Alzheimer’s rivals sepsis as the La Brea Tarpits of the pharma industry. 400+ clinical trials of new therapies were run between 2002-2012. They yielded exactly one approval. And that was for a drug (memantine) which treats symptoms but does not affect the course of the disease. Memantine was cleared in 2003; no new drugs have been approved since then.
Given this record of failure it is no surprise that the leading theory of the disease–the amyloid hypothesis–is being questioned.
The notion that Alzheimer’s might be an infectious disease has been on the table for years. Amyloid-β plaques are not confined to Alzheimer’s, but are associated with other chronic nervous system infections. Alzheimer’s shows inflammatory pathology consistent with infection, and amyloid-β has been shown to have anti-microbial activity. Epidemiological studies have suggested several potential pathogens, including Herpes Simplex Virus I, Chlamydomonas pneumoniae, Borrelia burdorferi, Helicobacter pylori–and of course, prions.
But this paper by Dominy et al in the 23 Jan issue of Science fingers an unexpected culprit: Porphyromonas gingivalis, the principal causative agent of chronic periodontitis. “Fingered” is far too casual a description of the evidence marshalled in this paper: periodontitis is a risk factor for AD; P. gingivalis proteases and DNA are found in the brains of AD patients; oral infections in mice stimulate AD-like pathology; inhibition of the proteases reverse the pathology. This is a great paper, a very thorough study, and you should definitely read the whole thing.
That’s not to say they have closed the case–if AD had a single simple etiology we would have found it long ago. But odds are good that P. gingivalis has significant involvement in a significant fraction of cases. It makes sense to focus efforts on this bug rather than to try yet another anti-amyloid agent: there’s a good chance that amyloid is a symptom or a response to the causative agent, rather than the cause itself.
The obvious therapeutic approach would be antibiotics. Obvious but perhaps wrong. P. gingivalis readily develops resistance to broad-spectrum antibiotics. And then there is the issue of penetrating the blood-brain barrier. Most antibiotics show poor perfusion into brain tissues; doxycycline and metronidazole are the most notable exceptions. Those are useful antibiotics, but they provide a very limited menu of therapeutic choices. If a course or two of these antibiotics (both are cheap and are used for a range of indications) was sufficient to reverse Alzheimer’s I’m sure some bright ID doc treating AD patients would have noticed.
The authors of the Science paper (some of whom are with Cortexyme) are instead pursuing an antivirulence strategy: developing inhibitors of the bacterial proteases that provoke plaque formation. The mouse model results reported in the paper speak to the potential of this approach.
Antivirulence therapies have much to recommend them, including the possibility of reduced development of resistance. But resistance is believed to be least likely to develop when targeted virulence factors encode a “public good” (an activity that benefits a community of bacteria) and most likely to develop when encoding a “private good” (an activity that benefits only the bug which produces the targeted virulence factor).
Gingipains (the culprit proteases) appear to neutralize the antimicrobial properties of β-amyloids, and there is (as yet) no evidence of bacterial community involvement, so the risk of resistance development is significant. Since anti-gingipain therapy alone is unlikely to clear P. gingivalis from the brain, this therapy would presumably be taken chronically and indefinitely, further increasing the likelihood of resistance development. Thus, like most potential antivirulence therapies, it will probably be used most effectively as an adjunct to antimicrobial therapies, rather than as a replacement for them.
I’ll suggest that phage therapy should be one of these antimicrobial therapies. Little known fact: phage readily cross the blood-brain barrier and accumulate in significant amounts in brain tissue.
This may be a little-known fact, but it is not a newly discovered one. Rene Dubos showed in 1943 that phage injected intraperitoneally accumulated and multiplied in the brains of mice with experimentally-induced Shigella meningitis, and provided some therapeutic protection.
And in the current millennium, filamentous phage have been used to deliver antibodies to brains–in order to image amyloid plaques. Straight-up studies of phage biodistribution show brain tissue to accumulate significant levels of phage, as in this study of orally-delivered anti-Salmonella phage in mice:
If you are surprised that so many orally-delivered phage show up in the organs–don’t be. Phage–unlike other biologics, such as antibodies–readily escape our guts. One study estimates that up to 30 billion phage pour into our bloodstreams every day. They get there not just through leaks (as bacteria often do) but by the process of transcytosis–they pass directly through epithelial cells, like ghosts through walls.
“Great” you say. “Let’s get some P. gingivalis phage and start dosing patients. Phage therapy is remarkably safe and the worst-case scenario is that AD sufferers will enjoy improved oral health.”
Unfortunately, a recent review of phages for oral pathogens uncovered no reports of P. gingivalis phages. The only serious search failed to induce any prophages from 43 tested isolates–but that was in 1993. Several genomes have been published since then, but none of them mention prophages or putative capsid proteins.
That’s discouraging, but it hardly means that there are no phage out there, a very unlikely scenario. A decade ago there were no Acinetobacter phages identified; now there are dozens. Finding phage to P. gingivalis will be faster and cheaper than finding small-molecule drugs that disarm or kill this bug. Someone just has to do it.
Unlike many proposed applications of phage therapy, like systemic infections, there is a strong case to be made here for PT: it would not be competing with established, effective therapies; the market is enormous; a single bacterium is likely to be the causative agent (if bacteria are indeed shown to be causative); biofilm involvement is likely; pharmacokinetics and biodistribution look favorable.
Maybe a PT effort is getting out in front of the evidence here. But the fallback position is to use anti-P. gingivalis PT as a therapy for oral periodontitis, a serious and widespread disease that is implicated in a whole host of other diseases. As Dominy et al note “A recent study found that 100% of patients with cardiovascular disease had P. gingivalis arterial colonization”.
Aspiring phage therapists have a real opportunity to make a significant contribution to public health here. They should stop wasting their time trying to develop salvage therapies for the few patients who fail antibiotic therapy and go after an indication that actually matters.
Thanks As a ageing Pharma just with a potentially genetic predispositions to AD I thought that I should google to see if there existed any research on phage treatment of P Gingivalis and here I am. Volunteering for any clinical trial that can persuade me that it is a serious contender. Any takers?
Great idea, which a few of us have thought of long ago. I’m not sold however that Porphyromonas gingivalis is the real target behind Alzheimer’s. There are more likely avenues.
Agreed that Porphyromonas is not likely. But it’s not crazy either. And we know where pursuing the most likely target (B-amyloid) has gotten us, right?
Simply pursuing B-amyloid is obviously a fool’s errand and it was my opinion, from the onset, that the target should never have been B-amyloid but rather those microorganisms which can lead to the deposition of B-Amyloid in Alzheimer’s brain to begin with. The Porohyromonas studies are interesting, but not necessarily from the standpoint of the P. gingivalis which the authors purportedly have isolated at the species level, and which was not long ago called Bacterioides gingivalis. When pursuing such a line of thought, one should be familiar with all of the microbes and the groups which are in the oral cavity and in particular which ones start periodontal disease, many of which are actinomycetes (actinobacteria). Such knowledge is actually quite important before initiating vaccine or phage attack.
There was a proposed vaccine for Porohyromonas gingivalis which the authors have been purposely unclear about, but which might shed more light on their thoughts and endeavors.