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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Page 14 of 51 November/December 2018 Clinical OMICs 13 opportunity in studying the microbiome. I just needed to find a place to do it. I presented my ideas to Den- nis (Kasper) who was studying Bacteroides fragilis. His response to me was, "Sarkis, I have no idea what you are talking about, but you can come to my lab and work on that." I decided to join Dennis's lab and canceled all of my other interviews. What is the most exciting work going on in your lab right now? Mazmanian: We are incredibly excited by the potential to change drug development in neuroscience. At the moment, almost exclusively, drug development efforts in neuroscience try to get drugs across the blood brain barrier (BBB.) In most cases, even in the drugs that do successfully cross the BBB, only a percent or a fraction of a percent get into the brain in pharmacological doses. The rest float around the body, hitting off target sites and causing side effects. So, the current approach is very challenging and not without its problems. We are trying to leverage the ability of the microbiome to communi- cate with the brain. Our idea is to drug the gut and not the brain. What is the rationale that drugging the gut will successfully treat neurological disorders? Mazmanian: There is a lot of evidence that the microbi- ome (in mouse models) affects the function of the brain, the development of the brain, the activity of circuits in the brain, and behaviors. This goes both ways. There are organisms and pathways that exacerbate these condi- tions and others that are protective. Our work centers around understanding all of them. We want to know what the molecules made by the bacteria in the gut are,and how they are mediating the gut-brain connec- tion. Once we know that, we can think about ways of drugging them. At the company that I started, Axial Biotherapeutics, we are executing this plan for both autism and Parkin- son's disease (PD.) We know that you can deliver mol- ecules to the gut, drugging microbial pathways (that inherently do not exist in humans or mice), and by manipulating those, you can exacerbate or ameliorate neurodegeneration and behaviors linked to autism. The drugs that are being developed are completely gut retentive—they do not enter the circulation. Yet, there are incredible changes in the brains of the animals that are being drugged. So, the main focus of our work is to bypass the hurdle of getting the drugs across the brain, and to let the microbiome do the work to connect the gut and the brain. Can you tell us, more specifically, about how the microbiome could treat a neurological disease like Parkinson's disease? Mazmanian: It is widely believed that the driving pathology of PD is the aggregation of the neuronal pro- (continued on next page) We are trying to leverage the ability of the microbiome to communicate with the brain. Our idea is to drug the gut and not the brain." ChrisChrisW / Getty Images

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