Michael Zasloff, MD, Ph.D., Professor of Surgery and Pediatrics at Georgetown University School of Medicine, and Founder, Chairman and CEO of Enterin Inc. was the senior author of a study that has helped clarify the function of alpha-Synuclein (αS), the protein implicated in Parkinson’s disease (PD) and other neurodegenerative diseases. Denise Barbut, MD, FRCP, Co-Founder, President and Chief Medical Officer of Enterin Inc. was senior co-author of the study.
Published in the Journal of Innate Immunity, the study finds that αS is released in response to an infection in the upper GI tract in children, inducing an immune response as part of the body’s innate immune system. According to the researchers, these findings suggest that frequent or chronic upper GI infections could overwhelm the body’s capacity to clear αS, ultimately leading to Parkinson’s disease.
This research builds upon prior studies, which showed that the buildup of αS in PD patients actually begins in the enteric nervous system (nerves in the GI tract). Animal studies have further shown that microbes in the GI tract can induce formation of toxic αS aggregates in the enteric nervous system, which can then travel up to the brain.
The study showed a positive correlation between the expression of αS in enteric nerves of the upper GI tract and the degree of acute and chronic inflammation in the intestinal wall. Furthermore, the study showed that αS could potently attract immune cells such as macrophages and neutrophils, and could ‘turn on’ dendritic cells to alert the immune system of the specific pathogen encountered.
As Dr. Zasloff explains, “When expressed in normal amounts following an infection of the upper GI tract, αS is a good molecule. It is protective. The nervous system within the wall of the GI tract detects the presence of a pathogen and responds by releasing αS. αS then attracts white blood cells to the site where it has been released. In addition, αS produced in one nerve can spread to others with which it communicates thereby protecting a large field. By this means, the nervous system can protect both itself as well as the GI tract as a whole in the setting of an infection.”
He adds, “It is well-known from animal studies that αS produced in the enteric nervous system can use the nerves connecting the GI tract to the brainstem as an escalator, trafficking αS from the gut to the brain and spreading to centers within the central nervous system. But too much αS — such as from multiple or chronic infections — becomes toxic because the system that disposes of αS is overwhelmed, nerves are damaged by the toxic aggregates that form and chronic inflammation ensues. Damage occurs both within the nervous system of the GI tract and the brain.”
Dr. Zasloff says the new findings “make sense” of observations made in PD patients, such as the presence of chronic constipation from damage to the enteric nervous system that develops decades before brain symptoms become apparent and that chronic upper GI distress is relatively common in people who develop PD.
The publication of this study coincides with an ongoing Phase 1/2a clinical trial at 12 U.S. sites, sponsored by Enterin Inc., targeting the accumulation of aS in the enteric nervous system. The clinical trial is examining the safety, tolerability, pharmacokinetics, and pharmacodynamics of ENT-01 to relieve constipation associated with Parkinson’s disease. Details of the RASMET study can be found on clinicaltrials.gov. ENT-01 is an oral drug that contains a synthetic derivative of squalamine, a natural steroid made by the dogfish shark. Research recently published by Dr. Zasloff and collaborators demonstrated that squalamine both reduced the formation of toxic αS clumps and their toxicity, in animal models of Parkinson’s disease.
About Enterin Inc.
Enterin Inc. is the first company in the world to develop a novel drug that repairs the dysfunctional gut-brain axis in patients with neurodegenerative disease. Enterin Inc. is pioneering the medical community’s understanding of the link between infections, dysfunction of the enteric nervous system of the gut, and the early onset and chronic progression of neurodegenerative disease. The lead compound, ENT-01, displaces membrane-bound alpha-synuclein (αS) aggregates from nerve cells in the enteric nervous system and improves neural signaling between the gut and the brain in preclinical models of Parkinson’s disease. In the gut, this results in improved motility. Enterin Inc. is now progressing ENT-01 through clinical trials aimed at reversing the constipation of Parkinson’s disease. For more information, please visit www.enterininc.com.