Turning bacteria’s own CRISPR defense system against them.
CEO: Paul Garofolo
Based: Morrisville, North Carolina
Clinical focus: Bacterial infections and microbiome-related diseases
The scoop: The idea of using bacteriophages to fight bacteria has been around for a century, but it died down after the successful introduction of antibiotics. Now, with superbugs on the rise, these bacteria-hunting viruses are making a comeback.
And to make phages more effective at killing bacteria, Locus Biosciences is arming them with CRISPR-Cas3, a defense mechanism bacteria originally used against phages. By combining phages’ precision with CRISPR-Cas3’s DNA-shredding ability, the Research Triangle Park biotech hopes to reform how we treat bacterial infections, including multidrug-resistant superbugs—and perhaps other microbiome-related diseases as well.
What makes Locus fierce: Naturally occurring phages could target bacteria, but “just like any other predator-prey relationship on the entire planet, a predator will never kill all of its prey,” Locus CEO Paul Garofolo explains. Natural phages always leave residual bacteria behind, leaving the door open for a pathogen to come back even stronger.
Many phage companies have emerged recently, but the difference is, Locus has CRISPR-Cas3. Unlike the Cas9 enzyme that's grabbed the limelight as a novel gene-editing tool, the Cas3 variant can chew up the DNA pathogens rely on to survive, leading to cell death.
Destructive as it is, however, Locus’ CRISPR-phage platform is theoretically safe for healthy cells because a phage only binds to specific bacteria—and only then injects the engineered CRISPR-Cas3 payload. To help find the right combination of phages for different bacterial species, in 2018, Locus acquired California biotech EpiBiome and its high-throughput phage discovery platform.
“Even if the drug product circulates through the human body, … it will only interact with that targeted set of bacteria, and all the other bacteria in the human body are safe, which is a dramatic difference in the way that antibiotics work,” Garofolo explains. And “even if somehow the CRISPR-Cas3 constructs got into a human cell, there would be no target for it to hit because we select against genes that are in the human genome,” Locus’ SVP of business development, Joseph Nixon, adds.
Locus’ approach has attracted Johnson & Johnson’s Janssen Pharmaceutical, which in January unveiled a deal worth up to $818 million for Locus’ programs. To Garofolo and Nixon, the deal shows Big Pharma is moving back into the antibacterial field, which “could hold the key to the next real disruptive revolution” in medicine—and Locus’ technology holds the greatest promise.
Currently, the collaboration focuses on two respiratory pathogens, and Locus’ lead project targets urinary tract infections caused by E. coli. While the CRISPR-phage system could potentially disrupt the infectious disease treatment landscape by replacing antibiotics in the front line, Garofolo said, he also believes it could reach far beyond that.
Pharma bigwigs “are not coming back to solve the antibiotic replacement problem alone,” he said. “They’re coming back because of the promise to be able to lean on that foundation while also being able to explore moving this therapy in other microbiome-related human diseases.” In that sense, infectious disease could serve as a steppingstone to a much larger market for Locus.
Researchers have linked the gut microbiome to obesity, diabetes, and even some cancer types and central nervous system diseases such as Parkinson’s, among others.
“Almost every microbiome investment that’s ever been made is in additive therapy,” Garofolo said. “They’re trying to add engineered bacteria and probiotics into the human body to try to reconstitute the microbiome in the human body.” In contrast, Locus aims to simply remove bacteria that might be implicated in these diseases.
Locus is now talking to J&J about expanding their deal, and it’s “in active discussions” with other pharma companies for additional assets. The company anticipates announcing a second deal, possibly next year, Garofolo said. And it hopes to get an FDA green light to start human testing of its lead drug later this year.
Investors: Artis Ventures, Tencent Holdings, Abstract Ventures, North Carolina Biotechnology Center, and others