Locus Biosciences Explained

Locus Biosciences
Type:Privately held company
Industry:Pharmaceutical company
Founded: in Raleigh, NC, USA
Hq Location City:Morrisville, North Carolina
Hq Location Country:United States
Brands:crPhage
Profit:-->
Profit Year:-->
Owners:-->
Num Employees:80
Num Employees Year:2021

Locus Biosciences is a clinical-stage pharmaceutical company, founded in 2015 and based in Research Triangle Park, North Carolina.[1] Locus develops phage therapies based on CRISPR–Cas3 gene editing technology, as opposed to the more commonly used CRISPR-Cas9, delivered by engineered bacteriophages.[2] The intended therapeutic targets are antibiotic-resistant bacterial infections.[3]

History

The company was founded as a spin-off from North Carolina State University (NCSU) in 2015 with licensed CRISPR patents from the university.[4] [5] The company started with a $5 million convertible note from Tencent Holdings and North Carolina Biotechnology Center.[6]

In 2017, the company closed a $19 million Series A led by Artis Ventures, Tencent Holdings Ltd, and Abstract Ventures. In 2020, the company sold convertible notes in a debt raise to roll into its next equity round in 2021.

In 2018, Locus acquired a high-throughput bacteriophage discovery platform from San Francisco-based phage therapy company Epibiome, Inc.[7] [8]

In 2019, the company entered into a strategic collaboration with Janssen Pharmaceuticals (a Johnson & Johnson company) worth up to $818 million to develop CRISPR-Cas3 drugs targeting two bacterial pathogens.[9] [10] [11] Locus received $20 million upfront and up to $798 million in milestones and royalties on net sales.[12]

In 2020, the company signed a $12.5 million partnership with the global non-profit, Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator (CARB-X). In November 2020, Locus had 52 employees;[13] by the end of 2021, it had about 80 employees.[14] As of January 2022, the company and all employees were contained in a single 25,000 square foot research and manufacturing facility.

In 2022, the company closed a $35 million Series B funding round, with participation from Artis Ventures, Tencent, Viking Global Investors, and Johnson & Johnson.[15] Locus announced in September 2022 that it had begun patient treatment in its trial of LBP-EC01, in partnership with the BARDA, for the treatment of UTIs caused by E coli bacteria.[16]

CRISPR CAS3

See main article: CRISPR.

CRISPR-Cas3 is more destructive than the better known CRISPR–Cas9 used by companies like Caribou Biosciences, Editas Medicine, Synthego, Intellia Therapeutics, CRISPR Therapeutics and Beam Therapeutics. CRISPR–Cas3 destroys the targeted DNA in either prokaryotic or eukaryotic cells.[17] Co-founder, Rodolphe Barrangou, said "Cas3 is a meaner system...but if you want to cut a tree and get rid of it, you bring a chain saw, not a scalpel".[18]

CRISPR-Cas systems fall into two classes. Class 1 systems use a complex of multiple Cas proteins to degrade foreign nucleic acids. Class 2 systems use a single large Cas protein for the same purpose. Class 1 is divided into types I, III, and IV; class 2 is divided into types II, V, and VI.[19] The 6 system types are divided into 19 subtypes.[20] Many organisms contain multiple CRISPR-Cas systems suggesting that they are compatible and may share components.[21] [22]

Difference between CRISPR-Cas3 and CRISPR-Cas9
Class Cas type Signature protein Function Reference
1 I Cas3 Single-stranded DNA nuclease (HD domain) and ATP-dependent helicase [23] [24]
2 II Nucleases RuvC and HNH together produce DSBs, and separately can produce single-strand breaks. Ensures the acquisition of functional spacers during adaptation. [25] [26]

Therapy development

The company enrolled its first patient in a Phase 1b clinical trial in January 2020. The trial intends to evaluate LBP-EC01, a CRISPR Cas3-enhanced bacteriophage against Escherichia coli bacteria which cause urinary tract infections.[27] Twenty patients will get a phage cocktail, and 10 will get a placebo.[28] The trial completed before March 2021 and a Phase II trial is expected to start within two years. The company has an agreement the US government's Biomedical Advanced Research and Development Authority which began in 2020 and provides funding to support Phase II and Phase III trials.

Publications

As of 2022, there are no peer-reviewed publications that are solely or primarily authored by Locus Biosciences staff.[29]

Notes and References

  1. News: Eanes . Zachery . March 9, 2021 . Locus using gene-editing technology to get ahead of drug-resistant bacteria . B4 . . August 19, 2022 . Newspapers.com.
  2. Gibney . Elizabeth . What to expect in 2018: science in the new year . Nature . 553 . 7686 . 12–13 . January 2, 2018 . 10.1038/d41586-018-00009-5 . 29300040 . 2018Natur.553...12G . free .
  3. News: Buhr . Sarah . Move over Cas9, CRISPR-Cas3 might hold the key to solving the antibiotics crisis . December 21, 2018. TechCrunch . July 18, 2020 . https://web.archive.org/web/20190220100141/https://techcrunch.com/2016/12/21/move-over-cas9-crispr-cas3-might-hold-the-key-to-solving-the-antibiotics-crisis/ . February 20, 2019 . live .
  4. News: Brown. Kristen V.. February 24, 2017. Scientists Are Creating a Genetic Chainsaw to Hack Superbug DNA to Bits. Gizmodo. G/O Media. live. July 18, 2020. https://web.archive.org/web/20181209122153/https://gizmodo.com/a-little-known-crispr-technique-could-be-the-key-to-fig-1792689477. December 9, 2018.
  5. News: Shieber . Jonathan . January 4, 2019 . Up to $818 million deal between J&J and Locus Biosciences points to a new path for CRISPR therapies . . live . March 8, 2019 . https://web.archive.org/web/20190203014835/https://techcrunch.com/2019/01/04/up-to-818-million-deal-between-jj-and-locus-biosciences-points-to-a-new-path-for-crispr-therapies/ . February 3, 2019.
  6. News: Martz. Lauren. August 31, 2017. Cutting through resistance. Biocentury. limited. July 18, 2020.
  7. News: July 17, 2018 . Locus Biosciences Acquires EpiBiome Bacteriophage Discovery Platform . Genomeweb . registration . February 27, 2019.
  8. News: CRISPR-Cas3 Platform Developer Locus Biosciences Acquires EpiBiome Phage Technology. July 17, 2018. Genetic Engineering & Biotechnology Nerws.
  9. News: Taylor . Phil . J&J takes stake in Locus' CRISPR-based 'Pac-Man' antimicrobials . February 27, 2019 . Fierce Biotech . January 3, 2019 . https://web.archive.org/web/20190306192547/https://www.fiercebiotech.com/biotech/j-j-takes-stake-locus-crispr-based-pac-man-antimicrobials . March 6, 2019 . live .
  10. Molteni . Megan . January 16, 2019 . Antibiotics Are Failing Us. Crispr is Our Glimmer of Hope . live . Wired . https://web.archive.org/web/20190123205808/https://www.wired.com/story/antibiotics-are-failing-us-crispr-is-our-glimmer-of-hope/ . January 23, 2019 . March 8, 2019.
  11. Schmidt . Charles . November 1, 2019 . Is Phage Therapy Here to Stay? . . 50–57 . October 23, 2019.
  12. News: Brown . Kristen . January 3, 2019 . J&J Bets $20 Million on DNA Tool to Battle Infectious Bacteria . Bloomberg . subscription . February 27, 2019.
  13. News: Maurer . Allan . November 19, 2020 . Gene editing success could turn Triangle startup Locus Biosciences into a billion dollar unicorn . WRAL TechWire . .
  14. News: Eanes . Zachery . January 29, 2022 . Locus Biosciences is eyeing immunology for its CRISPR tech . 158 . A6 . . 29 . August 19, 2022 . Newspapers.com.
  15. News: Bacteriophage producer Locus Biosciences raises $35m in financing. Jane Byrne. May 19, 2022. BioPharma Reporter.
  16. News: Locus Biosciences announces first patient treated in urinary tract infection trial. Emily Kimber. September 15, 2022. PM Live.
  17. 10.1038/nature.2017.22173. 28661508. Modified viruses deliver death to antibiotic-resistant bacteria. Nature. 546. 7660. 586–587. 2017. Reardon. Sara. 2017Natur.546..586R. free.
  18. News: Marcus . Amy Dockser . A Genetic 'Chain Saw' to Target Harmful DNA . Wall Street Journal . live . limited . February 27, 2019 . https://web.archive.org/web/20180306074907/https://www.wsj.com/articles/a-genetic-chain-saw-to-target-harmful-dna-1477081818 . March 6, 2018.
  19. Wright AV, Nuñez JK, Doudna JA . Biology and Applications of CRISPR Systems: Harnessing Nature's Toolbox for Genome Engineering . Cell . 164 . 1–2 . 29–44 . January 2016 . 26771484 . 10.1016/j.cell.2015.12.035 . free .
  20. Westra . Edze R. . Dowling . Andrea J. . Broniewski . Jenny M. . van Houte . Stineke . vanc . Evolution and Ecology of CRISPR . Annual Review of Ecology, Evolution, and Systematics . November 2016 . 47 . 1 . 307–331 . 10.1146/annurev-ecolsys-121415-032428 . free .
  21. Wiedenheft B, Sternberg SH, Doudna JA . RNA-guided genetic silencing systems in bacteria and archaea . Nature . 482 . 7385 . 331–8 . February 2012 . 22337052 . 10.1038/nature10886 . 2012Natur.482..331W . 205227944 .
  22. Deng L, Garrett RA, Shah SA, Peng X, She Q . A novel interference mechanism by a type IIIB CRISPR-Cmr module in Sulfolobus . Molecular Microbiology . 87 . 5 . 1088–99 . March 2013 . 23320564 . 10.1111/mmi.12152 . free .
  23. Sinkunas T, Gasiunas G, Fremaux C, Barrangou R, Horvath P, Siksnys V . Cas3 is a single-stranded DNA nuclease and ATP-dependent helicase in the CRISPR/Cas immune system . The EMBO Journal . 30 . 7 . 1335–42 . April 2011 . 21343909 . 3094125 . 10.1038/emboj.2011.41 .
  24. Huo Y, Nam KH, Ding F, Lee H, Wu L, Xiao Y, Farchione MD, Zhou S, Rajashankar K, Kurinov I, Zhang R, Ke A . Structures of CRISPR Cas3 offer mechanistic insights into Cascade-activated DNA unwinding and degradation . Nature Structural & Molecular Biology . 21 . 9 . 771–7 . September 2014 . 25132177 . 4156918 . 10.1038/nsmb.2875 .
  25. Gasiunas G, Barrangou R, Horvath P, Siksnys V . Cas9-crRNA ribonucleoprotein complex mediates specific DNA cleavage for adaptive immunity in bacteria . Proceedings of the National Academy of Sciences of the United States of America . 109 . 39 . E2579–86 . September 2012 . 22949671 . 3465414 . 10.1073/pnas.1208507109 . 2012PNAS..109E2579G . free .
  26. Heler R, Samai P, Modell JW, Weiner C, Goldberg GW, Bikard D, Marraffini LA . Cas9 specifies functional viral targets during CRISPR–Cas adaptation. Nature . 519 . 7542 . 199–202 . March 2015 . 25707807 . 4385744 . 10.1038/nature14245 . 2015Natur.519..199H .
  27. Web site: Locus Biosciences initiates world's first controlled clinical trial for a CRISPR enhanced bacteriophage therapy . January 8, 2020 . January 11, 2020.
  28. News: Scientists Modify Viruses With CRISPR To Create New Weapon Against Superbugs . May 28, 2019 . NPR . May 22, 2019.
  29. Web site: Locus Biosciences[Affiliation] - Search Results - PubMed ]. 2022-08-20 . PubMed . en.

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