Could P. gingivalis Gingipain Inhibition Work in Alzheimer Disease?

Stephen Dominy, MD, the chief scientific officer of Cortexyme

Stephen Dominy, MD

Recently, research has suggested that Alzheimer disease pathology could be driven in part by Porphyromonas gingivalis (P. gingivalis), an infectious agent involved in the development of chronic gum disease. Additionally, the findings showed that inhibiting its protease may be able to treat the neurodegenerative condition.

The investigators, including Stephen Dominy, MD, the chief scientific officer of Cortexyme, which has developed a gingipain inhibitor, CORE-388, identified the pathogen in the brains of patients with Alzheimer disease, as well as the organism’s gingipains—lysine-gingipain (Kgp), arginine-gingipain A (RgpA), and arginine-gingipain B (RgpB)—in the neurons of these patients.

To find out more about the study’s results and the possible implications they have on clinical practice and the understanding of Alzheimer, NeurologyLive spoke with Dominy in an interview.

NeurologyLive: What does this add to the literature on infectious agents in Alzheimer disease?

Stephen Dominy, MD: The reason there’s been so much press around it and the reason it’s been well received, even in the scientific community, is because for the first time we’ve got solid evidence connecting this pathogen, which is Porphyromonas gingivalis, in the development of Alzheimer’s disease.

And we’re building on prior work. There was evidence in the literature, epidemiological evidence, linking P. gingivalis to Alzheimer disease. There were even some mechanistic studies that had been done, and I’d like to point out that in October of just last year, Keiko Watanabe DDS, MS, PhD, and her group at the University of Illinois Chicago group actually orally infected wild type mice with P. gingivalis and demonstrated that it got into their brains. They could see the gingipains in the mouse brains, they saw that induction of amyloid-beta (Aß), and they saw the tau pathology.

In a sense, we actually replicated their work in the mouse model, but what we’ve done is actually taken it further and shown the evidence in the human brain, especially with our identification of the gingipains in the Alzheimer disease brains. This is what’s causing a lot of the excitement because we’ve actually got the evidence in the human brains, and in live Alzheimer disease subjects, now we can actually show evidence of the P. gingivalis in their cerebrospinal fluid. All of these things together, and the fact that we actually have, for the first time, a drug that can actually address it—these gingipain inhibitors—that’s what’s causing all the excitement.

What does the clinician community need to know regarding these findings?

It relates to them in the sense that we just completed a phase 1 clinical trial with the drug CORE-388, which is [Cortexyme’s] lead compound and gingipain inhibitor. We tested it for safety in healthy older adults and patients with Alzheimer disease, and it was very well tolerated. What they need to know is we’re actually moving into a larger, phase 2 clinical trial to test the efficacy later this year, and hopefully, if we’re more successful, it’ll be a new treatment for Alzheimer disease. That’s the message to clinicians: that we’ve already completed a phase 1 clinical trial and the drug is well tolerated and it will be initiating a large phase 2 trial later this year and we’ll have clinical trial sites coming online soon, in the second quarter of 2019. They can see what sites are opening up for treatment and they can refer patients that are interested in participating in a clinical trial (NCT03823404).

How does this relate to the APOE gene?

We point this out in the discussion section, but the APOE gene was found actually in the later 1990s, in experiments on APOE knockout mice, to be involved with the immune system response. They showed when they knocked out APOE in mice, they were more susceptible to bacterial infections. It could be that having the APOE4 allele is not as protective against the P. gingivalis infection as the other APOE alleles, so the APOE4 may have a higher brain load of P. gingivalis and gingipains. The other thing that we’re investigating around that is there’s been evidence—not from us but other researchers over the years—that the APOE4 is being fragmented into neurotoxic fragments. We are currently working on studies that on how the gingipains actually fragment the APOE4 versus the APOE3 and how that might relate to neurotoxicity.

REFERENCES

1. Dominy SS, Lynch C, Ermini F, et al. Porphyromonas

gingivalis

in Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors. Science Advances. 2019;5(1): eaau3333.

doi

: 10.1126/sciadv.aau3333.