Scientists create the first CRISPR-based drug candidate targeting the microbiome

Newswise — Numerous individuals have encountered E. coli infections, viewed mainly as bothersome and disagreeable. But, for certain patients such as those with blood cancer, there exists a danger that the microorganisms might spread to the bloodstream. In such situations, an E. coli infection frequently results in death. The fatality rate is between 15 and 20%.

The prevailing treatment for such infections involves antibiotics that can harm the patient's microbiome, which plays a crucial role in our overall physical and emotional health, and can cause additional adverse reactions. Additionally, increasing issues with antibiotic resistance make these therapies less efficient in curing infections.

A group of global researchers has recently developed the first CRISPR-based drug candidate (refer to the fact box) for treating E. coli infections that specifically targets the bacteria without harming the microbiome. This breakthrough is described in a newly published paper in Nature Biotechnology titled 'Engineered phage with antibacterial CRISPR–Cas selectively reduce E. coli burden in mice,' which details the progress of the drug candidate to a stage where it is prepared for human trials.

Utilizing extensive synthetic biology techniques, the team engineered four bacterial viruses that utilize CRISPR technology to accurately eliminate the undesired bacteria.

Morten Otto Alexander Sommer, a professor at DTU Biosustain, Co-founder of SNIPR Biome, and the primary author of the paper, asserts, "We are convinced that a drug with these characteristics, targeting a specific spectrum of bacteria, can be highly advantageous for cancer patients, among others, who frequently suffer from severe infections that are challenging to cure using existing antibiotics."

Engineering phages to target E. coli

The group, whose primary location is at SNIPR Biome, examined a collection of 162 naturally occurring phages (viruses that kill particular bacteria; refer to the fact box). They discovered eight phages that demonstrated potential in targeting E. coli. The team then employed gene editing to enhance the phages' ability to target E. coli.

The researchers discovered that a combination of four of these phages, which they named SNIPR001, effectively targeted biofilm bacteria and reduced the number of E. coli in a more significant way than naturally occurring phages. Moreover, they demonstrated that the phage cocktail was well-tolerated in the gut of mice and mini pigs, while decreasing the occurrence of E. coli. SNIPR001 is currently in clinical development and has been given Fast-Track designation (expedited review) by the US Food and Drug Administration.

FACT BOX: An overview of the SNIPR001 creation process:

1. Naturally occurring phages are screened against a panel of E. coli strains.
2. Phages with broad activity against E. coli are tail fibre engineered and/or armed with CRISPR–Cas systems containing sequences specific to E. coli, creating CAPs (Cas-armed phages).
3. These CAPs are tested for host range, in vivo efficacy, and CMC specifications.

SNIPR001 comprises four complementary CAPs and is a new precision antibiotic that selectively targets E.coli to prevent bacteremia in haematological cancer patients at risk of neutropenia (low levels of white blood cells).

Blood cancer patients are first in line

This latest development is particularly significant for blood cancer patients due to the side effects of their chemotherapy treatment. The treatment suppresses the production of blood cells by the patient's bone marrow and leads to intestinal inflammation. The inflammation increases the permeability of the intestines, allowing gut bacteria to enter the bloodstream, leaving the patient vulnerable to infections from bacteria like E. coli. In these instances, the use of SNIPR001 could be beneficial as it specifically targets E. coli without harming the patient's microbiome, which is essential for overall health and wellbeing.

Currently, patients at risk (i.e., those with low levels of white blood cells) receive antibiotic treatments before their chemotherapy, but E. coli has shown resistance to commonly used antibiotics in some cases. Additionally, antibiotics themselves have various side effects that may, in certain circumstances, reduce the effectiveness of cancer treatments.

Morten Otto Alexander Sommer emphasizes the necessity for a more comprehensive range of treatment options for these patients. He states, "It is crucial to have a broader selection of choices at our disposal to manage these patients, preferably ones that enable us to target the causative bacteria specifically, thereby avoiding side effects and contributing to the issue of antibiotic resistance."

In recent years, scientists have begun to reexamine the use of phages as a means of treating infections due to the rise in antibiotic resistance. Prior to the widespread availability of antibiotics, phages were extensively researched and utilized in countries that were then part of the Soviet Union. Nonetheless, there have been only a few clinical trials examining the efficacy of phages, and the results have not been conclusive, as reported in the paper.

Morten Otto Alexander Sommer expresses his optimism regarding the potential of utilizing phages as a means of treating infections through the development of emerging technologies such as CRISPR. He emphasizes that the study's results indicate the possibility of augmenting naturally occurring phages via genetic engineering. He adds, "My aspiration is that this method can serve as a model for the creation of new antimicrobials that target resistant pathogens."

FACT BOX: CRISPR, phages, and phage therapy

CRISPR technology is a way for scientists to edit DNA sequences in cells. It's based on a defence mechanism bacteria naturally use to protect themselves. CRISPR technology uses a molecule called Cas9, which works like a pair of scissors to cut DNA at a specific spot.

After the cut, the DNA can be fixed, or a new piece can be added. Scientists can use this tool to create genetically modified organisms, find new ways to treat genetic diseases, and learn more about how genes work.

Phages are tiny viruses that can kill specific bacteria. They're everywhere on Earth and help regulate bacterial populations and nutrient cycling. They infect and kill bacteria, and when the bacteria die, they release nutrients into the environment.

Scientists use phages to treat bacterial infections, which is called phage therapy. They identify and isolate phages that can kill a specific bacterial strain and use them to fight infections caused by that strain.

Phage therapy has some advantages to antibiotics, like targeting specific bacteria without side effects and potentially reducing antibiotic resistance.