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Unnatural born killers

Gene editing makes bacteria-killing viruses even more deadly

The viruses are engineered to damage essential E coli. genes.

Diana Gitig – | 56
Cartoon of a phage, showing a complex geometrical head connected to legs by a long stalk.
Credit: Getty Images
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Broad-spectrum antibiotics are akin to nuclear bombs, obliterating every prokaryote they meet. They’re effective at eliminating pathogens, sure, but they’re not so great for maintaining a healthy microbiome. Ideally, we need precision antimicrobials that can target only the harmful bacteria while ignoring the other species we need in our bodies, leaving them to thrive. Enter SNIPR BIOME, a Danish company founded to do just that. Its first drug—SNIPR001—is currently in clinical trials.

The drug is designed for people with cancers involving blood cells. The chemotherapy these patients need can cause immunosuppression along with increased intestinal permeability, so they can’t fight off any infections they may get from bacteria that escape from their guts into their bloodstream. The mortality rate from such infections in these patients is around 15–20 percent. Many of the infections are caused by E. coli, and much of this E. coli is already resistant to fluoroquinolones, the antibiotics commonly used to treat these types of infections.

The team at SNIPR BIOME engineers bacteriophages, viruses that target bacteria, to make them hyper-selective. They started by screening 162 phages to find those that would infect a broad range of E. coli strains taken from people with bloodstream or urinary tract infections, as well as from the guts of healthy people. They settled on a set of eight different phages. They then engineered these phages to carry the genes that encode the CRISPR DNA-editing system, along with the RNAs needed to target editing to a number of essential genes in the E. coli genome. This approach has been shown to prevent the evolution of resistance.

After testing the ability of these eight engineered phages to kill the E. coli panel alone and in combination, they decided that a group of four of them was the most effective, naming the mixture SNIPR001. But four engineered phages do not make a drug; the team confirmed that SNIPR001 remains stable for five months in storage and that it does not affect any other gut bacteria.

The researchers showed that SNIPR001 was well-tolerated in Göttingen minipigs—after oral administration, the pigs did not exhibit any clinical, biochemical, hematological, or immunological effects, and no phages were found in their blood, so there was no systemic exposure. In mice, oral administration of SNIPR001 reduced the amount of target E. coli in the feces, and none of the recovered E. coli were resistant to the phage cocktail.

Phage therapy, tempting though it is in theory, has a checkered history at best. But SNIPR BIOME’s goal of using CRISPR to precisely target only harmful bacteria may revitalize this technique, allowing us to continue vanquishing our bacterial foes without promoting drug resistance.

Nature Biotechnology, 2023. DOI: 10.1038/s41587-023-01759-y

Listing image: Getty Images

Diana Gitig Associate Writer
56 Comments
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lazybratsche
Genegineering viruses... what's the worst that could happen?

/s

To take your question at face value, biotechnology actually has a lot of experience making and routinely using replication-incompetent viruses. Essentially we split the viral genome so that the pieces that are essential to replication are not connected to the pieces that are packaged into the viral particle. One essential piece might be integrated into the DNA of an engineered host cell line, another essential piece introduced on a completely seperate DNA molecule, and then finally only the desired payload DNA molecule has sequences that let it interact with the viral proteins that package it up into the assembled virus.
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