Turning CRISPR into a bacteria killer. A new principle in antibiotics. Interview: Christian Grøndahl, CEO SNIPR BIOME:

Bugs are winning: WHO has issued dire warnings of 'the post-antibiotic era' in which any person regardless of age or country risk to suffer and die of untreatable bacterial infections. Multi-drug resistance is spreading fast, and we are running out of ways to kill bacteria, not least because of a decade's long discovery void of almost no new antibiotics.
This is where SNIPR BIOME may change things...

By: Rasmus Kragh Jakobsen - Nov. 26, 2019

(Interview is condensed and edited for clarity)

Founder and CEO of SNIPR BIOME, Christian Grøndahl, talks about developing a new paradigm for... — Founder and CEO of SNIPR BIOME, Christian Grøndahl, talks about developing a new paradigm for antibiotics. Credit: SNIPR BIOME.

- You are developing a new paradigm for antibiotics?

Exactly, We have come up with an entirely new way of killing bacteria by disrupting their genes using CRISPR.

All other antibiotics are small molecules - chemicals - that in some ways interfere with the lifecycle of the bacteria. Typically, if the bacteria make a mutation, they can ignore a whole class of antibiotics like tetracyclines.

With 25.000 dying in the US from multi-drug resistant infections and another 20.000 dying in Europe, something has to be done.

So we think it will be very important once we have our technology developed to go after specific bacteria.

- and the idea is to kill just the multi-drug resistant strains and not touch their bacterial neighbours?

Yes. Take, for instance, E. coli. Some of them are pathogenic, some of them cause diarrhea, some cause complicated urinary tract infection, some cause meningitis or sepsis, but you also have E. coli that are just commensals - good bacteria.

So one of our programs is in difficult to treat infections in very vulnerable immune-compromised patients such as cancer patients and solid organ transplantation patients. We are focusing on patients that have a colonization of E. coli that their immune system cannot get rid of. We will then target those E. coli before they cause a massive problem for these immune-compromised patients.

Finding the targets

- can you explain the principle?

We have a large clinical library within SNIPR BIOME of more than a thousand different isolates from patients in the US, Europe, Asia, and from collections of E. coli. It is comprehensive coverage of the latest and most relevant pathogens.

We sequence all of these to have the full genome make-up, and then we select a number of genes to disrupt. Some are essential genes, and some are fingerprint genes for just those pathogenic E. coli.

Then we design our CRISPR array to disrupt not just one gene but many genes in the same bacteria.
Finally, we also give a very very large bioinformatic exercise to make sure we do not touch all the other 'good' bacteria in the microbiome. That is a huge bioinformatic exercise that our regular computers can't do, but we have access to one of the strongest supercomputers in the world called Computerome. In an afternoon, it can easily make that calculation.

CRISPR like computer code

- So you end up having a target-specific kill sequence array?

Yes. That is really fascinating with CRISPR. It's almost computer code. You code in what genes you want to disrupt and make sure you are not disrupting other genes. And of course, we test it in our labs and animal studies.

“This is truly a designer drug”

This is truly a designer drug, because in contrast to other medicines we don't find our drug - we design it. We dial the activity in by deciding which nucleotides need to be in our CRISPR array, and then we manufacture the drug.

- and how is the drug delivered to the patients?

The drug format is either in CRISPR-armed phage particles or in the form of living bacteria, a probiotic like Lactobacillus or 'good' E. coli. Then we can deliver the drug as a pill - a capsule - that the patient will swallow. The capsule will protect the drug to the low pH in the stomach and release either the CRISPR particles or the living bacteria into the proper gut of the patient.

- Do you then have to do all this for each multi-drug bacteria that turns up in a patient?

No, not for each, we believe we can make a drug that will work for all E. coli around the world. Of course, it's different if it's not E. coli but a Pseudomonasor Helicobacter. Then we have to start from scratch.

Christian Grøndahl is co-founder and CEO of SNIPR BIOME - a CRISPR and microbiome company in Copenhagen, Denmark focusing on repurposing CRISPR as a very precise bacterial killing technology. A completely new antibiotic principle using CRISPR to disrupt bacteria genes. Here Christian Grøndahl talks to us about what makes SNIPR BIOME special, the first programs, when they expect to recruit patients, and more.

First patients in 2021

- What are the limitations or the hurdles you need to overcome before recruiting patients or are you already recruiting patients?

No, we are not recruiting patients today. But we have two programs that we are advancing towards the clinic. So we have a lot of activities that are focused on the platform and the technology, but then we also have two programs that we are taking forward.

One program is in these difficult to treat infections in very immune-compromised patients, and the target there is E. coli. For that program, we plan to lock the final drug format in 2020 and to recruit the first patients 12 months later, so in 2021. And for the other program, it will most likely be 6-9 months later if we are a little lucky and a little skilled.

Killing and rebuilding a healthy microbiome

- and what is the other program?

That is in an autoimmune disease called inflammatory bowel disease (IBD) - These patients do not have the normal composition in the gastrointestinal tract and have two problems. They have both lost the richness of many hundreds or many thousands of different bacteria, and they have an overgrowth of unwanted gram-negative bacteria.

We will deal with that overgrowth with our CRISPR targetting, and then we also add back in some of the bacteria that these patients have lost.

This is a more complicated thing than in our first project, where we are merely going after one pathogen that the hospital can easily identify. Here we have to do three things - one diagnostic and two interventions. First, very fine mapping of the microbiome to stratify the patients that have lost the diversity and have this overgrowth. Then we have to administer our CRISPR drug to take out the overgrowing bacteria and most likely also add bacteria to regain some of the lost diversity.

Microbiome melodies

- ok, that's great. I am afraid we are running out of time, but what is your long term vision for this technology?

Yes. For the longer term, our vision is that we are not only able to kill one bacteria - that, of course, is quite valuable to start with - but that's like playing on the piano and only using one key.

We want to be able to play with both hands and make a beautiful melody out of that, so we want to be able to take 5-10 bacteria down and also take 5-10 bacteria up. I think that is completely necessary if you're going to target such a complex ecosystem as the microbiome.

- thank you very much

In 2015 when CRISPR came forcefully alive, Christian Grøndahl was ideally positioned as part of the Wellcome Trust venture branch, helping to build biotech startups. He saw all the new technology coming alive, and while everybody else wanted to edit eukaryotic genomes, it occurred to him that nobody was active in bacteria.

With co-founders professor Morten Sommer at the Danish Technical University and patent lawyer Jasper Clube he set up SNIPR BIOME to repurpose CRISPR as a very precise bacterial killing technology.

Lundbeckfonden Emerge brought in the first seed of €2.6 million, and in 2017 they were awarded a very broad and valuable US patent as the first company globally.

Currently, SNIPR BIOME has issued 6 patents and early this year raised the biggest series A financing round ever in Denmark of $50 million (DKr330 million) to get through the first clinical readout.

The existing investing Lundbeckfonden Emerge is joined with new investors, including Dutch VC shop LSP, Danish North-East Family Office, and German Wellington Partners.

ArticleInterviewCrohn's Inflammatory Bowel Disease, IBDGene therapyMicrobiomeCRISPR-CasSNIPR Biome