Promising Data From First-ever CRISPR Phage Therapy Trial

What about efficacy?

With the concession that this clinical trial wasn't designed to test for efficacy, Ousterout says that he saw signs of the exact level of this viral amplification that one would expect if the treatment was working — good news for the future of targeted CRISPR phage treatments.

Of the patient data that the team has analyzed so far, nine out of 11 patients who received the experimental treatment demonstrated amplification. Data on the other two »look promising,« but it's too soon to know for sure.

»If you see amplification, that means you're killing the bug — the E. Coli,« Ousterout says.

It's too soon to definitively say that his phage treatment cured the urinary tract infections, but based on what data he does have, Ousterout is optimistic that the treatment will work.

»That's where this study gets a little beyond the intent of its design. This study is not designed, powered, or sampled to measure the curative effect. Instead, what we're able to clearly show is that they're getting the amplification. Now all the exploratory analysis that we expect to have over the coming weeks is determining what the effect it had on the E. Coli concentration level compared to the control,« Ousterout explains.

To measure that amplification, the researchers catheterized the volunteers. Every 12 hours, a dose of phage therapy was administered directly into the bladder, where the bacteria were growing. What the team found, however, was that the virus concentration in volunteers' urine never diluted to the extent a typical medication might. Instead, virus levels stayed high, indicating that the treatment successfully targeted, replicated inside, and killed off the bacteria even in between doses.

Of course, any commercially available version of the treatment would come in the form of an injection, not a catheterization, Joseph Nixon previously explained.

First, there are several important caveats. Chief among them is, of course, that the Locus Biosciences team isn't done with its analysis and that it still hasn't conducted a phase II trial. But some key details in this study's methodology will help put the tentative-yet-encouraging results into context.

For example, the phage treatment didn't actually cure any urinary tract infections. That's because none of the study volunteers actually had a diagnosable infection that could be cured. Rather, they had colonies of E. Coligrowing in their bladders that, while posing a serious problem that needed addressing, hadn’t reached the threshold of a full-blown infection.

»It was very unique in that we picked a patient population that is asymptomatic, but is what we call colonized by E. Coli. Not quite healthy but not quite actively infected,« Ousterout says.

So while there was clear evidence of viral amplification, it was impossible for the Locus Biosciences team to measure metrics like alleviated symptoms.

Phage therapy as a first-line rather than a last resort

If future clinical trials continue to go well, then Cas3 bacteriophages may prove effective at killing other kinds of pathogenic bacteria — even those that have grown to resist antibiotics like Penicillin. It could even, says Ousterout, help treat serious diseases — even potentially including cancers — by hunting and destroying bacteria in the microbiome or elsewhere that contributes to those diseases emerging.

»In colorectal cancer, there's some evidence that patients who have long term gastrointestinal inflammation have patchy biofilms in their intestinal tract that have consistent bacteria strains in it. One of the bacterial species produces a toxin that may mutate DNA. Another one essentially induces chronic inflammation. The action of those two create an environment that is more conducive to ulcerative colitis or cancer,« Ousterout says.

»It's a chicken and egg situation. We view our tool as being able to help test which is the chicken and which is the egg,« he adds.

Regardless of specific applications that may or may not emerge down the road, studies like these show that phage therapy is leaving the realm of the last resort tool used only in an emergency, which is where it exists today.

»The FDA wants to make sure that these drugs see the light of day in the clinic. They want it because they know they are a necessary component of the arsenal if they can work,« Ousterout says.

With increased interest among researchers and increased funding coming from major business and regulatory partners — Ousterout pointed toward his company's work with Johnson & Johnson — who want to help develop the next big antibiotic treatment, Ousterout predicts that bioengineered phage therapies are going to become a major contributor to the next generation of medical treatments.

To that end, Ousterout has ambitious goals for his Cas3 phages — and high hopes for how they'll fare.

»We're going to move on to phase II and really put it to the test. And for us, that's the signature trial for this UTI indication — to take a rigorous clinical study that demonstrates phage therapy in an actively symptomatic population.«

Dan Robitzski is a science journalist and former neuroscientist based in Los Angeles.