Worm-Derived Drugs May One Day Treat Allergic and Autoimmune Diseases

By Deborah Borfitz

December 13, 2023 | After more than a decade of eavesdropping on the language of worms, Andrea Choe, M.D., Ph.D., now has several worm-derived molecules under development, including one heading into clinical trials in 2024. As the cofounder and CEO of startup Holoclara, she has made it her life’s work to discover if the molecular language of worms could be a “Rosetta stone” for treating allergic and autoimmune diseases.  

The bigger question initially was why no one else had seriously investigated the linkage, backed by epidemiological evidence, between the presence of roundworms in the gut to the absence of conditions related to the immune system, she says. People throughout human history, King Richard III most notably among them, have been infected with roundworms in their intestines as have mummies from Utah to China.   

Only with industrialization, when parasitic worms came to be viewed as gross and uncivilized, did anthelmintics come on the scene to expel them from the human body, points out Choe. “Lo and behold that is also when allergic and autoimmune diseases started coming out on the scene” with prevalence rates doubling if not tripling over the last couple of decades. 

Patients unable to find a working therapeutic option for their immune-related disorder and desperate for a cure have trekked to the other side of the world to introduce worms into their bodies on purpose, as reported by The New York Times Magazine (The Parasite Underground) and other major news outlets.  Choe was a Ph.D. student at California Institute of Technology (Caltech) when she stumbled onto a Radiolab podcast about a man with intractable asthma who walked barefoot in Africa to get a roundworm infection, sparking the idea to undertake a project about the molecular languages of roundworms which, as it turned out, held constant over time and across species. 

She saw the unmet clinical need firsthand during her subsequent medical school training at the University of Southern California. Many hospitalized patients with autoimmune diseases, often undiagnosed, were being treated with either steroids powerful enough to shut down their entire immune system or biologics targeting one molecular pathophysiology that didn’t always work. 

But it wasn’t until she returned to Caltech as a postdoctoral scholar that the idea firmly took root to start Holoclara, which borrows from a Greek word meaning “complete.” In a series of preclinical studies, Choe identified several worm-derived molecules that demonstrated significant therapeutic effect against both allergic and autoimmune diseases. 

“This is something we’ve been sitting on for hundreds of millions of years,” Choe enthuses. Given renewed medical interest in borrowing from nature—CRISPR came from bacteria, optogenetics from algae, and Ozempic from Gila monsters, she cites as examples—there has never been a better time to start mining worms for answers. 

Holoclara’s initial program is replicating the language of worms using traditional synthetic chemistry to possibly treat, and potentially cure, many common diseases with orally available drugs. The company, founded in 2017 and backed by some of the top investors in the industry, is currently focused on allergic diseases with roundworm-derived molecules. 

Endless Possibilities

Choe’s Ph.D. thesis didn’t start out as a paper about the common communication mechanism in worms, but the unique languages bestowed on different species by evolution. The Human Genome Project had recently been completed and scientific interest in working with Caenorhabditis elegans, the humble nematode whose genome sequence served as a pilot project, was by now universal. 

It was at Caltech that Choe became enamored with the simplicity of studying genetics using roundworms. A laser microscope can be used to look at any cell type at any stage of life to ask what happens next, she explains. The worms can also be fed modified bacteria to knock out a particular gene, or neural cells can be ablated, to see the effects on motor activity and lifespan. It was also one of the first animals to have every synaptic connection between nerve cells mapped.  

“The possibilities were endless so of course I wanted to get involved,” says Choe. “I was like a kid in a candy store.” 

But when her advisor left town on sabbatical, she “totally went rogue” on the intended genetics project, she says. After observing the worms under a microscope moving in interesting ways, sometimes together and other times apart, she became fascinated by the mystery of what was driving their behavior. “I actually fell in love with the question of what they are saying.” 

The subject was broader than C. elegans, the worm species starring in multiple Nobel prizes, Choe says. She wanted to understand the shared language of worms that transcended evolution. 

Worms can be sequenced to know exactly at what point in history they evolved, she says, but after studying dozens of them and placing them on their respective spots on a biogenetic tree, the fact remained that they were all still using the same molecular language. “What are the chances of that? Nobody saw that coming.”   

Regulatory-Grade Molecules 

The molecular secretions being examined by Holoclara for its lead program is informing the creation of a small molecule that can be taken orally. And that’s important, says Choe, because the idea is to as closely as possible reproduce the health-enhancing capabilities of the gut-dwelling worms.  

Other types of therapeutic worms exist but gut-dwelling roundworms are the focus of Holoclara—specifically, the ones known to have a positive effect on human health and not those burrowing into the eyeballs, brains, or muscles, says Choe. It’s an expansive arena—the gut takes in most of the stomach, the first part of the duodenum, and all the small intestine, caecum and appendix, transverse colon, sigmoid colon and rectum—and worms can preferentially dwell in any of those sections. 

The plan is for Holoclara to introduce therapeutic molecules made by these various worms without patients ever having to eat a worm, a yuck factor that has been the downfall of efforts to date, she says. Living roundworms would in any case be a nightmare to regulate in terms of the reproductive capacity of the worms and the timing of their therapeutic secretions. 

Candidate molecules will be individually developed and brought forward for approval by the Food and Drug Administration (FDA), says Choe. An announcement is forthcoming about the soon-to-launch clinical trial of a small molecule that in animals has shown to be safe and efficacious in treating both allergic and autoimmune diseases. 

Research efforts are supported by a crackerjack team of experts that includes company cofounders Paul Sternberg, Ph.D., a biology professor and genetics expert from Caltech, and metabolomics expert Frank Schroeder, Ph.D., a Cornell chemistry professor. Other principals include Caltech professor Brian Stoltz, Ph.D., a leading synthetic chemist and entrepreneur serving as an advisor, and board member Peter Hutt, former chief counsel to the FDA. 

World-renowned worm researcher and immunologist Rick Maizels, Ph.D., professor of parasitology at the University of Glasgow, also serves as an advisor. A scientist in his lab is currently working exclusively for Holoclara, reports Choe. For guiding growth ambitions the company has Stan Lapidus, a serial biotech entrepreneur who was founding CEO of three medical diagnostics companies, including the highly successful Cytyc Corp and EXACT Sciences. 

As experience has shown, “anything is possible,” says Choe. “The answer might be right under your nose, and it could have been there the whole time.” That, she adds, is the most compelling part of her unlikely pivot from medical doctor to extreme biology pioneer.