Kallyope: Mining the Gut-Brain Axis for Therapies

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July 2021 – Brain and gut like to talk to each other – a lot – and they are having quite the conversation. Complex hormonal and nerve signals are impacting metabolism, immunity, mental health, and other areas. That’s the starting point for Kallyope Inc., which wants to modulate this gut-brain chatter to improve health.

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Founded in 2016 by Columbia University researchers Richard Axel, MD, Tom Maniatis, Ph.D., and Charles Zuker, Ph.D., the company is illuminating these gut-brain signaling mechanisms to develop therapeutics that work in a fundamentally new way.

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“Kallyope is leveraging many of the same sophisticated technologies being used to map neural circuits in the brain to understand the cross-talk between the gut and the brain,” said Nick Naclerio, Ph.D., Founding Partner at Illumina Ventures. “The goal is to develop a comprehensive understanding of gut-brain circuits and target those for therapeutic advantage.”

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The Conversation

The lines of communication between brain and gut include hormone-producing enteroendocrine cells, the enteric nervous system (which has half a billion neurons), the parasympathetic nervous system’s vagus nerve, immune cells, and the microbiome.

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“This system is relevant to multiple conditions of high unmet need,” said Nancy Thornberry, CEO at Kallyope. “First, the gut-brain axis is clearly involved in the regulation of satiety and glucose control, so diabetes and obesity are obvious potential indications. Gut motility and other gastrointestinal disorders, such as celiac and inflammatory bowel disease, are also relevant to this system. There are possible central nervous system applications, such as depression, migraine, and epilepsy.”

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To unravel these circuits, Kallyope has integrated a wide range of sophisticated technologies. Single-cell sequencing helps interrogate each specialized cell type within the gut-brain axis. The vagus nerve alone has over 20 distinct, specialized neuron types.

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But it's not enough to simply identify each cell type. To unravel the circuits, it’s important to understand how these cells communicate with each other. Kallyope uses viruses, imaging, and other means to map these conversations. They also apply opto- and chemo-genetics to activate different cell types and examine their function. To translate these findings, the company is using human and murine gut organoids to assess hormone secretion and gut barrier function.

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Emerging Interventions

Once Kallyope researchers identify these diverse and complex hormonal and neural circuits, they can develop small molecule compounds to target them in the gut, limiting systemic exposure.

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“Our lead program focuses on metabolic circuits associated with diabetes and obesity,” said Thornberry. “Here, we are targeting hormones involved in satiety and glucose control. We leveraged our platform to understand which cell types and molecular targets to pursue and which regions of the gut we should target to maximize secretion of these hormones.”

Kallyope’s second program targets gut barrier function. Thornberry notes that the gut’s surface area is a hundred times larger than the skin’s. And, like the skin, the gut is a sensory organ that also works as a barrier, separating things that should be kept apart. Keeping this barrier intact is essential to preserve health.

“It's become increasingly clear that a disrupted barrier occurs in inflammatory bowel disease,” said Thornberry. “It has also been linked to celiac disease, food allergies, and even autism.”

Kallyope’s lead program on obesity and diabetes is now in the clinic, and they expect important study data in 2022-2023. The gut barrier program is not too far behind.

“We have such an outstanding, productive team,” said Thornberry. “I'm really impressed that, in five and a half years, they've been able to move so fast, from the ground up, to get to the point where we're actually testing molecules in the clinic.”

To learn more, visit https://www.kallyope.com/​.