Gene editing makes bacteria-killing viruses even deadlier – Ars Technica

Cartoon of a phage, showing a complex geometric head connected to the legs by a long stem.

Broad-spectrum antibiotics are like nuclear bombs, wiping out any prokaryotes they encounter. They’re good at killing pathogens, sure, but they’re not so good at maintaining a healthy microbiome. Ideally, we need precision antimicrobials that can only target harmful bacteria while ignoring the other species we need in our bodies, letting them thrive. Enter SNIPR BIOME, a Danish company founded to do just that. Its first drug, SNIPR001, is currently undergoing clinical trials.

The drug is designed for people with cancers involving blood cells. The chemotherapy these patients need can cause immunosuppression as well as increased intestinal permeability, so they can’t fight off any infections they might get from bacteria leaking from their intestines into their bloodstream. . The mortality rate from these infections in these patients is approximately 15-20%. Many infections are caused by E.coliand a big part of it E.coli is already resistant to fluoroquinolones, the antibiotics commonly used to treat these types of infections.

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

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

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

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

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

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