A Link Between Gum Disease and Alzheimer’s?

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Sometimes it seems like just about every disease, including heart attacks, have been linked to gum disease. And sometimes it seems like just about everything from aluminum pots to herpes virus has been linked to Alzheimer’s. So why not link gum disease to Alzheimer’s? Several years ago studies suggested a link.

Researchers with the biopharma company Cortexyme published research in the journal Science Advances recently describing the role Porphyromonas gingivalis (Pg), a bacteria that causes gingivitis, or chronic gum disease, to Alzheimer’s disease.

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Cortexyme is based in South San Francisco on the Google/Alphabet Verily Campus. The company is focused on developing drugs to treat Alzheimer’s and other neurodegenerative disorders.

“Infectious agents have been implicated in the development and progression of Alzheimer’s disease before, but the evidence of causation hasn’t been convincing,” stated Stephen Dominy, Cortexyme co-founder, chief scientific officer, and lead author of the study. “Now, for the first time, we have solid evidence connecting the intracellular, Gram-negative pathogen, Pg, and Alzheimer’s pathogenesis while also demonstrating the potential for a class of small molecule therapies to change the trajectory of disease.”

The team discovered Pg in the brain of Alzheimer’s patients. Then, in mouse models, oral Pg infection led to brain colonization, which led to increased production of amyloid beta, the proteins associated with Alzheimer’s. They also identified gingipains, the Pg’s toxic proteases, in the neurons of Alzheimer’s patients.

The team further correlated the gingipain levels with disease pathology linked to two markers: tau, a protein needed for normal neuronal function, and ubiquitin, a protein tag that marks damaged proteins for degradation and is found in both tau tangles—common in the later stages of Alzheimer’s—and amyloid beta. Gingipains were found to be neurotoxic in the brains and in cell cultures.

They then designed a series of small molecule drugs that targeted Pg gingipains. Those experiments are described in the paper in preclinical models. They showed that COR388 inhibited gingipains, reduced the bacterial load of an established Pg brain infection, blocked amyloid beta 42 production, decreased neuroinflammation, and protected neurons in the hippocampus. This part of the brain is involved in memory and is often atrophied early in Alzheimer’s disease development.

On October 24, 2018, Cortexyme announced “encouraging results” from its Phase I clinical trial of COR388, its lead small molecule in development for Alzheimer’s. The objective of the trial was to assess the safety, tolerability and pharmacokinetics of COR388 in older healthy volunteers. They presented a poster at the 11th Clinical Trials in Alzheimer’s Disease (CTAD) Conference that week, showing the drug was safe and well tolerated.

Although the study wasn’t designed to evaluate efficacy, the drug did show positive trends in several cognitive tests in patients with Alzheimer’s. The company expects to launch a large Phase II trial of COR388 in mild to moderate Alzheimer’s sometime this year.

At the time, Casey Lynch, Cortexyme’s co-founder and chief executive officer, stated, “The presentation of these results at CTAD is an important milestone for Cortexyme as we advance a potential new approach to tackling one of medicine’s most pressing challenges. We are committed to moving quickly to advance COR388 for the benefit of the global Alzheimer’s community in need of new therapeutic options. Following the completion of our Series B financing this past summer, we are well resourced to advance COR388 into Phase II clinical development.”

Although certainly intriguing, it’s important to remember that late-stage clinical trials are where literally dozens of Alzheimer’s therapies have failed after showing promise in preclinical and early-stage trials. At least one statistic shows a failure rate for Alzheimer’s drugs of 99.6 percent. On the other hand, this study seems to support the latest thinking that although amyloid is significant in the disease, it is the actual inflammation in the brain that causes the damage resulting in cognition and memory loss.

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