Development of CRISPR-Cas3 Weaponized Bacteriophages As Novel Antimicrobials

Ousterout, D., Locus Biosciences
The rapid rise of antibiotic resistance has presented a significant challenge to combating bacterial disease and is projected to cause nearly 10 million deaths by 2050 if new approaches are not developed. This high unmet need has renewed interest in developing novel antimicrobials based on small prokaryotic viruses called bacteriophages. While phage therapy has long been associated with safety, therapeutic efficacy has yet to be demonstrated in well controlled clinical trials. Locus Biosciences is an emerging biotechnology company that is developing narrow spectrum antimicrobials to combat antibiotic resistant infections by exploiting the novel mechanism of action of CRISPR-Cas3 to trigger programmed cell death in targeted bacterial populations. CRISPR-Cas systems naturally act as adaptive immune systems in bacteria that can be readily programmed to target DNA for destruction. We have adapted Type I CRISPR-Cas3 systems as programmable exonucleases to destroy DNA efficiently, specifically, and beyond repair, thereby killing a targeted bacterium. Locus is pairing CRISPR-based killing technology with phages to create CRISPR-phages (crPhages) that act as DNA delivery vectors to achieve robust infection and sequence-specific programmed cell death in targeted bacterial populations. We will present work demonstrating proof-of-concept data for a crPhage product with activity against E. coli isolates in vitro and in vivo, as well as preliminary preclinical studies that support the use of designer crPhage products to eliminate bacterial diseases.