Clinical OMICS

NOV-DEC 2018

Healthcare magazine for research scientists, labs, pathologists, hospitals, cancer centers, physicians and biopharma companies providing news articles, expert interviews and videos about molecular diagnostics in precision medicine

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14 Clinical OMICs November/December 2018 www.clinicalomics.com tein α-synuclein found in presynaptic vesicles. In its normal function, it is a monomer that aids in dopamine transmission. When it aggregates, it leads to the death of the cell. One interesting finding about PD patients that was first documented in 1817 in the first paper written on PD—at that time, referred to as "shaking palsy"— by James Parkinson, was that many patients had GI issues. We now know that up to 80% of PD patients suffer from constipation. We wanted to follow up on why people with a neu- rological condition have GI issues. What we showed is that if you remove the microbiome from a PD mouse model, the mouse exhibits no motor symptoms (hall- mark disturbances in gait and posture stability). Additionally, the germ-free version of this mouse has no motor symptoms, which gave us a tool to test the human microbiome. We knew, through research that sequenced the DNA in fecal samples, that the microbiome is differ- ent between a PD patient and a healthy control. But we wanted to test the causal relationship between the human microbiome and PD. So, we took micro- biota from human PD patients and healthy controls and transplanted them into the germ-free mice. The mice that received the microbiomes from PD patients developed severe PD symptoms (motor symptoms, α-synuclein, neuroinflammation). However, mice that received microbiota from a healthy human control had much less disease. This told us that the microbiome is, indeed, contrib- uting to the symptoms and they are not a consequence of some other change. This experiment also developed a mouse model with human microbes as opposed to mouse microbes, (there is only a 5% overlap between the mouse and human microbiota) where the microbiome is driving the symptoms. We then asked what is different about the human microbiota in PD? To find that, we mined our microbi- ome data and publically available databases and iden- tified candidates of both species of bacteria and genetic microbial pathways that were dysregulated between healthy controls and PD patients. Although we are working our way through all of the potential candidates, Axial is currently leveraging a sin- gle species of bacteria that induces all PD phenotypes in the mice upon transplantation. To take it one step further, we have identified the genes that are respon- sible for inducing the PD symptoms. When the gene is knocked out, the symptoms are no longer present. These genes are not found in metazoans—they are completely microbial pathways. Axial has developed small molecule inhibitors against the gene produces in that pathway. Using them, they can, essentially, drug the ability of this bacteria to pro- duce this product. When they do this, the bacteria are completely viable, but the mice are absolutely healthy. In addition, the molecules are made to be completely gut selective. Meaning that they do not enter the circula- tion—the molecule is not found in the urine, serum, nor the brain. This is proof of concept that we can deliver molecules that are highly gut specific and target micro- bial pathways to achieve benefits in a classic neurolog- ical condition. Given these data, in theory, by drugging the micro- biome, you should be able to restore health and that is what we are doing at Axial, by developing drugs and going into the clinic. Our first clinical trial will begin at the end of this year with a gut selective molecule that targets a microbial pathway, that is completely inert to a mammalian system, in about 100 PD patients. Is the microbiome solely sufficient to induce PD? Mazmanian: Well, I'm completely speculating, because no one has the answer to this. But, I think that it is pos- sible. However, because the microbiome is so malleable and diverse, I don't think that any particular state of the microbiome is going to be sufficient. Meaning that a particular composition of the microbiome would be sufficient if someone has an underlying genetic predis- position. And, we know that there are polymorphisms in genes that are more likely to be enriched in the PD population than healthy controls. (continued from previous page) As we sit here today, we are much closer to knowing nothing than we are to knowing anything as far as function of the microbiome." The assertion that a company can tell you what diet to eat to 'fix' your microbiome is simply unsubstantiated."

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