10:34 AM
 | 
Aug 31, 2017
 |  BC Innovations  |  Product R&D

Cutting through resistance

How Locus Biosciences is using CRISPR-Cas3 to tackle antibiotic resistance

Most companies employing CRISPR-Cas9 for therapeutics are using it to edit human cells, but Locus Biosciences Inc. is betting the lesser-known CRISPR-Cas3 system will do a better job of treating bacterial infections and could be the long-sought solution to antibiotic resistance.

The company was launched two years ago to develop an antimicrobial platform that turns bacteria's natural CRISPR-Cas3 defense system against itself to eliminate specific pathogenic species while sparing human cells and the microbiome.

Locus has over $7 million in funding, which includes equity financing, a loan and a $5 million convertible note from the North Carolina Biotechnology Center and Chinese investor Tencent Holdings Ltd. The company hopes to close a series A round this fall -- at which point, the $5 million note would convert to equity --, giving it enough financing to bring it into the clinic.

The standard CRISPR approach uses the Cas9 endonuclease to make targeted double-stranded breaks in DNA and relies on the cell's natural, but imperfect, DNA repair mechanisms to disrupt individual genes by creating insertion-deletion mutations during the repair process. By contrast, the Cas3 exonuclease works by first nicking a target site, then chewing through the rest of the DNA, which destroys not only the DNA but the cells themselves.

For that reason, this system has been largely overlooked for human therapeutics, but it provides a unique advantage when targeting pathogens.

"Cas9 is the famous endonuclease because it has been good for making precise, clean cuts that lead to DNA repair in eukaryotic cells, but Cas3 is actually the most dominant, widely distributed type of CRISPR-Cas system in nature," said Locus co-founder and CSO Rodolphe Barrangou.

He added: "Cas3 is so widespread in nature because it can very effectively kill predator cells. And that's why we decided to repurpose it, to generate damage in pathogenic organisms."

"We are the only company to have the Cas3 technology, and I think it works at an efficacy level that no one else can touch. I think it can change the face of medicine to eradicate antibiotics."

Rodolphe Barrangou, Locus Biosciences

For treating bacterial infections, the CRISPR-Cas3 platform also offers fewer safety concerns and a less complicated IP landscape than standard CRISPR-Cas9 approach.

Locus CEO Paul Garofolo said targeting the CRISPR-Cas3 system to bacterial cells negates the risk of off-target effects on human genes because the system doesn't even enter human cells. That means the path through the clinic should be shorter than for standard CRISPR-Cas9.

And while ownership of the CRISPR-Cas9 gene editing technology is tied up in an IP dispute between the Broad Institute of MIT and Harvard and the University of California Berkeley, Cas3 falls "100% outside the scope of those claims," he said.

He told BioCentury the company has a "dominant and exclusive" IP position surrounding CRISPR-Cas3 based on over a decade of research from Barrangou and...

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