry has lured a stream of talent from Merck, including current CEO and President Jay Galeota, who spent 28 years at Merck, and Ann Weber, who contributed to more than 40 development candidates, including JANUVIA (sitagliptin) for the treatment of type 2 diabetes (T2D).Nancy Thornberry, Founding CEO and Chair of R&D at KallyopeJay Galeota, Current CEO and President of KallyopeUnder their supervision, Kallyope is leveraging many advanced technologies that have emerged in the study of systems neuroscience to enable a more comprehensive molecular understanding of the neural and hormonal circuitry underlying the gut–brain axis and identify new therapeutic approaches. Together, this platform is called Klarity.One of the technologies at the core of Kallyope's platform is single-cell sequencing, which was a new technology when the company was conceived in 2015. Over the past 8 years, Thornberry said that Kallyope has generated a comprehensive understanding of every specialized cell type in every major component of the mouse and human gut–brain axis, including the gut epithelium, enteric nervous system, and immune cells.“It was a pretty heroic effort, and we're probably the only ones who have those comprehensive atlases,” said Thornberry. “That allows you to start to think about what those specialized cell types do and how they work in a circuit to modulate physiology.” Kallyope has also harnessed circuit-mapping technologies such as optogenetics, chemogenetics, anatomical tracing, and computational mapping to delineate the function of neural circuits.Another critical part of Kallyope's platform is gut organoids, which were also a new technology when the company launched, prompting the recruitment of Hans Clevers to the scientific advisory board. Thornberry said that they have been able to create what is probably an industry-leading platform in gut organoids to look at hormone secretion and gut barrier function.“What Kallyope has accomplished is to take fundamental, basic discoveries that so broadly define entire lines of communication between the body and the brain and decompose them into their elementary components in a way that they can now probe or arrange, which I think is very exciting,” said Zuker.Therapeutic PipelineBehind the Klarity platform, Kallyope has built a portfolio with two programs in clinical trials and several more coming. Galeota said that for Kallyope's lead program, the clinical data have impressive translation at every step and provide some validation for the platform. Clinical data from the second program are expected soon. Kallyope's therapeutic areas of focus are gastrointestinal disease, metabolism, and neurological disorders.“For each of the programs, the platform has been very enabling, and in some cases, it's allowed us to take known biology and think about it in an entirely different way because it's in a totally different context,” said Thornberry.Kallyope is advancing an oral approach to T2D and obesity, two conditions of epidemic proportions in need of improved treatment options. For these metabolic disorders, Kallyope's approach is to induce the secretion of a full spectrum of satiety hormones rather than targeting just one. Kallyope is also advancing novel, oral, nonimmunosuppressive therapeutics to improve gastrointestinal barrier function for gastrointestinal diseases. Their multitargeted approach involves improving epithelial cell homeostasis, restoring appropriate immune responses, and repairing secretory cell function. Additionally, Kallyope has made advances in identifying multiple targets for neurological disorders, including migraine, using a proprietary Human Genetics Platform.“One of the first things I learned when I joined Kallyope is that the surface area of the gut is a hundred times the surface area of the skin,” said Galeota. “So, when you think about the sensory role that the skin plays and how it elicits systemic responses in the brain, imagine a hundred times that and the potential for therapeutic impact. To actually have chased that hypothesis down to the point of being able to demonstrate that it actually works as we've done now and that you can influence systemic response through gut-brain relationships is really exciting.”So far, Kallyope is sticking to small molecules, specifically ones that were already designed for targeting the gut with very low systemic exposure, which results in a low risk for off-target activities and, according to Thornberry, has really paid off. This is critical for their lead program, which is in metabolism and is scheduled to enter Phase II, where safety is paramount, next year.Nevertheless, the Klarity platform is modality agnostic, and Kallyope has entered several partnerships to explore modalities beyond small molecules. In collaboration with Novo Nordisk, Kallyope will discover novel peptide therapeutics to treat obesity and diabetes, and with Sosei Heptares, they aim to identify and validate novel G protein-coupled receptor targets with the goal of creating new drug discovery programs in the area of gastrointestinal diseases. Kallyope is also working with Brightseed, creators of Forager, a pioneering artificial intelligence platform that illuminates the connections between nature and human health, to screen plant compounds to identify and validate active agents that can be further derived into potential therapeutics targeting weight loss management and glucose control.“We have a goal of one new IND per year, and we think that the platform will sustain that for the foreseeable future,” said Galeota. “So, there is this constant need to backfill the funnel with new science that we're supporting.”“We definitely want to fully leverage that and resource it for the identification of the next wave of targets,” said Thornberry. “I don't think we're a company that's going to only advance a portfolio of programs and completely abandon our target discovery efforts with the platform, but that balance will shift in terms of the percent of resources that go to development versus discovery.”A New View of the BrainZuker's role at Kallyope is purely as a scientific advisor. He continues to work on hardwired circuits—those that trigger predetermined responses—that define the most elementary of functions like fight or flight and the sense of hunger and thirst. Zuker likens simple, hardwired circuits to the connectivity within a piano: play a key, send a signal, and get a predetermined response.“[Hardwired circuits are for] things where your brain wants to ensure that you don't think about the response, but you trigger the appropriate response,” said Zuker. “This doesn't mean that they're not flexible and tunable, but it means that they're predetermined—you're born liking sweet, and you're born seeking food when you're hungry and seeking water when you're thirsty. The gut-brain axis is actually one example of a hardwired circuit. You have these unique lines that inform the brain of the state of your body.”But his work has given him a new view of the brain.“Historically, we view the brain as the center of our thoughts, our feelings, our memories, and our emotions—it turns out that the brain does far more than that,” said Zuker. “The brain is the conductor of body biology. It's monitoring the function of every single organ in your body, and it's making sure that it's working within the appropriate range; if not, it sends a descending signal. Such a role is so fundamental at the core of controlling biology.”With Kallyope, Zuker has created a force in developing gut-restricted molecules that can be used to not only play the keys of biology but to lead the orchestra of natural circuits in our bodies to sculpt the physiological and metabolic symphonies of human lives.References1. Tan H-E, Sisti AC, Jin H, et al. The gut–brain axis mediates sugar preference. Nature 2020;580(7804):511–516; doi: 10.1038/s41586-020-2199-7 Crossref, Medline, Google Scholar2. Décarie-Spain L, Hayes AMR, Lauer LT, et al. The gut-brain axis and cognitive control: A role for the vagus nerve. Semin Cell Dev Biol 2023;S1084-9521(23)00032-0; doi: 10.1016/j.semcdb.2023.02.004 Crossref, Medline, Google Scholar3. Wachsmuth HR, Weninger SN, Duca FA. Role of the gut–brain axis in energy and glucose metabolism. Exp Mol Med 2022;54(4):377–392; doi: 10.1038/s12276-021-00677-w Crossref, Medline, Google Scholar4. Hill DA, Artis D. Intestinal bacteria and the regulation of immune cell homeostasis. Annu Rev Immunol 2010;28:623–667; doi: 10.1146/annurev-immunol-030409-101330 Crossref, Medline, Google Scholar5. Bonaz B, Sinniger V, Pellissier S. Vagus nerve stimulation: A new promising therapeutic tool in inflammatory bowel disease. J Intern Med 2017;282(1):46–63; doi: 10.1111/joim.12611 Crossref, Medline, Google Scholar6. Evrensel A, Ceylan ME. The gut-brain axis: The missing link in depression. Clin Psychopharmacol Neurosci 2015;13(3):239–244; doi: 10.9758/cpn.2015.13.3.239 Crossref, Medline, Google Scholar7. Leclercq S, Forsythe P, Bienenstock J. Posttraumatic stress disorder: Does the gut microbiome hold the key? Can J Psychiatry 2016;61(4):204–213; doi: 10.1177/0706743716635535 Crossref, Medline, Google Scholar8. Williams EK, Chang RB, Strochlic DE, et al. Sensory neurons that detect stretch and nutrients in the digestive system. Cell 2016;166(1):209–221; doi: 10.1016/j.cell.2016.05.011 Crossref, Medline, Google Scholar9. Goldstein A, Hofstra R, Burns A. Building a brain in the gut: Development of the enteric nervous system. Clin Genet 2013;83(4):307–316; doi: 10.1111/cge.12054 Crossref, Medline, Google Scholar10. Furness JB. The enteric nervous system: normal functions and enteric neuropathies. Neurogastroenterol Motil 2008;20:32–38; doi: 10.1111/j.1365-2982.2008.01094.x Crossref, Medline, Google Scholar11. North CS, Hong BA, Alpers DH. Relationship of functional gastrointestinal disorders and psychiatric disorders: Implications for treatment. World J Gastroenterol 2007;13(14):2020–2027; doi: 10.3748/wjg.v13.i14.2020 Crossref, Medline, Google Scholar12. Yu CD, Xu QJ, Chang RB. Vagal sensory neurons and gut-brain signaling. Curr Opin Neurobiol 2020;62:133–140; doi: 10.1016/j.conb.2020.03.006 Crossref, Medline, Google Scholar13. Breit S, Kupferberg A, Rogler G, et al. Vagus nerve as modulator of the brain–gut axis in psychiatric and inflammatory disorders. Front Psychiatry 2018;9:44; doi: 10.3389/fpsyt.2018.00044 Crossref, Medline, Google ScholarFiguresReferencesRelatedDetails Volume 2Issue 5Oct 2023 InformationCopyright 2023, Mary Ann Liebert, Inc., publishersTo cite this article:Jonathan D. Grinstein.Kallyope Is Digesting Gut–Brain Biology into Medicines.GEN Biotechnology.Oct 2023.338-341.http://doi.org/10.1089/genbio.2023.29116.jgrPublished in Volume: 2 Issue 5: October 16, 2023PDF download