Eligo Bioscience modifies microbiome that could inactivate antibiotic-resistant genes

16 Jul 2024 --- Scientists at microbiome in vivo gene editing pioneer Eligo Bioscience have demonstrated a way to genetically modify bacteria in the gut of animals. This lays the groundwork for strategies to better understand how genes from the microbiome drive disease and creates opportunities to develop new therapies.

“We can now not only develop highly targeted gene editing therapies for the microbiome, inactivating with unprecedented precision bacterial genes that drive disease. But this technology unlocks the capability for scientists to really decipher and understand the relationship between a specific bacterial gene and its implication in disease progression, Xavier Duportet, Ph.D, co-founder and CEO of Eligo Biosciences, tells Nutrition Insight.

“We believe this tool can really boost microbiome research and the identification of new therapeutic targets.”

The company demonstrated how to engineer a bacteriophage-derived capsid with a synthetic DNA payload encoding a base-editor system, a targeted method of genome editing. The capsid was orally administered to mice and the payload was delivered with precision to bacterial populations residing among hundreds of bacterial species in the gut.

Editing disease-driving genes
The study, published in Nature, describes how the researchers engineered a phage-derived particle to deliver a base editor and modify Escherichia coli in the bacteria colonies of the gut. While CRISPR-derived tools have successfully edited disease-driving genes in human cells, scientists need the tools to achieve the same success for bacterial targets in situ.

“Until now, we only had the opportunity to kill bacteria or bring new ones, but not alter the existing ones. This tool is the first one that can lead to precise editing of a target gene without modifying the surrounding microbiome,” Duportet explains.

“It brings two opportunities — novel targeted therapeutic interventions and the discovery of novel therapeutic targets by studying the structure and function of specific bacterial genes.”To further the research, scientists must create relevant animal models to observe this form of bacterial editing.     

Editing the β-lactamase gene in a model E. coli strain resulted in a median editing efficiency of 93% of the target bacterial population with a single dose. Edited bacteria were stably maintained in the mouse gut for at least 42 days following treatment. The scientists then leveraged this approach to edit several genes of therapeutic relevance in E. coli and Klebsiella pneumoniae strains.

“We are already using it in two undisclosed therapeutic programs,” says Duportet.

Eligo Bioscience pioneers microbiome in vivo gene editing and is advancing a highly differentiated pipeline of precision medicines to address unmet medical needs in immuno-inflammation, oncology and infectious diseases.

Bacterial peptides
The researchers have gained further insights on the role of bacterial genes in disease, such as bacterial peptides that trigger autoimmune diseases to virulence factors that contribute to inflammation, tumor formation and neurodegenerative diseases.

Editing a gene in situ bypasses the need to remove the target bacterium and replace it with a genetically modified strain. This is challenging without imposing strong perturbation of the gut environment. The delivery method used in the current study avoids perturbations as in previous studies using phages achieved delivery.  

“What Eligo has achieved shows that it’s now possible to make specific changes to the DNA of bacteria in the gut, similar to how scientists have been editing human genes to investigate or treat genetic disorders,” says David Bikard, cofounder of Eligo Bioscience and researcher at the Institut Pasteur in Paris.

The new system can precisely inactivate antibiotic-resistance genes by creating single-base pair mutations in the corresponding genes. When targeting E. coli strains, the technology modifies the target gene in over 90% of the bacteria, reaching up to 99.7% in some cases.

According to the researchers, future research will focus on developing relevant animal models to demonstrate that in situ bacterial editing can benefit the host. 

Meanwhile, researchers at the University of Oxford, UK, suggest diverse communities of resident bacteria can protect the human gut from harmful pathogens by consuming nutrients that these disease-causing microorganisms need. They note that their findings could help develop new strategies to optimize gut health.

By Inga de Jong