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Locus Biosciences Lifts Lid on Crafty CRISPR to Bust Bad Bacteria

The lid is off Locus Biosciences.

The Raleigh bioscience spinout of North Carolina State University is using a version of the hot gene-editing technology called CRISPR to cut a new path to the discovery and development of novel antibiotics. In a biotech bow to Pac-Man, it’s coaxing naturally occurring microscopic enzymes to chomp away DNA in bad bacteria in order to kill the target pathogen.

CRISPR is an acronym for a phenomenon in DNA structure called Clustered Regularly Interspaced Short Palindromic Repeats. Bacteria have evolved with it over millions of years to use it as a defense mechanism against invaders. In the past decade or so, scientists have found a number of accompanying enzymes that perform a variety of functions within bacterial cells, from cutting and killing to repression and activation of genes.  The most well-known enzyme these days is Cas9, which can be used as a highly accurate “molecular scissors” to clip DNA at specific places inside both bacterial and human cells.   

The Cas9 can trigger a cell's DNA repair machinery to address, say, a genetic defect. In other words, it can precisely cut out a mutated section of DNA and replace it with one that functions properly. What “cut-and-paste” does for word processing, CRISPR can do for gene editing.

Locus co-founders Rodolphe Barrangou, Ph.D. (left) and Kurt Selle, Ph.D., advance CRISPR-Cas3 technology at company's lab on the NCSU campus. -- Locus photos

Cas9 is the enzyme most studied and used so far, but researchers are also exploring CRISPR systems that use other enzymes. One of the most prominent scientists leading that charge is Rodolphe Barrangou, Ph.D., professor in the NCSU Department of Food, Bioprocessing and Nutrition Sciences, who is also one of five Locus co-founders.  

Barrangou has discovered how to hijack the CRISPR-Cas3 mechanism to turn the bacterial immune system on itself, thereby driving programmed cell death inside bacterial targets.  The Cas3 technology enables the specificity and accuracy of CRISPR to be used for novel applications in the antimicrobial and microbiome space.  

Barrangou notes that the understanding of CRISPR function and mechanism of action has allowed the development of CRISPR-based technologies for a variety of useful applications. They range from vaccination of food cultures to gene therapy and next-generation antimicrobials. It could also lead to new kinds of crops and animal proteins that could, technically, avoid the controversial category of genetically modified organisms.

Barrangou, who joined the NCSU faculty in 2013, was honored for his pioneering CRISPR work as one of seven esteemed scientists to receive the 2016 Canada Gairdner International Award – sometimes referred to as the “Canadian Nobel.”

Powerful technology brings careful development

Currently the buzz over CRISPR-Cas9 is based on its unprecedented precision in editing DNA. But that’s also why it’s under heavy scientific and ethical scrutiny. It’s important and elegant, but it raises big questions like, “Where are the boundaries on editing the human race -- and all other organisms for that matter?”

Even so, CRISPR is drawing early investment to all three of the largest Triangle research universities. For example, an Atlanta-area company, Cocrystal Pharma, recently licensed certain patents and know-how from Duke and Emory Universities related to CRISPR-Cas9 technologies, to help it develop cures for hepatitis B and human papilloma virus (HPV) infections.

Cambridge, Massachusetts-based Editas Medicine became the first publicly traded company using CRISPR to develop drugs. Editas has licensed technology from Duke that the university’s researchers are testing in mice to treat Duchenne muscular dystrophy. The University of North Carolina at Chapel Hill is also using CRISPR-Cas9 in lab animals.

Other publicly traded companies seeking to commercialize CRISPR technologies include CRISPR Therapeutics AG, of Basel, Switzerland, and another Cambridge company, Intellia Therapeutics, also co-founded by Barrangou.

Garofolo

Because of its breakthrough potential, CRISPR-Cas9 is also the topic of a patent dispute between Boston’s Broad Institute of MIT and Harvard, and scientists from the University of California, Berkeley. The groups at both coasts contend they have exclusive rights to the technology.

CRISPR-Cas3 bacterium

Locus co-founder and CEO Paul Garofolo, a veteran pharmaceutical industry executive, says the Locus team has sought to avoid the noise by operating in what they’ve called “stealth mode” since setting up shop on the NCSU Centennial Campus in 2015. And it’s also significant that they’re working with a different version of the technology, Cas3, which causes targeted bacteria to self-destruct.   Their plans involve developing a series of novel smart-antimicrobials to potentially address the growing global epidemic of antibiotic resistance.  

They started the company with the help of a $75,000 Company Inception Loan from the North Carolina Biotechnology Center. NCBiotech followed that with a $250,000 Small Business Research Loan in early 2016. The company has also completed a $1.5 million initial round of venture capital investment, and expects to close on an additional $20 million Series A round of funding in 2017.

Early NCBiotech funding paying off with investment, employment

Locus already has six full-time employees, and is in the process of hiring a seventh -- a full-time lab technician.

Garofolo is a former executive vice president of Patheon, a contract manufacturer based in Durham. In the mid-2000s, he held the chief information officer position at Valeant Pharmaceuticals.

Another Locus co-founder, Dave Osterout, Ph.D., is the company’s chief technology officer. The other full-timers include Nick Taylor, MMB, MBA, previously a consultant with the Biotech Center and now the Locus project/program manager of R&D. The company’s bench scientists so far include Sandi Wong, Ph.D., and Kurt Selle, Ph.D.

“When our Series A funding gets placed, we’ll go up to 20 full-time people in 2017,” says Garofolo, “and probably expand ultimately to a top capacity of about 65 people.”

This is a Locus with a focus. It has the potential for delivering a Pac-Man punch to a growing list of drug-resistant bugs. And now it’s definitely out of stealth mode, with a bacteria-busting technology that has the potential to be safer, yet more powerful, than existing antimicrobials.

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