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The approval of the drug oligomanate in China earlier this month to treat mild-to-moderate Alzheimer’s disease has met with surprise and skepticism from some in the scientific community, who say preclinical data raise questions about the underlying mechanism of the disease. drug. A microbiome researcher has pointed out inconsistencies between the researchers’ data and their proposed mechanism for how oligomannate might treat Alzheimer’s.
The field is viewing this with a heavy dose of skepticism, Mal Tansey, a neuroimmunologist at the University of Florida School of Medicine, tells The Scientist.
On November 2, Shanghai Green Valley Pharmaceuticals announced that oligomannate, a mixture of oligosaccharides derived from brown algae, had been approved by the National Medical Products Administration (NMPA), the Chinese equivalent of the US Food and Drug Administration. The announcement followed the completion of a phase 3 clinical trial in China that found the drug appeared to slow cognitive decline in Alzheimer’s patients. In addition, researchers led by Meiyu Geng at the Shanghai Institute of Materia Medica published a paper in Cell Research in September on the ability of oligomannates to remodel the gut microbiome in mice and reduce neuroinflammation. There is an emerging link between the gut microbiome and Alzheimer’s disease in humans.
In the study, researchers administered oligomannate to mice genetically modified to display physical and behavioral symptoms similar to those of Alzheimer’s disease. The team collected feces from mice to study the microorganisms present in the gut microbiota, drew blood to analyze the presence of immune cells, and also examined the levels of cytokines, which are inflammatory compounds, in the brain. They found that oligomannate treatment altered the mouse gut microbiome, increased levels of some cytokines in the brain while decreasing others, reduced microglia activity, and reduced the number of proinflammatory helper T cells in the brain and blood, which suggests that oligomannate decreases neuroinflammation in mice by remodeling the microbial community in the intestines.
See China approves Alzheimer’s treatment that targets the microbiome
Not everyone is convinced of that conclusion. Liping Zhao, a microbiome researcher at Shanghai Jiao Tong University and Rutgers University, says that not all of the data in the papers supports the hypothesis that oligomannate reduces neuroinflammation by changing the gut microbiome. For example, bacteria called Desulfovibrionaceae, which produce an endotoxin that can increase inflammation, became more abundant in oligomannate-treated mice than in untreated mice. There are many, many publications showing that members of this family of bacteria are pro-inflammatory, Zhao tells The Scientist.
He also points out that bacteria of the genus Rosburia , a known beneficial group of bacteria associated with reducing inflammation, was decreased in the experimental mice. When I first saw this data, I really couldn’t believe my eyes, she says. I was very surprised because such a change is actually the opposite of what you would expect.
Jeffrey Cummings, a neuroscientist at the University of Nevada, Las Vegas, and the Cleveland Clinic Lerner School of Medicine, who consults Green Valley, tells The scientist that Zhao is making a prediction based on his understanding of the microbiome, which I assume is an expert and I respect him. On the other hand, they actually measured inflammatory cells in the blood. . . and showed them to go down. So the data contradicts his opinion. I would say that the important observation here, from my point of view, is that the decrease in peripheral inflammatory cells adheres to what they say is the mechanism.
Tansey, who is not affiliated with Green Valley, says Zhao makes a very relevant point. When people say inflammation, it is a general term. He adds that it can be difficult to interpret whether inflammation is increasing based on cytokine levels. Some of these cytokines . . they have an anti-inflammatory role, but are produced during inflammation. You could interpret it either way. If it’s inflammation, pro-inflammatory cytokines will go up, but so will anti-inflammatory cytokines because the body is trying to work out that inflammation, he tells The Scientist.
A global phase 3 trial is underway to further test oligomannate before it is approved in other countries. We were planning quite a few different blood biomarkers. . . which cumulatively should help us understand the mechanism of the , says Cummings, who is helping Green Valley with the trial design.
Oligomanate is the first Alzheimer’s disease drug approved since 2003, and hundreds of potential treatments have failed to gain FDA approval in the past two decades, according to health line. The field needs a lot of hope, but we need to be careful about hype, says Tansey. We need to be able to show that a drug really hits the mark.
Meiyu Geng and Green Valley did not immediately respond to requests for comment.
Emily Makowski is an intern at The Scientist. Send an email to emakowski@the-scientist.com.